However, other studies have not achieved similar effects. Tsiloulis and colleagues collected scWAT of obese men after 6 weeks of physical training and the mRNA levels of UCP1, CD, CITED, TBX1, LHX8, and TCF21 were not altered [ ]. Many factors may be involved in this diversity of results since the duration, frequency, and degree of intensity are associated with these effects.

Thus, more human studies need to be conducted as many questions still need to be clarified. The fibroblast growth factor family FGF performs a range of cellular metabolic and physiological responses to maintain overall homeostasis. FGF 21 was first identified in mice and humans in 2, by Nishimura and colleagues through cDNA identification in different organs [ ].

While the gene in mice is located in chromosome 7 and encodes a preprotein of amino acids aa , in humans it is found in chromosome 19 and encodes a preprotein of aa.

Most FGF family members have a high affinity to heparin sulfate, except for the endocrine FGF FGF subgroup, which consists of FGF 19 FGF 15 in rodents , FGF 21 e FGF 23 in humans [ ]. FGF molecules lack an extracellular heparin-binding domain and thus can enter the blood system [ ].

FGF 21 binds to a fibroblast growth factor tyrosine kinase receptor FGFR , which can be found in seven isoforms: 1b, 1c, 2b, 2c, 3b, 3c, and 4. The FGF 21 requires its dimerization with a klotho protein, called beta-klotho KLB.

Thus, the FGFR-KLB receptors lead to the intracellular cascade that goes through the phosphorylation of FGFR substrate 2α FRS2α and the activation of Ras-MAPKs and PI3K-Akt kinases [ , , ].

Once FGF21 signaling requires KLB to activate FGFRs, the co-expression of these two receptors determines the sensitivity of a tissue or organ to FGF21 [ ].

FGF 21 is defined as a stress-responsive hormone [ ], which effect is subtle in physiological conditions but significantly exacerbated under nutritional, metabolic, oxidative, hormonal, or environmental challenges. FGF 21 is synthesized mainly in the liver and thymus but is also detected in skeletal muscle, pancreas, intestine, heart, β cells, and WAT and BAT [ ].

As an important metabolic regulator, acting mostly in glucose and lipid homeostasis, FGF 21 triggers lipolysis and FFAs released in circulation from WAT during prolonged fasting or starvation [ 29 , ]. PPAR-α is activated in the presence of FFA and improves FFA oxidation and ketone bodies formation for acting as energy sources during prolonged fasting.

Thus, when PPAR-α activity increases, the production of FGF 21 in the liver also augments, leading to energy production, increased ketogenesis, gluconeogenesis, appetite, and systemic glucose uptake as adaptive responses to starvation [ ].

The activity of FGF 21 is not limited to starvation conditions, but it is also increased in adaptation to high-fat HF intake [ ]. Human studies inform that FGF21 production is stimulated in situations of decreased thermogenesis, reduction in adiponectin levels, and tissue breakdown markers, such as transaminases elevation mare than changes in levels of FFAs [ ].

Another means of increasing FGF21 levels, through PPAR-α activity, is through intense physical activity, growth hormone therapy, lactation, and milk ingestion in neonates [ , ]. Macronutrients such as proteins also regulate FGF 21 production through amino acid restriction [ ].

This process starts when the general control non-derepressible 2 GCN2 -eukaryotic initiation factor 2 eIF2 α pathway is activated inducing the binding of activating transcription factor 4 ATF4 to PGC-1 α [ , ]. After being secreted, its most important target is WAT, where FGF21 improves insulin sensitivity [ , ] and increments GLUT1 expression and consequently glucose uptake, as shown by in vitro 3T3-L1 adipocyte analyses [ , ].

The response element-binding protein ChREBP is sensitive to carbohydrates in the liver and ChREBP interaction with PPAR-γ in adipocytes modulates the expression of FGF In other words, the upregulation of ChREBP may induce the expression of this FGF [ ].

Another example of FGF 21 influence on carbohydrate metabolism is through the suppression of hepatic pyruvate dehydrogenase PD complex through PD kinase 4 activity [ ].

Additional transcription factors, such as retinoic acid RA receptor β RARβ , TRβ, cyclic AMP response element-binding protein H CREBH , RA receptor-related orphan receptor α RORα , respond to determinants in the liver and regulates FGF 21 production [ ].

WAT is not only a target of FGF21, but it is the major mediator of its effects. The processes of glucose- and insulin-sensitive responses depend on adiponectin production and secretion by this tissue [ ].

Adiponectin also reduces the levels of sphingolipid ceramides in obese animals, which have been associated with lipotoxicity [ ]. The action of FGF21 in WAT includes paracrine and autocrine actions and is mediated through the induction of PGC-1α protein in cold and through the enhanced levels of the thermogenic protein UCP1, which is a key protein for heat production [ ].

FGF 21 impact derives from increased PGC-1α levels and, consequently, expression of UCP1 [ ]. In conclusion, FGF 21 is involved in glucose uptake, lipogenesis, and lipolysis, depending on the metabolic state of the adipocytes.

This dual phenomenon may depend on nutritional condition, FGF21 concentrations reached between pharmacological administration and physiological secretion [ ].

Thyroid Hormone TH is essential for metabolism in mammals and associates with many processes, including organism development, metabolic regulation, neural differentiation, and growth [ ]. TH is produced in the follicles of the thyroid gland and is synthesized through iodination of tyrosine residues in the glycoprotein thyroglobulin [ , ].

The main means of regulator its production is through thyroid-stimulating hormone TSH , which binds to the TSH receptor TSH-R expressed in the thyroid follicular cell basolateral membrane and is released by the anterior pituitary in response to a circulating TH [ ].

The biological response of TH is complex and highly regulated. It is mediated by thyroid hormone nuclear receptors TRs. The TR genes produce two main types of receptors, α and β, and their isoforms α1, α2, α3, β1, β2, and β3, but only α1, β1, β2, and β3 are T3-binding receptors, which are differentially expressed in tissues and have distinct roles in TH signaling [ , ].

TH enters the cell through membrane proteins monocarboxylate transporter 8 MCT8 and solute carrier organic anion transporter family member 1C1 9 OATP1C1 , then interacts with TR in the nucleus, which binds to the genomic thyroid-hormone responsive elements TREs and other nuclear proteins, including corepressors, coactivators, and cointegrators, leading to chromatin remodeling and the regulation of the UCP1 gene transcription [ , ].

This hormone is correlated with weight and energy expenditure. Thus, hypothyroidism, characterized by diminished TH levels, leads to hypometabolism, a condition associated with reduced resting energy expenditure, weight gain, high cholesterol levels, reduced lipolysis, and gluconeogenesis.

On the other hand, hyperthyroidism, and elevated TH levels, induce a hypermetabolic state, characterized by increased resting energy expenditure, lower cholesterol levels, increased lipolysis and gluconeogenesis, and weight loss.

Consequently, TH controls energy balance by regulating energy storage and expenditure regulating key metabolic pathways [ ]. TH regulates basal metabolic rate BMR through ATP production, used for metabolic processes, and by generating and maintaining ion gradient [ , , ]. TH maintains the BMR levels through the uncoupling oxidative phosphorylation in the mitochondria.

When ATP production is compromised in skeletal muscle, TH increases the leak of protons through the mitochondrial inner membrane, stimulating more oxidation to maintain ATP synthesis [ ].

TH regulates metabolism primarily through actions in the brain, WAT, BAT, skeletal muscle, liver, and pancreas [ ]. This action, as already said, is through TH receptors TR isoforms, WAT has the adrenergic signaling increased by TRα [ ], otherwise BAT expresses TR α and β, as it needs TRα for adrenergic stimulation and TRβ for stimulating of UCP1, both for thermogenesis [ ].

TH regulates several aspects of lipid metabolism and human BAT from lipogenesis to lipoprotein signaling [ ]. Rats administrated with T3 showed how the central nervous system is important to the activation of BAT by TH through inhibition of hypothalamic AMP-activated protein kinase AMPK.

Stimulation of sympathetic nervous system SNS activity leads to thermogenic gene expression in BAT [ ]. As discussed previously, β-AR is stimulated by NE in response to SNS [ 1 ]. The expression of UCP1, required for BAT thermogenesis, is regulated by NE and T3 synergistically, once the induction in separate is twofold, while combined is 20 -fold [ ].

Another way that UCP1 expression and thermogenesis are induced is through bile acid stimulation. G protein-coupled membrane bile acid receptor TGR5 is stimulated in BAT and results in D2 stimulation and local T3 production [ ].

In conclusion, several mechanisms have been proposed for the TH influence in the browning process, including cold exposure, adrenergic activation [ ], and bile acid signal [ ]. Thus, the stimulation of BAT activation and WAT browning increase the energy expenditure, loss of weight [ ], D2 activation, UCP1 level increase, and consequent thermogenesis [ ].

As previously discussed here, several exogenous factors are able to elicit browning of WAT and BAT activation. However, endogenous factors also play an important role in regulating the phenotype and physiology of these tissues.

One of the most important endogenous factors that are related to the regulation of AT is the circadian rhythm, which is a refined system that acts as a master biological clock synchronizing daily and seasonal variations with the behavioral, cellular and tissue-autonomous clock, as well as several biological processes that include sleep—wake cycle, hormone secretion, lipid and glucose homeostasis, energy balance and body temperature [ ].

Disruption of circadian rhythm caused by aging, shift-work, irregular sleep, insomnia, or long exposure to light during the night is associated with sleep and metabolic disorders such as cardiovascular diseases, diabetes type 2 and obesity. Regarding metabolic diseases, AT plays a central role in metabolic and whole-body energy homeostasis, once its secretes several adipokines that regulate diverse processes in CNS and peripheral tissues.

Leptin, a hormone mainly produced by adipocytes, is released into the circulation where it crosses the blood—brain barrier BBB , through a saturable system, and interact with its receptor in the hypothalamus LepRb [ , ].

Hsuchou and colleagues demonstrated that leptin signaling disruption through a pan-leptin receptor knockout POKO in mice was able to dysregulate feeding behavior, metabolic and circadian rhythm profile and thus promote an accentuating of obesity [ ].

Beyond control of feeding and metabolic processes, leptin also displays a role in energy balance through the increase of AT thermogenesis in BAT by sympathetic activation [ , ]. Recent studies have proposed that diurnal rhythm promotes differential modulation in activity, thermogenesis and fat oxidation in BAT.

It was observed that plasmatic lipid metabolism was improved during daytime with a higher expression of lipoprotein lipase, FA uptake, and modulates lipid plasmatic concentration in BAT [ ]. In the same line, Matsushita and colleagues, assessed forty-four healthy men who received diet-induced thermogenesis DIT under room temperature 27 °C and cold 19 °C in the morning and in the evening by using 18 F-fluorodeoxy-D-glucose positron emission tomography.

It was observed that thermogenic parameters presented better performance during the morning [ ]. Moreover, several studies have established that melatonin directly impacts BAT morphology and function, also, in a mechanism dependent on adrenergic activation mediated by NE release.

Melatonin is related to an increase of BAT volume, and thermogenic capacity, associated with the increase of UCP1 mRNA expression and mitochondrial mass and functionality, as well as seric lipid concentration.

These profiles are significatively impaired under melatonin deficiency but reverse with oral melatonin replacement [ , , ]. Growing evidence confirms the intimate relationship between circadian rhythm and AT, with emphasis on metabolic homeostasis and modulation of BAT activity.

The characterization of how this process happens emerges as a strong diagnostic tool as well as a therapeutic approach concerning sleep disorders and metabolic diseases.

Several studies suggest that food items can affect AT function. Curcumin stimulation was unable to induce the same effects in the epididymal WAT, though. This process was mediated by the NE-β3-AR pathway since the levels of NE and β3-AR were elevated in the inguinal WAT [ ].

Although studies are scarce regarding the impact of thyme in the WAT browning process, it was observed that 20 µM of thymol, a substance present in the essential oils of thyme, in the complete medium when placed in contact with 3T3-LI preadipocytes for 6—8 days was able to induce an increased gene and protein expression of the PGC-1α, PPARγ, and UCP1.

Such increases were related to the activation of β3-AR, AMPK, PKA, and Mitogen-activated protein kinase p38 MAPK being accompanied by an increase in mitochondrial biogenesis [ ].

Cinnamon oil contains trans-cinnamic acid, which exposure to 3T3-L1 white adipocytes at µM high gene expression of Lhx8, Ppargc1, Prdm16, Ucp1, and Zic1 and markers of UCP1, PRDM16, and PGC-1α, indicating WAT browning [ ]. Quercetin, a flavonoid present in the onion, also proved to be efficient in the browning process since mice fed for 8 days with 0.

Just as the combination of quercetin and resveratrol also induces the WAT browning phenotype [ ]. The resveratrol, present in the bark of grapes and other plants, also increases the expression of UCP-1, PRDM16, and PPARγ, suggesting that resveratrol induces the formation of beige adipocytes through the phosphorylation of AMPK, once treatment coupled with inhibition or the deletion of AMPK did not produce the same effects [ ].

The same was observed in the substances found in the mushroom and honey, which induced increased expression of brown fat markers via AMPK and PGC-1α [ ]. The peppers have capsaicin, an active compound responsible for the burning sensation that is also involved in the browning of WAT.

The WT animals showed an increase in the expression of Ucp-1, Pgc-1α, Sirt-1, Prdm16, and exhibited browning of WAT via activation of the transient receptor potential vanilloid 1 TRPV1 , which is related to the synthesis of catecholamine or sirtuin 1 SIRT1 -mediated deacetylation of PPARγ, facilitating PPARγ-PRDM interaction.

Other substances, such as carotenoids, are involved in the WAT browning process. Fucoxanthin, β-carotene, and citrus fruits are efficient in modulating the Ucp1 expression , , Another food component that is involved in the browning process of WAT is berberine, a molecule derived from the plants Coptis chinensis and Hydrastis canadensis.

The group discovered berberine promotes BAT thermogenesis and WAT browning, since the igWAT, but not the epididymal, showed high levels of mRNA and UCP1 protein expression and increased mitochondrial biogenesis after injections.

The brown adipocyte markers PGC-1α, CIDEA, Cox8b, and lsdp5 were also elevated and AMPK and PGC-1α are involved [ ]. In another study, the polyphenols from tea extracts 0. Another analysis with the extract induced In Magnolia Officinalis, two magnolol compounds 20 µM and Honokiol 1—20 µM when used to stimulate 3T3-L1 adipocytes increased protein levels of PGC-1α, PRDM16, and UCP-1 [ ].

Honokiol also increased protein expression levels of CIDEA, COX8, FGF21, PGC-1α, and UCP1 [ ]. The herb panax ginseng contains ginsenoside Rg1 10 μM of ginsenoside Rb1 , which is capable of considerably increasing the mRNA expression of UCP1, PGC-1α, and PRDM16 in mature 3T3-L1 adipocytes via PPARγ [ ], as well as activating the AMP-activated protein kinase pathway [ ].

The fish oil is rich in n-3 polyunsaturated fatty acids PUFAs , components that are associated with the formation of beige adipocytes, among them is eicosapentaenoic acid EPA. Mice fed different diets, including with EPA, for 8 weeks showed increased expression of β3-AR, PGC-1α, and UCP1 and exhibited high expression of PPAR [ ], though this effect is controversial since another animal study investigating a diet containing pure EPA 3.

Docosahexaenoic acid DHA 1. However, knockout mice for TRPV1 did not achieve the same effect, showing that such events were mediated by SNS, TRPV1, and catecholamines [ ]. Conjugated linoleic acids CLAs also showed potential to induce browning process in the WAT [ ]. Once the overwhelming impact of infectious diseases has been alleviated by the development of efficient therapeutics, life expectancy has been continuously increasing World Health Organization, Age-associated diseases, including type 2 diabetes T2D , cardiovascular diseases CVDs , neurodegenerative pathologies, and obesity statistics are alarming and correlates with changes in the lifestyle of individuals throughout the world, including the diet, and impair the health spam rise.

Western diets WDs are composed by food items enriched in processed sugar, white flour and salt and poor in fibers, vitamins and minerals [ ]. At the same time, the diet may be the remedy against the burden caused by these chronic diseases. While overnutrition often correlates with inflammatory and metabolic detrimental effects at molecular level, undernutrition without starvation presents many benefits.

Calorie restriction CR and intermittent fasting IF are promising interventions against the overweight and obesity numbers, climbing specially in Western countries [ ]. CR, defined as reduced calorie consumption without malnutrition, is the best studied dietary intervention that increase health spam in experimental models.

A plethora of human studies place CR as beneficial for expanding the health spam [ ]. These studies proceeded Weindruch and Sohal positive correlations between CR and health spam [ ] Click or tap here to enter text..

AT plasticity is one of the connections between CR and health benefits. Fabbiano and colleagues analyzed mice under CR and described that this regimen induces functional beige fat development in WAT, phenomenon that occur via enhanced type 2 immune response and SIRT1 expression in AT macrophages [ ].

The stress resistance provided by the IF practice places this regimen as a feasible dietary intervention against various devastating complex pathologies.

Differently from CR, intermittent fasting IF does not influence the meal size, but decrease the number of meals in a given period [ ]. The fasting state leads to a metabolic switch, which increases the usage of free fatty acid FFA as energy source in comparison to glucose.

In addition, IF favors the synthesis of ketone bodies KBs by the liver, molecules that act as an energy source during nutrient deprivation and induce a plethora of beneficial effects on the organism by acting upon the muscle, liver, heart, brain, intestine and AT [ , , ].

IF also impacts positively on AT remodeling. A DIO animal model submitted to repetitive fasting cycles displayed increased glucose tolerance, and diminished adipocyte hypertrophy and tissue inflammation [ ]. Mouse studies show that IF induces WAT mass decrease, elevation of AT UCP1 expression and thermogenic capacity [ , ], and augmented beige pre-adipocytes recruitment to WAT [ , , ] Fig.

The impact of circadian rhythm and different diets on the WAT browning modulation. The secretion of melatonin, a circadian rhythm regulating neurohormone, is mediated by the release of Norepinephrine NE , which binds to β-adrenergic receptors.

Adrenergic activation is one of the main mechanisms of WAT browning induction and BAT activation. Intermittent fasting IF associates with weight reduction, improved metabolic status due to increased glycemic tolerance, decreased white adipocyte hypertrophy and AT inflammation, and augmented expression of thermogenic genes such as UCP1 and recruitment of beige adipocytes.

IF is also modulates the intestinal microbiome composition and diversity, a shift closely related to the induction of browning in the WAT. Caloric restriction CR is also associated with weight loss, promotes greater recruitment of beige adipocytes through the participation of M2 macrophage and eosinophil infiltration and in WAT.

Finally, obesity-inducing diets correlate with increased lipid accumulation, WAT unhealthy expansion and dysregulation. Abnormal expansion of WAT promotes ER stress, greater induction of adipose cell apoptosis and inflammation through NF-κB transcription factor activation and increased pro-inflammatory cytokines secretion.

An elegant study conducted by Li and colleagues informed that mice under IF cycles display an intestinal microbiome composition shift associated with increased levels of the fermentation products lactate and acetate.

They also show that the modulation of the gut microbiota by IF is crucial for its browning effect, as microbiota-depleted mice present impaired IF-induced AT beiging and fecal microbiota transfer from these mice to antibiotics treated animals display increased browning of WAT [ ] Fig.

Unexpectedly, a human study conducted by von Schwartzenberg and colleagues showed that CR may diminish bacterial abundance, deeply change gut microbiome composition and diversity, impair nutrient absorption, and favor the outgrowth of the pathobiont Clostridioides difficile.

This diet also led to a decrease in bile acid BA levels [ ]. BA, nonesterified fatty acids, are synthesized during the browning of WAT, a phenomena associated with the potentiation of the lipolytic machinery [ ]. These fatty acids can not only activate UCP-1 allosterically, but also serve as fuel for oxidative phosphorylation and consequently heat generation in BAT [ 1 ].

Furthermore, in the liver they are used for the generation of acylcarnitines and VLDL which is used as source for thermogenesis [ ]. Moreover, studies show that the increase in brite and brown adipocytes in WAT leads to an elevation in lipoprotein lipase LPL activity and subsequently an increase in circulating lipids available for BAT through intravascular hydrolysis of chylomicron triglycerides [ ].

Consequently, these mechanisms result in the generation of cholesterol-enriched lipoprotein remnants, which upon activation of BAT accelerates the flow of cholesterol to the liver [ ].

BA are steroid acids derived from dietary cholesterol catabolism. These acids are synthesized in the liver and act to aid digestion and absorption of fat in the intestine, in addition to playing an essential role in lipid metabolism.

BA act in other tissues, such as AT, as signaling molecules through interaction with the nuclear Farnesoid X receptor FXR and the G protein-coupled membrane receptor TGR5 [ ].

Recent studies have shown that BA play a relevant role in BAT activation and increased thermogenesis in adipocytes. In rodents, the activation of BAT by BA is dependent on its interaction with the TGR5 receptor and expression of the enzyme type 2 iodothyronine deiodinase DIO2.

Additionally, experiments with oral supplementation of BA in humans indicated increased BAT activity in humans [ , ]. Another experiment performed under thermoneutrality, demonstrated an improvement in glycemic metabolism and lipogenesis in the liver and fat accumulation in the TA and also induced an improvement in thermogenic parameters and mitigation of the impact of diet-induced obesity after feeding mice with HFD associated with BA [ ].

Moreover, BAT activation also promotes liver protection. In a study performed with animals under alcohol-induced hepatic steatosis or liver injury, activation of the TGR5 receptor induced improvement of clinical condition.

The increase in thermogenesis in BAT promotes an increase in lipid metabolism with lower availability of circulating FFA and, consequently, lower absorption of these molecules by the liver [ ]. However, if on the one hand BAs have been shown to be effective in inducing browning, on the other hand the excess of these acids is capable of promoting an antagonistic effect, such as mitochondrial dysfunction and expression of genes associated with cellular senescence in adipose cells [ ].

ATs are embryologically distinct from other tissues and are formed according to specific stimuli during embryo development, including Bone morphogenetic proteins BMPs , pleiotropic molecules that interact with type I and type II BMP receptors and influence embryogenesis [ , ].

Noteworthy, BMP4 overexpression was found to increase UCP1 and other beiging markers, as Hoxc9, Tbx1, and Tbx15 [ ]. These different phenotypes induced by the BMPs, including the induced beige adipocytes, highlight how relevant transcriptional regulation is for determining the cells functions and characteristics.

The main proteins that regulate gene expression are the transcriptional factors TFs , DNA binding proteins that modulate gene transcription by interacting with the gene promoter or cis-regulatory elements, such as enhancers and silencers, and include PPAR proteins, PGC-1α, and PRDM16 [ , ].

In addition to its roles in ATs development [ ], PPARγ is a central TF for adipogenesis and lipid storage regulation, influences cell thermogenic capacity, and impacts lipid metabolism and insulin sensitivity [ ].

This TF is expressed in elevated levels in ATs [ ], and upon ligand binding PPARγ recruits different cofactor sets for controlling the expression of specific genes.

The use of PPARγ full agonists is associated with improved insulin sensitivity and induces WAT browning, but can cause detrimental effects, such as undesirable weight gain and augmented visceral adiposity [ ]. PPARα acts synergistically with PPARγ in inducing robust WAT browning in vivo [ ], and is currently considered a prominent target for treating metabolic disorders [ ].

A way that PPAR agonists provoke WAT browning is by stabilizing PRDM16 [ ], a protein that activates a complete set of thermogenic genes in WAT [ ]. PRDM16 is essential for browning particularly in scWAT, once its induction in visceral depots does not correlate with thermogenesis [ ].

Mice lacking Prdm16 in scWAT are unable to induce browning within subcutaneous depots after stimuli [ ]. Ectopic PRDM16 expression induce thermogenic genes in several cell types [ ]. PRDM16 AT overexpression in rodents copes with augmented energy expenditure and DIO resistance [ ] PRDM16 acts by binding to specific regulatory sequences in DNA and by interacting with other proteins [ ], such as PGC-1α [ ].

PGC-1α plays a key role in the adapting thermogenesis. First described in cold-induced adaptive thermogenesis analyses [ ], this transcriptional coactivator participates in the regulation of a plethora of cellular functions, including mitochondrial biogenesis, oxidative phosphorylation, and gluconeogenesis [ , ].

Once PGC-1α influences genes related to energy metabolism, it is expressed mostly in tissues that require an elevated amount of energy, like AT, liver, skeletal muscle, and brain [ ]. When overexpressed, Pgc1α induces mitochondrial biogenesis [ ]. Another key regulator of the browning process is CIDEA.

Initially described as a mitochondrial protein, CIDEA was further discovered to be associated with cell lipid droplets LD [ , , ]. This molecule leads to the occurrence of browning by inhibiting the suppression of UCP1 gene expression mediated by liver-X receptors LXRs and increasing PPARγ binding strength to the UCP1 enhancer [ ].

As detailed in this review, UCP1 is found in the inner mitochondrial membrane and acts by uncoupling the electron transport chain and oxidative phosphorylation, releasing energy as heat [ 1 ]. The existence of molecular markers for the browning process can be useful for investigating AT plasticity status and correlate with health and disease.

Zfp is a TF that directly binds to the UCP1 and PGC1α promoters and induce WAT browning upon cold exposure. Zfp overexpression copes with augmented multilocular lipid droplets LDs biogenesis and increased oxygen consumption and UCP1 levels [ ].

HSF1 was described to cooperate with PGC1α in igWAT, favoring the induction of the thermogenic and mitochondrial gene programs, which leads to augmented energy consumption. HSF1-deficient mice are cold intolerant due to decreased β oxidation and UCP1 expression.

HSF1 activation associates with scWAT browning, non-shivering thermogenesis and energy consumption [ , ]. IRF4 also cooperates with PGC1α and was described to inhibit lipogenesis in adipocytes [ ]. While IRF4 overexpression favors beiging in epididymal WAT, the absence of this factor is linked to diminished energy expenditure and increased risk to hypothermia [ ].

The TF NFIA presents a crucial role in the initial steps of thermogenic gene regulation, as its increased levels in thermogenic adipocytes precedes PPARγ upregulation in these cells [ ].

The TF EBF2 uncouples adipocyte mitochondrial respiration and is sufficient for WAT browning. Increased EBF2 levels in WAT leads to activation of the thermogenic program, favoring increased oxygen consumption and resistance for weight gain.

EBF2-KO mice show impaired WAT browning and ablates the brown fat-specific characteristics of BAT [ , , ]. EBF2 activity is regulated by the action of ZFP, which binds to EBF2 and recruits NuRD nucleosome remodeling deacetylase corepressor complex to suppress EBF2 activity in thermogenic genes regulatory sequences [ ].

Absence of ZFP associates with PPARγ binding to thermogenic gene enhancers, WAT browning and non-shivering thermogenesis [ ]. The protein transducin-like enhancer of split 3 TLE3 was first described by Villanueva and colleagues to increase PPARγ adipogenic activity [ ].

Deletion of TLE3 copes with increased energy expenditure and mitochondrial oxidative metabolism in adipocytes, characteristics associated with the browning process [ ] KLF11, TAF7L, ZBTB16, EWS, PLAC8, ERRα, ΕRRγ and other TFs that were described to promote WAT browning.

In contrast, FOXO1, TWIST1, p, LXRα, pRB, RIP, REVERBα acting repressing AT beiging by impacting on the activity of EBF2, PRDM16, PGC1α and other activating TF [ , , ]. In order the transcription to occur, chromatin needs to be accessible to polymerases and TFs.

Remodeling enzymes, which are classified in covalent histone modifiers and ATP-dependent chromatin remodeling complexes, actively modify chromatin status in response to environmental cues [ ].

Histone covalent modifiers are enzymes that chemically modify positively-charged amino acids mainly lysine present in these proteins. Histone acetyltransferases HATs and histone deacetylases HDACs catalyze the removal or insertion of acetyl group, respectively, influencing histone acetylation pattern [ ].

The HAT CBP was shown to inhibit the browning process, once it is key in white adipocyte differentiation [ ]. Histone acetylation pattern has been described to present a critical role in adipocyte identity, as cold exposure leads beige adipocytes to show histone acetylation pattern associated with brown phenotype [ ].

HDACs catalyze the deacetylation of amino acid residues in histones, reactions favor gene repression. These enzymes are categorized into four groups, namely class I HDAC1—3 and 8 , class IIa HDAC4, 5, 7, and 9 , class IIb HDAC6 and 10 , class III SIRT1—7 , and class IV HDAC11 [ ].

HDAC1 expression is augmented in WAT and copes with decreased levels of proteins associated with non-shivering thermogenesis, as UCP1 and PPARγ [ ]. HDAC3 levels also suppress WAT browning, as absence in WAT correlates with H3K27ac on enhancers of Ucp1 and Ppar g , signature associated with tissue improved oxidative capacity, mitochondrial biogenesis, and thermogenesis [ ].

Experiments involving the deletion of HDAC9 shows that this enzyme also contributes for the metabolic dysfunction characteristic of HFD-fed rodents [ ]. HDAC11 is another element that impairs WAT beiging, once its removal favors at thermogenesis in diet-induced obese DIO mice [ ].

Other key HDAC is the SIRT family SIRT1, SIRT2, SIRT3, SIRT5, and SIRT6. SIRT1 deletion in HFD-treated mice is associated with diminished amounts of PGC-1α, FGF21, and UCP1 in epididymal WAT eWAT [ ]. Histones can also be post-translationally modified by histone methyltransferases HMTs and histone demethylases, which influence gene activation or suppression depending on the modified residue position and valency [ ].

There are two categories of HMTs: lysine methyltransferases KMTs and arginine methyltransferases RMTs. Rodent studies show that inactivation of the KMT MLL3 favors improved insulin sensitivity and augmented energy expenditure [ ].

Absence of another KMT, the EHMT1, was shown to impair the thermogenic program in WAT [ ]. Histone demethylases HDM catalyze histone demethylation processes and are also classified according to the characteristics of the modified amino acid.

The KDM LSD1 expression, which was found to be induced by chronic cold exposure and β3-adrenergic stimulation, leads to increased mitochondrial activity in WAT by cooperating with NRF1 [ , , ].

In addition, rodents presenting increased LSD1 levels are associated with igWAT browning in lean animals and with lower weight gain in the context of DIO [ ] Also induced by β3-adrenergic stimulation, the KDM3A JMJD1A directly regulates ppar a and ucp1 genes and was found to be crucial for WAT browning [ ].

Specific DNA sequences called CpG islands can also be methylated for gene transcription regulation by DNA methyltransferases DNMTs , which switches off gene expression. Ten-eleven translocation TET family enzymes switch on the gene expression by demethylation [ ].

Gene transcription can also be impacted by the action of ATP-dependent chromatin remodeling complexes, which, differently from the covalent histone modifiers, alter the interaction between the DNA and the nucleosome non-covalently using ATP hydrolysis as an energy source.

Abe and colleagues suggested that BRG1 is necessary for thermogenesis induction [ ]. Other key actors in gene transcription regulation are the microRNAs MiR , small non-coding regulatory ribonucleic acids maximum nucleotides that influence gene expression post transcriptionally.

These elements regulate gene expression by several mechanisms, including binding to mRNA strands to repress protein translation and to favor decapping, deadenylation and ultimately degradation of target mRNA in P-bodies, and direct translation inhibition.

However, many studies suggest that miRNAs are also capable of activating transcription protein translation, fact that highlights miRNAs as central participants in the fine regulation of gene expression in response to specific stimuli [ ].

Raymond and others described that miR inhibition copes with impaired WAT browning [ ]. Another miRNA that influences WAT homeostasis is miR, which deletion leads to WAT enlargement and overexpression inhibits the progression of obesity in the DIO in mice [ ]. In contrast, miR, miR, and miR inhibit TFs associated with the browning process [ 61 , 63 , ].

Fu and colleagues showed that miRa inhibits WAT beiging via FGF21 [ ], miRNA, miRNA Let-7i-5p and miRb- 5p are molecules that impair WAT browning process, which inhibition promotes beiging [ , , ] Fig.

Other small non-coding RNAs sncRNAs impact on gene expression and are extensively reviewed elsewhere. WAT browning transcriptional regulation. The transcriptional regulation of the WAT beiging process involves the action of a plethora of specific proteins and nucleic acids.

This orchestra of trans-acting factors modulates genes associated with oxidative capacity, mitochondrial biogenesis and non-shivering thermogenesis. While the action of some factors, such as PGC-1α, IRF4, PRDM16, ZFP, EHMT1 and RNAs, copes with WAT browning, TLE3, ZFP, and the NuRD complex, another set of RNAs e others inhibit this process, favoring adipogenesis and white adipocyte differentiation.

Non-coding RNAs that present average length longer than nucleotides are called LncRNAs [ , ] These nucleic acids have been described to influence gene transcription through several mechanisms, including the induction of more efficient protein translation by binding to an internal ribosome entry site IRES , increase of mRNAs stability, polyubiquitination process inhibition thus increasing protein stability, binding to specific proteins in the cytoplasm, and acting as a sponge sequestering miRNAs [ , , , , ].

Zhao and collaborators identified lncRNA 1 Blnc1 as a driver for beige adipocyte differentiation and WAT browning [ ]. LncRNAs also interact with other TFs, such as PGC-1α, ZFP, and PRDM16 for full transcription [ , , ]. PRDM16, a coregulator of PPAR, cooperates with EHMT1 for WAT browning induction.

As EHMT1, other covalent histone modifiers form complexes with ATP-dependent chromatin-remodelers [ ]. The chromatin-remodelers BRG1 and the BAF also interact with the TF EBF2 for gene transcription [ , ].

Noteworthy, AT functional and morphological plasticity is represented by the extreme dynamic beige adipocyte chromatin state. Beige adipocytes show a chromatin signature similar to the pattern presented by brown adipocytes after cold exposure and display a chromatin signature associated with white adipocytes after re-warming to 30 °C.

However, if the beige adipocytes were cold-induced, these cells displayed epigenetic marks that favored rapid thermogenic genes expression upon β-adrenergic stimulation, even after temperature rise, suggesting the occurrence of epigenomic memory [ , ]. For the past decades, the browning process has been deeply explored for managing both metabolic syndromes, and hypermetabolic diseases.

Proposing treatment, the cold was the pioneer mechanism associated with a great elicitation of this event in mice. However, the applicability and outcomes of this approach in humans are far from exciting. Technological advances provide efficient mechanisms that can be employed to improve a biological system.

Recent studies applied bioengineers to achieve the improvement of browning in adipose tissue. The injection of M2 AT macrophages ATMs from transgenic mwRIPKD mice, a specific knockdown of RIP that is related to activation of M1 polarization, in HFD-fed obese wild type mice could recover the disruption induced by obesity through browning induction [ ].

WAT-derived stem cells ASCs from humans and rats could be differentiated into BAT under browning conditions in three-dimensional 3D polyethylene glycol PEG hydrogel [ ]. In addition to bioengineering, a field that has been explored is the transplantation or re-implantation of BAT, also termed ex-BAT, to increase this endogenous tissue.

The harvested scWAT is differentiated into brite and then is re-implanted in the same area promoting the local increase of BAT, displaying great outcomes [ ].

Aiming for a less invasive procedure, the use of a microneedle patch to address the browning agents directly to the scWAT for inducing browning of this tissue is another strategy investigated presently [ ].

These strategies aim to promote the increase of endogenous BAT, as well as its activity with an applicable method, reducing the degree of invasiveness and risks of rejection by the body.

Several studies have targeted increasing BAT mass and activity, but when the aim is inhibiting the browning process to avoid a worsening prognosis, what is proposed? Expanding knowledge of the pathways involved is the main way of inhibiting that event.

It is well established the role of parathyroid hormone PTH in the elicitation of browning. In the tumor context, it was identified as a peptide-derived tumor, parathyroid hormone-related protein PTHrP that favors browning and cachexia [ 16 ]. Blocking PTHR specifically in ATs inhibits browning and wasting of this tissue, as well preserves muscle integrity, and ameliorates muscle-related strength, protecting mice from cachexia [ ].

Currently, some pharmacological approaches have displayed alternative and prominent ways to restrain browning. Metformin demonstrated to be efficient to prevent the browning of the scWAT, as well as the inhibition of mevalonate pathways by the use of Statin or Fluvastatin, which implicates in the disruption of browning [ , ].

However, further studies should be conducted to promote a broader and more detailed debate on the topic. Given the data presented, it is evident that the benefits and dangers associated with activation or inhibition of the browning process are closely linked to the type of disorders displayed in the individual's body at the metabolic, cellular, or physiological level.

Taking as criteria patients with metabolic syndromes and obesity, browning process emerges as a promising therapeutic approach, mainly due to its several benefits, such as improvement of clinical conditions associated with lower side effects, and the multi-stimulatory character, which allows numerous safe and feasible ways of induction.

In contrast, the ways and means of inhibiting browning to prevent the development of comorbidities in cases of chronic or acute hypermetabolism are still poorly explored. In this way, browning process needs to be deeply explored and can be used as a key factor in different therapeutical approaches in health and diseases.

Emerging insights into the metabolic and immunological role of browning of the white adipose tissue are also discussed, along with the developments that can be expected from these promising targets for therapy of metabolic and chronic disease in the forthcoming future.

A major discussion pointed by the scientific community about the investigation of AT in mice is how much the results obtained in the animal model would reproduce the anatomorphophysiologies of these tissues in humans, since, unlike humans, mice have a significant amount of BAT during embryonic and adult, as well as they differ in several other factors, such as expression of molecular markers, activation profile and location.

Human BAT was discovered to be more similar to beige compared to classical BAT markers [ , ]. Another relevant point concerns the fact that the BAT deposits most used for research purposes are the BAT located in the interscapular region iBAT , while in humans there is a greater abundance of this tissue in the clavicular and neck regions, presenting compositional differences that represent obstacles in the overlapping of scientific findings.

In this sense, Mo and colleagues identified an analogous deposit of BAT in mouse embryos, which is maintained during adulthood, and in humans called supraclavicular BAT scBAT.

The scBAT shows similarities to scBAT in humans in terms of location, morphology and thermogenic capacity [ ]. In which the authors observed a greater similarity between several cellular and molecular parameters between the BAT of humans and mice [ ].

The technique generated controversies that were discussed by Kajimura and Spiegelman and replicated by the authors of the original article , Current research place WAT browning as an extremely dynamic process that is influenced by several factors , including temperature, physical exercising, thyroid hormones, circardian rhythm, food components and dietary regimens.

The participation of AT plasticity on the organism metabolic health and inflammatory status spot this process as a promising therapeutic target for decreasing the risk associated with many chronic diseases. Further efforts in investigating AT plasticity must alleviate the burden of these devastating life-style associated pathologies.

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Mitochondrial metabolism is often altered in inherited diseases, such as inborn errors of metabolism IEMs that impinge upon ROS generation.

Inhibition of OXPHOS increases ROS generation due to a backlog of electrons in the various complexes, resulting in electron leak, ROS generation, and production of H 2 O 2. In IEMs affecting the ETC or other pathways of ATP generation, increased oxidative stress is often observed, while the exact mechanisms for increased ROS production are unknown.

It is hypothesized that mutations affecting the formation of the protein complexes in the ETC or mutations that modify their assembly increase ROS generation by facilitating electron leak Olsen et al.

Additionally, accumulation of toxic intermediates, often observed in IEMs, can increase the ROS generation by further decreasing OXPHOS activity, as in the case of medium-chain acyl-CoA dehydrogenase MCAD deficiency.

MCAD deficiency reflects the accumulation of medium-chain fatty acid derivatives, including cisdecenoic acid, octanoate, and decanoate, with these metabolites altering levels of antioxidants and increasing markers of oxidative stress Schuck et al. Intriguingly, IEMs display metabolic reprograming with a switch to glycolysis for both ATP production and muted ROS generation Olsen et al.

Specifically, in myoclonic epilepsy with ragged red fibers MERRF , increased intracellular H 2 O 2 levels correspond with increased AMPK phosphorylation and expression of GLUT1, hexokinase II, and lactate dehydrogenase. These results, as well as increased lactic acid production, all point to increased glycolysis De la Mata et al.

In multiple acyl-CoA dehydrogenase deficiency MADD , mutations in ETFa , ETFb , or ETFDH , lead to decreased ATP production with an accumulation of organic acids, including glutaric acid as well as acyl-carnitines. A subset of these patients is riboflavin responsive RR-MADD with high dose riboflavin alleviating some symptoms.

Similar to MERRF, many RR-MADD patients exhibit increased oxidative stress Cornelius et al. This defect may be due to defective electron transfer and increased electron leak from the misfolded ETFDH protein and decreased binding of CoQ10 Cornelius et al.

Treatment with CoQ10, but not riboflavin, decreased ROS levels Cornelius et al. Analysis of mitochondrial function from RR-MADD fibroblasts showed increased mitochondrial fragmentation and reduced β-oxidation, while supplementation with the antioxidant CoQ10 decreased fragmentation and mitophagy Cornelius et al.

While obesity and IEMs are distinct disorders, both conditions impinge on energy balance in WAT. Even though these disorders have very different manifestations, oxidative stress plays an important role in both and may be a therapeutic target.

For example, CoQ10 is often given as a broad-spectrum treatment to individuals with IEMs, and while its effectiveness is debated, the anti-inflammatory effects may be beneficial in reducing oxidative stress and the pathogenesis of the disease Cornelius et al. Mitochondria represent control centers of many metabolic pathways.

Interventions that enhance adipocyte mitochondrial function may also improve whole-body insulin sensitivity.

Mitigation of mitochondrial ROS production and oxidative stress may be a possible therapeutic target in type 2 diabetes and IEMs because some mitochondrial-targeted antioxidants and other small molecule drugs improve metabolic profiles in mouse models Feillet-Coudray et al.

Thiazolidinediones TZDs are PPARγ agonists used for treating type 2 diabetes Kelly et al. TZDs, such as rosiglitazone and pioglitazone, enhance insulin sensitivity by improving adipokine profiles Maeda et al. TZDs also promote insulin sensitivity by directing fatty acids to subcutaneous fat, rather than visceral fat.

Subcutaneous fat expandability, even in the context of obesity and type 2 diabetes, correlates with insulin sensitivity in rodents and humans Ross et al. Numerous in vitro and in vivo studies demonstrate TZDs enhance mitochondrial biogenesis, content, function, and morphology.

Rosiglitazone also induces cellular antioxidant enzymes responsible for the removal of ROS generated by increased mitochondrial activity in adipose tissue of diabetic rodents Rong et al. Taken together, TZDs impact WAT mitochondrial function in multiple ways that ultimately improve systemic fat metabolism and insulin sensitivity.

Other therapeutic strategies include mitochondria-targeted scavengers Smith et al. However, these methods to enhance mitochondrial function display a narrow therapeutic range that limits safe use for obesity. Although the development of insulin resistance does not require impaired mitochondrial function Hancock et al.

Aerobic exercise and caloric restriction disrupt this vicious loop, potentially by preventing accumulation of injured mitochondrial proteins with substantial improvement of insulin sensitivity.

In insulin-resistant people, aerobic exercise stimulates both mitochondrial biogenesis and efficiency concurrent with an enhancement of insulin action Mul et al. Ultimately, exercise engages pathways that reduce ROS coupled with insulin sensitivity and improved mitochondrial function in WAT.

Obesity is the result of excessive expansion of WAT depots due to a chronic imbalance between energy intake and expenditure. Many studies demonstrate that oxidative stress in fat cells links obesity and its comorbidities. The fact that WAT remains the sole organ for storing surfeit lipid renders the macromolecules in adipocytes particularly vulnerable to carbonylation and other modifications driven by oxidative stress.

Prolonged oxidative stress negatively influences endocrine and homeostatic performance of WAT, including disruption of hormone secretion, elevation of serum lipids, inadequate cellular antioxidant defenses, and impaired mitochondrial function Figure 2.

Metabolic challenges, such as persistent nutrient intake and sedentary behaviors that promote impaired glucose and lipid handling, also elevate mitochondrial ROS production to cause adipocyte dysfunction. Consequently, adipocytes cannot engage appropriate transcriptional and energetic responses to enable insulin sensitivity.

Figure 2. Impact of oxidative stress on adipocyte function. Increased plasma glucose and free fatty acids contribute to increased oxidative stress by increasing the production of reactive oxygen species ROS and decreasing antioxidant concentrations. Increased oxidative stress occurs via enzymes in the cytoplasm, such as NADPH oxidase, and the mitochondria.

The oxidative environment increases lipid storage resulting in hypertrophic adipocytes. Additionally, increased mitochondrial ROS mtROS alters the activity state of metabolic enzymes either directly or by changing the oxidative state of protein side-chains or by other post-translational modifications, including lipid peroxidation and protein carbonylation.

Cumulatively, increased adipocyte oxidative stress decreases adipogenesis and secretion of adipokines, leading to unbalanced energy homeostasis, insulin resistance, and type 2 diabetes.

The increasing prevalence of obesity suggests lifestyle intervention as the principal method to treat obesity is unlikely to succeed. Currently, all available anti-obesity medications act by limiting energy intake through appetite suppression or inhibition of intestinal lipid absorption.

However, these medications are largely ineffective and often have adverse side effects. The central role of mitochondria in nutrient handling provides a logical entry point for improving metabolism in obesity. While approaches to understanding and intervening in oxidative damage evolve, exploration of mitochondria redox balance may enable development of dietary and small molecule therapies for obesity and its comorbidities.

This work was funded by the American Diabetes Association IBS and NIH R01DK The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Because FAs are chemically more reduced molecules than carbohydrates, FAs are theoretically able to produce more energy when completely oxidised than an equivalent carbohydrate molecule.

In other words, the complete oxidation of six-carbon glucose consumes six oxygen molecules and produces six carbon dioxide molecules accompanied by the synthesis of 36 ATP molecules. On the other hand, the complete oxidation of six-carbon hexanoic acid consumes eight oxygen molecules and produces six carbon dioxide molecules for 44 ATP molecules.

Therefore, a switch to the oxidation of FAs as the major energy substrate should result in less efficient ATP production and an increase in whole-body energy expenditure that could lead to a loss of fat mass if energy intake remains constant Clapham a , b , Leverve et al.

Pathways of substrate metabolism in muscle. Oxidation pathways of glucose, FAs and amino acids converge at the level of acetyl CoA. This proton motive force is dissipated by ATP synthesis and by proton leak via the adenine nucleotide transporter ANT and activated uncoupling proteins UCPx.

Demand for ATP and proton leak are greater determinants of oxygen consumption and heat production than the substrate being oxidised. Citation: Journal of Endocrinology , 2; Indirect calorimetry is often used in human and animal studies to determine total energy expenditure indirectly by the measurement of oxygen consumption and carbon dioxide production , and the measurement of oxygen consumption and carbon dioxide production can also be used to calculate the relative use of glucose and FAs to support that energy expenditure respiratory exchange ratio, RER , assuming that any contribution of protein oxidation is relatively small and constant Ferrannini , Arch et al.

However, in practice, it is unlikely that such theoretical calculations can be applied to the regulation of energy balance with any certainty. For instance, rarely does the measured RER shift from complete glucose oxidation 1. counter-ion transport and uncoupling protein activity Mazat et al.

The concepts of efficiency and plasticity in the coupling of substrate oxidation to energy conservation ATP synthesis have been expanded on in several authoritative review articles Harper et al. In reality, coupling efficiency can vary significantly depending on changes in proton leak or ATP demand, but in cell systems at least, changes in substrate oxidation do not appear to influence the relationship between oxygen consumption and ATP synthesis Brand et al.

The above discussion clearly leads to the conclusion that the cost of generating mitochondrial ATP in terms of ETC activity and oxygen consumption can vary significantly and is not affected to any large extent by the substrate being oxidised to provide the reducing equivalents for electron transport.

Despite this, it is not uncommon to read about studies in whole animal systems particularly genetically modified mice where differences in fat mass are often mechanistically related to changes in the mRNA levels of FA metabolism genes in a variety of tissues without appropriate consideration of the contribution of these tissues to whole-body energy expenditure Abu-Elheiga et al.

For example, expression of oxygen consumption or heat production on a kilogram body weight basis can be misleading if animals have significantly different amounts of fat tissue, because the metabolic rate of fat per gram is much lower in tissues such as muscle and liver Frayn et al.

Similarly, the difference in daily food intake needed to contribute to a significant gain of body fat over several weeks in mice can be so small as to be undetectable unless large numbers of mice — are used for the comparison Tschop et al.

Changes in the body weight and body fat of groups of adult mice with different genotypes on different diets should reflect cumulative differences in energy intake and energy expenditure.

However, any differences might not be easily detected if animals are assessed for food intake and energy expenditure individually in indirect calorimetry systems, away from their home cage and communal environment for only a 24—h period of the several weeks over which body weight and fat mass have been monitored.

AMP-activated protein kinase AMPK is recognised as a master regulator of energy metabolism, particularly in times of energy stress such as exercise, hypoxia and starvation Hardie et al. The activation of AMPK has been shown to acutely increase FA and glucose uptake and metabolism in a variety of experimental situations including in vitro and in vivo experiments in muscle Iglesias et al.

The long-term effects of AMPK activation in muscle lead to the activation of gene transcription pathways that increase mitochondrial biogenesis and proteins of oxidative metabolism Winder et al. The acute regulation of FA oxidation by AMPK is largely through the phosphorylation and inactivation of the enzyme acetyl CoA carboxylase 2 ACC2.

The pharmacological activation of AMPK has been shown to produce changes in muscle metabolic pathway capacity similar to those produced by exercise training O'Neill et al. A series of studies employing genetic deletion of Acc2 Acacb have reported reduced fat depots in association with increased FA oxidation in isolated muscle Abu-Elheiga et al.

These results suggest that the inhibition of ACC2 by the activation of AMPK or development of ACC2 inhibitors might promote FA oxidation and produce fat loss. Subsequent studies using independently generated Acc2 -knockout mice did not reproduce these effects, reporting that although these mice exhibited increased FA oxidation at the whole-body and isolated muscle level, there was no measurable difference in energy expenditure, fat mass or food intake Hoehn et al.

However, there was an increased glycogen content in muscle, an effect of AMPK activation noted previously Winder et al.

Another study using independently generated genetically manipulated mice has reported no difference in body weight, food intake or fat mass in global or muscle-specific Acc2 gene-deleted mice Olson et al. Therefore, it would appear that apart from theoretical calculations suggesting that increasing fat oxidation will drive increased energy expenditure, there is little experimental evidence to support the idea that energy expenditure can be increased simply by increasing substrate availability or by switching to oxidise FAs.

From an energy metabolism point of view, the flow of different substrates to tissues for oxidation or storage is largely under the control of the circulating hormone insulin.

After a meal, direct stimulation of the β-cells of the islets of Langerhans of the pancreas by nutrients glucose, FAs and amino acids increases insulin release into the circulation.

Certain gut hormones GLP1 and GP can also augment insulin secretion, as can neural signals from the brain Thorens Insulin has many stimulatory and inhibitory actions in different tissues mediated by a complex intracellular signalling pathway, but for the purpose of this discussion, the actions of insulin to stimulate glucose uptake and metabolism in muscle and regulate FA metabolism will be a major focus.

The failure of insulin to appropriately regulate glucose and FA metabolism is termed insulin resistance, and this condition is most frequently observed in the muscle and liver of overweight or obese individuals Eckardt et al.

Insulin resistance is considered a significant predisposing factor for the development of type 2 diabetes T2D and therefore there is considerable research effort put into determining the mechanistic relationship between excess lipid accumulation obesity and insulin resistance, particularly in muscle.

Studies from over 20 years ago first showed that triglyceride accumulation in the muscle of high-fat diet-fed rats coincided with insulin resistance Storlien et al.

Since then, the relationship between muscle lipid accumulation and insulin resistance has also been established in humans, and many mechanisms have been put forward to explain how lipid accumulation could generate insulin resistance Bosma et al.

Over the last decade, the major challenge has been determining whether these proposed mechanisms are universal or specific to the model of lipid-induced insulin resistance being studied. It is also possible that different mechanisms are important at different times during the development of insulin resistance and that some proposed mechanisms depend on the experimental methods used to assess insulin action.

All discussions of the relationship between increased fat metabolism and insulin action are dependent on the methodology used to assess insulin resistance and the assumptions associated with different methodologies.

As has been mentioned previously, nearly all investigations of lipid-induced insulin resistance in rodent models utilise high-fat diet feeding to increase adiposity, but the methods of assessing insulin action can be quite varied and rely on glucose tolerance tests or insulin tolerance tests and less frequently because of the technical difficulty on hyperinsulinaemic—euglycaemic clamps.

Various technical considerations of glucose and insulin tolerance tests must be considered when discussing the metabolic implications of these tests for muscle insulin action.

The timing and route of administration of glucose and duration of fast before glucose administration influence the results of glucose tolerance tests Andrikopoulos et al.

Insulin tolerance tests were devised largely to assess the effectiveness of counter-regulatory mechanisms in response to insulin-induced hypoglycaemia and therefore the utility of these tests to assess peripheral insulin action is debatable. Neither glucose tolerance nor insulin tolerance tests give specific data regarding insulin effectiveness in muscle, although several methodological variations have used concurrent injection of radioactive tracers to assess glucose clearance into muscle during a glucose tolerance or insulin tolerance test Crosson et al.

The hyperinsulinaemic—euglycaemic clamp with glucose tracer administration gives the most reproducible assessment of muscle glucose clearance in response to constant insulin stimulation and constant glucose availability Ayala et al. This technique relies on plasma insulin levels not insulin infusion rates during the comparison of the clamp being matched between the groups.

In many studies, plasma insulin levels during the clamp are not reported, making the assessment of muscle insulin action difficult Chapman et al. In vitro assessment of insulin effectiveness in isolated soleus or extensor digitorum longus muscle is also often used to demonstrate the effects of FA exposure Thompson et al.

reliance on diffusion and not on perfusion. While all the above methods can give useful information about the effects of muscle lipid accumulation on insulin action, this information can be specific for the test employed. Even the data obtained from hyperinsulinaemic—euglycaemic clamp studies describe fluxes measured after at least an hour of exposure to constant insulin stimulation and constant glucose availability, a situation that is unlikely to ever exist in the normal h feeding—fasting cycle.

Therefore, it would seem important to consider the method used to demonstrate a difference in insulin action with lipid accumulation, when assessing the relevance of various mechanisms to reduced glucose metabolism in muscle when no restrictive experimental conditions e. in vitro assessment, constant infusion and i.

As has been mentioned above, the association between intramyocellular triglyceride IMTG content and insulin resistance is now well established in animals and obese humans, and most studies investigating the mechanisms of insulin resistance in muscle use high-fat diet rodent models. It has also become standard practice in assessing the phenotype of genetically manipulated mice to place them on high-fat diets to investigate whether there is any impact favourable or detrimental of gene manipulation on glucose and energy homoeostasis.

There is a reasonable assumption that, independent of genetic background in animals or humans, overconsumption of energy-dense diets plays a major role in the accumulation of fats and development of metabolic derangements in muscle.

In humans, overconsumption of energy-dense diets for a few weeks is enough to increase fat mass and have detrimental effects on whole-body insulin action Samocha-Bonet et al. In mice, high-fat feeding for as little as a few days can impair glucose tolerance Turner et al.

Studies that improved insulin sensitivity by low-calorie diets in patients with T2D were accompanied by a reduction in IMTG content Jazet et al. Insulin resistance associated with ageing Nakagawa et al. Current opinion is reasonably clear on the fact that IMTG is a useful marker of the level of cytosolic lipid accumulation, but it is more likely that active lipid metabolites such as LCACoAs, DAGs and ceramides or intermediates of FA oxidation pathways interfere with insulin action via a variety of potential mechanisms Fig.

These mechanisms are largely based on the idea that insulin resistance in muscle is the result of reduced transduction of the insulin signal through the phosphorylation cascade leading to the translocation of the glucose transporter GLUT4 to the sarcolemmal membrane Stockli et al.

Since that time, research into the molecular mechanism of FA-induced insulin resistance in muscle has mainly focused on linking excess FAs to defects in the insulin signalling pathways that regulate glucose uptake.

However, there are some established and some more speculative mechanisms that also link increased FA metabolism with reduced insulin action, and these are discussed in the subsequent sections. Proposed mechanisms for the build-up of bioactive lipid species and how they interfere with insulin action in muscle to produce insulin resistance.

DAG can activate lipid-sensitive kinases to serine phosphorylate and reduce tyrosine phosphorylation of IRS1. Ceramide can inhibit Akt phosphorylation and reduce transduction through the insulin signalling pathway.

Circulating cytokines or FAs themselves are reported to activate inflammatory pathway serine kinases that interfere with insulin signalling.

Reduced or dysregulated FA oxidation in mitochondria could create a build-up of bioactive lipids and generate reactive oxygen species ROS that also activate kinases that interfere with insulin signalling. IMTGs are considered to be relatively benign with regard to insulin resistance Goodpaster et al.

However, despite the general consensus that IMTGs are metabolically inert, it is possible that the expanded IMTG pool generates intermediates of lipid metabolism that are more likely to play a mechanistic role in the development of muscle insulin resistance. In this respect, the bioactive lipid metabolites DAG and ceramide are leading candidates.

The levels of both DAG Turinsky et al. While less is known about the role of these lipids in humans, it has been reported that acute lipid-induced insulin resistance is associated with muscle DAG accumulation Itani et al. Furthermore, interventions that enhance insulin action, such as exercise training, cause reductions in muscle DAG and ceramide content Bruce et al.

Specifically, DAG accumulation is thought to impair insulin action via the activation of novel protein kinase C PKC isoforms, which subsequently inhibits insulin signal transduction to glucose transport via serine phosphorylation of insulin receptor substrate 1 IRS1; Yu et al.

Ceramide has been reported to cause insulin resistance by impairing insulin signalling at the level of Akt Schmitz-Peiffer et al. In addition, ceramide is a potent activator of inflammatory molecules, including c-Jun N-terminal kinase JNK; Westwick et al.

However, while inflammation has been proposed as a critical factor causing insulin resistance, studies carried out by our group and other groups suggest that inflammation is not involved in the initiation of lipid-induced insulin resistance, but may be more important in the exacerbation and maintenance of insulin resistance once obesity is established Lee et al.

Although there is mounting evidence supporting a role for DAG and ceramide in the regulation of insulin sensitivity, it is important to highlight that the accumulation of these lipids is not always associated with insulin resistance.

In fact, a recent study has found that total DAG content is actually elevated in the muscle of highly insulin-sensitive endurance-trained athletes compared with the skeletal muscle of obese individuals Amati et al.

Furthermore, a positive correlation between total muscle ceramide content and insulin sensitivity has been reported Skovbro et al.

These data suggest a more complex role for DAG and ceramide in the regulation of insulin action Amati et al. While the bioactive lipid hypothesis has gained strong support, an alternative concept linking the accumulation of intermediates of mitochondrial FA oxidation with muscle insulin resistance has gained attention Koves et al.

This model proposes that lipid oversupply drives an increase in mitochondrial β-oxidation that exceeds the capacity of the Krebs cycle, leading to the accumulation of by-products of FA oxidation Koves et al. This is supported by studies demonstrating an increase in incomplete FA oxidation and an accompanying increase in intramuscular acylcarnitine levels in obese rodents Koves et al.

While data in humans are currently limited, there is evidence that acylcarnitine does accumulate in the muscle of humans in response to a high-fat diet Putman et al. However, it is not clear whether acylcarnitine plays a direct role in the modulation of skeletal muscle insulin sensitivity by disrupting signalling processes or whether it simply reflects a state of mitochondrial stress.

Unravelling the role of acylcarnitine in muscle insulin sensitivity will no doubt be a focus of future research. Another prominent theory on the aetiology of insulin resistance implicates abnormalities in mitochondrial function as a major causative factor leading to reductions in insulin sensitivity.

More specifically, defects in mitochondrial metabolism have been suggested to lead to inadequate substrate oxidation, precipitating a build-up of intracellular lipid metabolites, impaired insulin signalling and the subsequent development of insulin resistance Lowell and Shulman , Kim et al.

The initial studies that set the platform for this theory in the late s showed that there was reduced mitochondrial enzyme activity and decreased fat oxidation in the skeletal muscle of obese, insulin-resistant subjects and in individuals with T2D Kelley et al. Kelley et al. In the following year, two prominent microarray studies were published, describing a coordinated down-regulation of genes involved in mitochondrial biogenesis and oxidative phosphorylation in subjects with T2D and, importantly, also in non-diabetic individuals with a family history of T2D Mootha et al.

In the ensuing decade since the publication of these landmark studies, many groups have reported defects in different mitochondrial parameters in the skeletal muscle of a range of different insulin-resistant populations obese, T2D and PCOS. Functional studies in muscle biopsy samples or in vivo using magnetic resonance spectroscopy have also reported decreases in mitochondrial oxidative capacity in insulin-resistant individuals Petersen et al.

Collectively, all these studies suggest that at some level, mitochondria in insulin-resistant individuals are not as effective at burning fuel substrates in muscle and this compromises insulin action.

Despite the large body of evidence described above, this area is controversial, as many studies report a dissociation between insulin resistance and mitochondrial dysfunction.

For example, providing rodents with excess fat in their diet leads to an enhancement of mitochondrial oxidative capacity in muscle while at the same time inducing insulin resistance Turner et al.

Several lines of mice with genetic manipulations that cause compromised mitochondrial function in muscle do not exhibit insulin resistance Vianna et al. Conversely, two separate lines of muscle-specific Pgc1 α Ppargc1a transgenic mice displayed a significant enhancement in the markers of mitochondrial content and yet were insulin resistant due to excessive FA delivery and reduced GLUT4 SLC2A4 expression in muscle Miura et al.

A growing number of studies in humans have also reported intact mitochondrial function in various insulin-resistant populations De Feyter et al. Collectively, these studies suggest that mitochondrial dysfunction in muscle is not an obligatory factor required for the accumulation of intramuscular lipids and the development of insulin resistance.

normal free-living conditions Hancock et al. In addition to their role as major sites for energy transduction, mitochondria are also known to be a major source of reactive oxygen species ROS , which are produced as a by-product of normal metabolic reactions Andreyev et al.

ROS have the capacity to damage macromolecules, and when the production of these reactive species is in excess of the antioxidant defences, a state of oxidative stress results. FA catabolism is known to promote mitochondrial ROS production St-Pierre et al.

Importantly, many studies have shown that insulin action is improved when mitochondrial ROS production is attenuated Houstis et al. Before the elucidation of the insulin signalling pathway and recognition of the complex processes involved in the translocation of GLUT4 from intracellular vesicles to sarcolemmal membrane, there was a large amount of experimental data pointing to significant FA regulation of glucose metabolism at the level of PDH Randle et al.

If humans, animals or in vitro preparations of muscle are exposed to an increased availability of FAs in the presence of glucose, the oxidation of FAs increases and the oxidation and uptake of glucose decrease Boden et al.

On the other hand, reduction of the availability of FAs by inhibiting lipolysis Vaag et al. Although the initial observations of Randle and colleagues on the reciprocal relationship between glucose and FA metabolism were made 50 years ago, the idea that increasing or reducing FA availability will reciprocally affect glucose utilisation is no less valid today.

Therefore, in the context FA-induced insulin resistance, a role for substrate competition and regulation at the level of PDH should not be overlooked.

As outlined in other sections of this review, the current dogma suggests that the major mechanisms for FA-induced insulin resistance in muscle involve active lipid species interfering with insulin signalling via the activation of various serine kinases Fig.

The canonical insulin signalling cascade comprises scaffolding proteins e. IRS1 and enzymes e. Mitochondrial insufficiency and ROS are also thought to feedback and impinge on the efficiency of insulin signalling via the activation of regulatory kinases.

While there are many studies showing clear differences in the phosphorylation status of various insulin signalling proteins after insulin stimulation in control and FA-exposed or obese or high-fat diet-fed muscle, these changes are not always consistent. There are a number of studies reporting that insulin-stimulated Akt activation is in fact not impaired in the muscle of obese individuals with insulin resistance, of glucose-intolerant first-degree relatives of patients with T2D and of patients with T2D Kim et al.

This dissociation between measured changes in insulin-stimulated glucose flux and insulin effects on signalling proteins has a number of implications. First, it might highlight the technical difficulties of obtaining reliable, quantitative data on protein modification using the essentially non-quantitative technique of immunoblotting.

The ability to detect differences with this methodology can also depend on the affinity of individual antibodies, and the amount of phosphorylation does not necessarily correlate linearly with the activity of the signalling protein. The introduction of mass spectrometry techniques to analyse changes in global protein phosphorylation in response to insulin, as has been applied in adipocytes Humphrey et al.

Another possibility is that phosphorylation is not the only post-translational modification of proteins involved in the generation of lipid-induced insulin resistance. Recently, the emergence of nitrosative modifications White et al. Another area of research that is increasingly realised to have a significant impact on metabolic disease is circadian biology.

The suprachiasmatic nucleus in the brain is considered to be the master regulator of circadian behaviour because of its ability to coordinate inputs from the environment light, food, exercise and temperature , but it is now clear that every tissue has the molecular components that comprise the clock, raising the possibility that circadian processes in tissues could be regulated directly by some inputs.

Some mouse models with genetic manipulations of core clock genes have altered circadian rhythms and are more prone to developing obesity Turek et al. If there is an underlying rhythm to metabolism in muscle driven by the molecular clock Lefta et al.

In fact, a recent report has suggested that the time of day can have a significant effect on the data obtained from euglycaemic-hyperinsulinaemic clamps in mice Shi et al. The correlation between increased FA availability and reduced insulin-stimulated glucose metabolism is well established.

Despite this clear relationship, to date, there has been no unifying mechanism that explains lipid-induced reductions in insulin action under all circumstances.

However, there are an increasing number of experimental situations where reduced effects of insulin in muscle have been observed without significant changes in the phosphorylation of signalling proteins or where differences in phosphorylation are only observed with stimulation by supraphysiological insulin concentrations.

This suggests that other control mechanisms or other forms of protein modification may predominate depending on the exact experimental conditions used to examine insulin resistance e.

bolus insulin injections, hyperinsulinaemic clamps and glucose or lipid infusion. Figure 3 summarises some of the key control points other than insulin signalling for GLUT4 translocation that could alter the balance between glucose and FA metabolism and affect insulin-stimulated glucose disposal.

For example, utilisation of glucose and FAs is dependent on their availability in the circulation and delivery to the muscle tissue, and changes in microvasculature occur with obesity and contribute to muscle insulin resistance St-Pierre et al. Other work Furler et al.

The phosphorylation of glucose by hexokinase and the pathway for conversion of glucosephosphate to glycogen are subject to regulation by glucosephosphate and glycogen respectively, and decreased glucose phosphorylation and glycogen synthesis will affect glucose uptake Fueger et al.

Another well-documented node regulating the metabolism of glucose is centred on the activity of PDH. The activity of this enzyme complex is inhibited by phosphorylation via PDH kinase 4 PDK4. Interestingly, the amount of PDK4 in muscle is significantly increased in high-fat diet-fed, insulin-resistant animals and PDK4 is activated by acetyl CoA, providing evidence that this regulatory node could significantly affect glucose metabolism in muscle as hypothesised by Newsholme and Randle many years ago Randle et al.

Nodes of control of glucose metabolism other than insulin-stimulated translocation of GLUT4 that could be influenced by the excess availability of FAs.

Utilisation of glucose and FAs is dependent on their availability in the circulation and delivery to the muscle tissue.

The phosphorylation of glucose and conversion to glycogen are regulated by substrate availability and GP concentration. PDH is a critical regulator balancing glucose use and FA oxidation to support energy requirements.

The regulation of FA sequestration in, or release from, muscle fat droplets can control the level of bioactive lipid species.

The regulation of FA metabolism at the AMPK—ACC2—malonyl CoA—CPT1 axis also has a significant impact on the balance between FA and glucose metabolism.

There are a number of newly recognised post-translational modifications that can occur on key metabolic or signalling proteins and would be expected to be influenced by changes in the availability and metabolism of FAs. FA metabolism in muscle can also be regulated at the membrane by transporter proteins such as CD36 , and at activation to acyl CoA by acyl CoA synthase Glatz et al.

The partitioning of FAs towards triglyceride storage or mitochondrial oxidation may depend on the activity of key enzymes such as glycerol phosphate acyltransferase and adipose triglyceride lipase Greenberg et al. The entry of long-chain FAs into the mitochondria for oxidation is thought to be largely regulated by the activity of CPT1.

The activity of CPT1 is modulated allosterically by malonyl CoA, and numerous studies, including our recently published papers using genetic and pharmacological interventions Bruce et al.

Depending on the experimental design used, acutely increasing fatty oxidation in muscle can decrease glucose utilisation Hoehn et al. Interestingly, acute blockade of FA oxidation increases insulin-stimulated glucose uptake Oakes et al.

These differences in acute and chronic responses when substrate metabolism is manipulated may be reconciled by considering the fact that energy metabolism is not constant in animals and humans, but has a substantial diurnal variation that is highly relevant to designing appropriate experiments to investigate lipid-induced insulin resistance.

In conclusion, it may be unrealistic to expect that a unifying mechanism may explain all situations where there is reduced glucose metabolism in muscle in response to insulin, as multiple factors may contribute to the establishment and long-term maintenance of insulin resistance in this tissue.

With the emergence of powerful techniques for determining global changes in gene expression, protein modifications and metabolite profiles, it will hopefully become possible to gain a more comprehensive idea of the factors and pathways that may contribute to the aetiology of lipid-induced insulin resistance in muscle.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review. The work carried out in the laboratories of the authors is supported by Program and Project grant funding from the National Health and Medical Research Council of Australia NHMRC , the Australian Research Council ARC and the Diabetes Australia Research Trust.

NT is supported by an ARC Future Fellowship. G J C and E W K hold research fellowships from the NHMRC and C R B has received a career development award from the NHMRC.

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Of note, systemic oxidative stress and insulin resistance did not coincide with inflammatory cytokines in plasma nor ER stress in WAT. These findings provide a causal link between oxidative stress and insulin resistance in humans.

Mitochondrial metabolism is often altered in inherited diseases, such as inborn errors of metabolism IEMs that impinge upon ROS generation. Inhibition of OXPHOS increases ROS generation due to a backlog of electrons in the various complexes, resulting in electron leak, ROS generation, and production of H 2 O 2.

In IEMs affecting the ETC or other pathways of ATP generation, increased oxidative stress is often observed, while the exact mechanisms for increased ROS production are unknown.

It is hypothesized that mutations affecting the formation of the protein complexes in the ETC or mutations that modify their assembly increase ROS generation by facilitating electron leak Olsen et al.

Additionally, accumulation of toxic intermediates, often observed in IEMs, can increase the ROS generation by further decreasing OXPHOS activity, as in the case of medium-chain acyl-CoA dehydrogenase MCAD deficiency. MCAD deficiency reflects the accumulation of medium-chain fatty acid derivatives, including cisdecenoic acid, octanoate, and decanoate, with these metabolites altering levels of antioxidants and increasing markers of oxidative stress Schuck et al.

Intriguingly, IEMs display metabolic reprograming with a switch to glycolysis for both ATP production and muted ROS generation Olsen et al. Specifically, in myoclonic epilepsy with ragged red fibers MERRF , increased intracellular H 2 O 2 levels correspond with increased AMPK phosphorylation and expression of GLUT1, hexokinase II, and lactate dehydrogenase.

These results, as well as increased lactic acid production, all point to increased glycolysis De la Mata et al. In multiple acyl-CoA dehydrogenase deficiency MADD , mutations in ETFa , ETFb , or ETFDH , lead to decreased ATP production with an accumulation of organic acids, including glutaric acid as well as acyl-carnitines.

A subset of these patients is riboflavin responsive RR-MADD with high dose riboflavin alleviating some symptoms. Similar to MERRF, many RR-MADD patients exhibit increased oxidative stress Cornelius et al. This defect may be due to defective electron transfer and increased electron leak from the misfolded ETFDH protein and decreased binding of CoQ10 Cornelius et al.

Treatment with CoQ10, but not riboflavin, decreased ROS levels Cornelius et al. Analysis of mitochondrial function from RR-MADD fibroblasts showed increased mitochondrial fragmentation and reduced β-oxidation, while supplementation with the antioxidant CoQ10 decreased fragmentation and mitophagy Cornelius et al.

While obesity and IEMs are distinct disorders, both conditions impinge on energy balance in WAT. Even though these disorders have very different manifestations, oxidative stress plays an important role in both and may be a therapeutic target.

For example, CoQ10 is often given as a broad-spectrum treatment to individuals with IEMs, and while its effectiveness is debated, the anti-inflammatory effects may be beneficial in reducing oxidative stress and the pathogenesis of the disease Cornelius et al.

Mitochondria represent control centers of many metabolic pathways. Interventions that enhance adipocyte mitochondrial function may also improve whole-body insulin sensitivity. Mitigation of mitochondrial ROS production and oxidative stress may be a possible therapeutic target in type 2 diabetes and IEMs because some mitochondrial-targeted antioxidants and other small molecule drugs improve metabolic profiles in mouse models Feillet-Coudray et al.

Thiazolidinediones TZDs are PPARγ agonists used for treating type 2 diabetes Kelly et al. TZDs, such as rosiglitazone and pioglitazone, enhance insulin sensitivity by improving adipokine profiles Maeda et al. TZDs also promote insulin sensitivity by directing fatty acids to subcutaneous fat, rather than visceral fat.

Subcutaneous fat expandability, even in the context of obesity and type 2 diabetes, correlates with insulin sensitivity in rodents and humans Ross et al. Numerous in vitro and in vivo studies demonstrate TZDs enhance mitochondrial biogenesis, content, function, and morphology.

Rosiglitazone also induces cellular antioxidant enzymes responsible for the removal of ROS generated by increased mitochondrial activity in adipose tissue of diabetic rodents Rong et al. Taken together, TZDs impact WAT mitochondrial function in multiple ways that ultimately improve systemic fat metabolism and insulin sensitivity.

Other therapeutic strategies include mitochondria-targeted scavengers Smith et al. However, these methods to enhance mitochondrial function display a narrow therapeutic range that limits safe use for obesity. Although the development of insulin resistance does not require impaired mitochondrial function Hancock et al.

Aerobic exercise and caloric restriction disrupt this vicious loop, potentially by preventing accumulation of injured mitochondrial proteins with substantial improvement of insulin sensitivity.

In insulin-resistant people, aerobic exercise stimulates both mitochondrial biogenesis and efficiency concurrent with an enhancement of insulin action Mul et al. Ultimately, exercise engages pathways that reduce ROS coupled with insulin sensitivity and improved mitochondrial function in WAT.

Obesity is the result of excessive expansion of WAT depots due to a chronic imbalance between energy intake and expenditure. Many studies demonstrate that oxidative stress in fat cells links obesity and its comorbidities. The fact that WAT remains the sole organ for storing surfeit lipid renders the macromolecules in adipocytes particularly vulnerable to carbonylation and other modifications driven by oxidative stress.

Prolonged oxidative stress negatively influences endocrine and homeostatic performance of WAT, including disruption of hormone secretion, elevation of serum lipids, inadequate cellular antioxidant defenses, and impaired mitochondrial function Figure 2.

Metabolic challenges, such as persistent nutrient intake and sedentary behaviors that promote impaired glucose and lipid handling, also elevate mitochondrial ROS production to cause adipocyte dysfunction. Consequently, adipocytes cannot engage appropriate transcriptional and energetic responses to enable insulin sensitivity.

Figure 2. Impact of oxidative stress on adipocyte function. Increased plasma glucose and free fatty acids contribute to increased oxidative stress by increasing the production of reactive oxygen species ROS and decreasing antioxidant concentrations.

Increased oxidative stress occurs via enzymes in the cytoplasm, such as NADPH oxidase, and the mitochondria. The oxidative environment increases lipid storage resulting in hypertrophic adipocytes. Additionally, increased mitochondrial ROS mtROS alters the activity state of metabolic enzymes either directly or by changing the oxidative state of protein side-chains or by other post-translational modifications, including lipid peroxidation and protein carbonylation.

Cumulatively, increased adipocyte oxidative stress decreases adipogenesis and secretion of adipokines, leading to unbalanced energy homeostasis, insulin resistance, and type 2 diabetes. The increasing prevalence of obesity suggests lifestyle intervention as the principal method to treat obesity is unlikely to succeed.

Currently, all available anti-obesity medications act by limiting energy intake through appetite suppression or inhibition of intestinal lipid absorption. However, these medications are largely ineffective and often have adverse side effects.

The central role of mitochondria in nutrient handling provides a logical entry point for improving metabolism in obesity. While approaches to understanding and intervening in oxidative damage evolve, exploration of mitochondria redox balance may enable development of dietary and small molecule therapies for obesity and its comorbidities.

This work was funded by the American Diabetes Association IBS and NIH R01DK The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Save this study. Warning You have reached the maximum number of saved studies Brown Fat Activation and Browning Efficiency Augmented by Chronic Cold and Nutraceuticals for Brown Adipose Tissue-mediated Effect Against Metabolic Syndrome BEACON BEAMS Study The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.

Listing a study does not mean it has been evaluated by the U. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. gov Identifier: NCT Recruitment Status : Recruiting First Posted : October 20, Last Update Posted : February 23, See Contacts and Locations.

View this study on the modernized ClinicalTrials. Singapore Institute of Food and Biotechnology Innovation SIFBI. Melvin Leow, Singapore Institute for Clinical Sciences.

Study Details Tabular View No Results Posted Disclaimer How to Read a Study Record. Study Description. Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information. Show detailed description. Hide detailed description.

Detailed Description:. The participants will then be required to come for the 4th visit third test session and 5th visit fourth test session at week 12 after completing the 3 months of intervention , as per follows: On the 4th visit third test session at week 12, participants will repeat the same procedures as per that of the 2nd visit first test session.

Resource links provided by the National Library of Medicine MedlinePlus related topics: Metabolic Syndrome. Genetic and Rare Diseases Information Center resources: Chronic Graft Versus Host Disease.

FDA Resources. Arms and Interventions. Subjects will consume mg of curcumin daily for the next 12 weeks or 3 months. Subject will consume mg of curcumin a naturally-occurring polyphenol antioxidant that is found in turmeric ginger rhizome root. Subjects will undergo a mild cold stimulation of about 14 degrees Celsius by wearing a cooling vest for approximately an hour and consume mg of curcumin daily for the next 12 weeks or 3 months.

Subject wear a cooling vest and consume mg of curcumin. Outcome Measures. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Layout table for eligibility information Ages Eligible for Study: 21 Years to 50 Years Adult Sexes Eligible for Study: All Accepts Healthy Volunteers: Yes Criteria.

anaphylaxis to peanuts Having active Tuberculosis TB or currently receiving treatment for TB Have any known Chronic Infection or known to suffer from or have previously suffered from or is a carrier of Hepatitis B Virus HBV , Hepatitis C Virus HCV , Human Immunodeficiency Virus HIV Are a member of the research team or their immediate family members.

Immediate family member is defined as a spouse, parent, child, or sibling, whether biological or legally adopted. Enrolled in a concurrent research study judged not to be scientifically or medically compatible with the study of the CNRC Have poor veins impeding venous access Have any history of severe vasovagal syncope blackouts or near faints following blood draws History of surgery with metallic clips, staples or stents Presence of cardiac pacemaker or other foreign body in any part of the body History of claustrophobia particularly in a MRI scanner.

Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials.

gov identifier NCT number : NCT More Information. Layout table for additonal information Responsible Party: Melvin Leow, Principal Investigator, Singapore Institute for Clinical Sciences ClinicalTrials. FDA-regulated Drug Product: No Studies a U.

FDA-regulated Device Product: No Additional relevant MeSH terms:. Layout table for MeSH terms Metabolic Syndrome Insulin Resistance Hyperinsulinism Glucose Metabolism Disorders Metabolic Diseases.

For Patients and Families For Researchers For Study Record Managers. The increasing prevalence of obesity suggests lifestyle intervention as the principal method to treat obesity is unlikely to succeed.

Currently, all available anti-obesity medications act by limiting energy intake through appetite suppression or inhibition of intestinal lipid absorption. However, these medications are largely ineffective and often have adverse side effects. The central role of mitochondria in nutrient handling provides a logical entry point for improving metabolism in obesity.

While approaches to understanding and intervening in oxidative damage evolve, exploration of mitochondria redox balance may enable development of dietary and small molecule therapies for obesity and its comorbidities. This work was funded by the American Diabetes Association IBS and NIH R01DK The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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