UCP1 in Brite/Beige Adipose Tissue Mitochondria Is Functionally Thermogenic

Shabalina, Irina G.; Petrovič, Nataša; Jong, Jasper de; Kalinovich, Anastasia V.; Cannon, Barbara; Nedergaard, Jan

doi:10.1016/j.celrep.2013.10.044

Cited by 532 publications

(422 citation statements)

References 26 publications

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“…Unlike BAT, which has relatively well-defined anatomical locations, beige fat cells are dispersed throughout WAT. Nevertheless, the mechanism of cold-induced Ucp1 expression is shared between BAT and beige fat cells (17), and Ucp1 in beige fat cells has its full thermogenic capacity (42). Therefore, ROS may be essential for inducible Ucp1 expression and Ucp1-mediated thermogenesis in beige fat cells as well.…”

Section: Discussionmentioning

confidence: 99%

Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species

Nam

Jang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Uncoupling protein 1 (Ucp1), which is localized in the mitochondrial inner membrane of mammalian brown adipose tissue (BAT), generates heat by uncoupling oxidative phosphorylation. Upon cold exposure or nutritional abundance, sympathetic neurons stimulate BAT to express Ucp1 to induce energy dissipation and thermogenesis. Accordingly, increased Ucp1 expression reduces obesity in mice and is correlated with leanness in humans. Despite this significance, there is currently a limited understanding of how Ucp1 expression is physiologically regulated at the molecular level. Here, we describe the involvement of Sestrin2 and reactive oxygen species (ROS) in regulation of Ucp1 expression. Transgenic overexpression of Sestrin2 in adipose tissues inhibited both basal and cold-induced Ucp1 expression in interscapular BAT, culminating in decreased thermogenesis and increased fat accumulation. Endogenous Sestrin2 is also important for suppressing Ucp1 expression because BAT from Sestrin2 −/− mice exhibited a highly elevated level of Ucp1 expression. The redox-inactive mutant of Sestrin2 was incapable of regulating Ucp1 expression, suggesting that Sestrin2 inhibits Ucp1 expression primarily through reducing ROS accumulation. Consistently, ROS-suppressing antioxidant chemicals, such as butylated hydroxyanisole and N-acetylcysteine, inhibited cold-or cAMP-induced Ucp1 expression as well. p38 MAPK, a signaling mediator required for cAMP-induced Ucp1 expression, was inhibited by either Sestrin2 overexpression or antioxidant treatments. Taken together, these results suggest that Sestrin2 and antioxidants inhibit Ucp1 expression through suppressing ROSmediated p38 MAPK activation, implying a critical role of ROS in proper BAT metabolism.aging | mouse | homeostasis | β-adrenergic signaling A lthough reactive oxygen species (ROS) are normal products of cellular metabolism, excessive accumulation of ROS resulting from nutritional imbalance and/or environmental stresses can provoke oxidative damage of diverse cellular macromolecules, such as DNA, RNA, and proteins (1). Accumulation of ROS has been associated with diverse degenerative diseases, such as cancer, neurodegeneration, and obesity-associated metabolic syndrome (2-4). To minimize detrimental consequences of ROS accumulation, cells are equipped with various antioxidant proteins, including superoxide dismutases, catalases, peroxiredoxins, and sestrins (5-7). Several ROS-scavenging chemicals or dietary supplements, such as butylated hydroxyanisole (BHA), N-acetylcysteine (NAC), and antioxidant vitamins, can assist with eliminating excessive amounts of ROS (8-10) and were once considered to be potential inhibitors of degenerative diseases associated with aging and obesity (11-13). However, most animal and human clinical studies failed to demonstrate the benefits of dietary antioxidants in restoring metabolic homeostasis or in promoting health and lifespan (13,14).Uncoupling protein 1 (Ucp1) is an anion-carrier protein located in the inner membrane of the mitochondria. By dissipatin...

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Section: Discussionmentioning

confidence: 99%

Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species

Nam

Jang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…It has been shown that in addition to brown fat, brite/beige cells present in iWAT depots also may contribute to thermogenesis (4,26). Thus, we assessed whether ablation of Foxa3 would affect these cells and alter browning in s.c. fat tissues.…”

Section: Ablation Of Foxa3 Protects Against the Development Of Obesitmentioning

confidence: 99%

Role of forkhead box protein A3 in age-associated metabolic decline

Гаврилова

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Aging is associated with increased adiposity and diminished thermogenesis, but the critical transcription factors influencing these metabolic changes late in life are poorly understood. We recently demonstrated that the winged helix factor forkhead box protein A3 (Foxa3) regulates the expansion of visceral adipose tissue in high-fat diet regimens; however, whether Foxa3 also contributes to the increase in adiposity and the decrease in brown fat activity observed during the normal aging process is currently unknown. Here we report that during aging, levels of Foxa3 are significantly and selectively up-regulated in brown and inguinal white fat depots, and that midage Foxa3-null mice have increased white fat browning and thermogenic capacity, decreased adipose tissue expansion, improved insulin sensitivity, and increased longevity. Foxa3 gain-of-function and loss-of-function studies in inguinal adipose depots demonstrated a cell-autonomous function for Foxa3 in white fat tissue browning. Furthermore, our analysis revealed that the mechanisms of Foxa3 modulation of brown fat gene programs involve the suppression of peroxisome proliferator activated receptor γ coactivtor 1 α (PGC1α) levels through interference with cAMP responsive element binding protein 1-mediated transcriptional regulation of the PGC1α promoter. Overall, our data demonstrate a role for Foxa3 in energy expenditure and in age-associated metabolic disorders.obesity | diabetes

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“…In rodents, beige cells can be induced by a variety of stimuli, including β3-selective adrenergic agonists (Ishibashi and Seale, 2010), cold-exposure (Petrovic et al, 2010), exercise (Stanford et al, 2015a,b;Sutherland et al, 2009;Trevellin et al, 2014;Boström et al, 2012;Cao et al, 2011) and an enriched environment (Cao et al, 2011). Upon stimulation, beige adipocytes express very high levels of Ucp1, show increased fuel oxidation and contribute to non-shivering thermogenesis Shabalina et al, 2013). The presence of beige adipocytes in humans has not been studied as extensively as it has in rodents; however, human scWAT has been shown to contain cells that, upon activation, express high levels of UCP1 and other beige markers (Elabd et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Exercise-induced adaptations to white and brown adipose tissue

Lehnig

Stanford

2018

Journal of Experimental Biology

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The beneficial effects of exercise on skeletal muscle and the cardiovascular system have long been known. Recent studies have focused on investigating the effects of exercise on adipose tissue and the effects that these exercise-induced adaptations have on overall metabolic health. Examination of exercise-induced adaptations in both white adipose tissue (WAT) and brown adipose tissue (BAT) has revealed marked differences in each tissue with exercise. In WAT, there are changes to both subcutaneous WAT (scWAT) and visceral WAT (vWAT), including decreased adipocyte size and lipid content, increased expression of metabolic genes, altered secretion of adipokines and increased mitochondrial activity. Adaptations specific to scWAT include lipidomic remodeling of phospholipids and, in rodents, the beiging of scWAT. The changes to BAT are less clear: studies evaluating the effect of exercise on the BAT of humans and rodents have revealed contradictory data, making this an important area of current investigation. In this Review, we discuss the exerciseinduced changes to WAT and BAT that have been reported by different studies and highlight the current questions in this field.

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UCP1 in Brite/Beige Adipose Tissue Mitochondria Is Functionally Thermogenic

Cited by 532 publications

References 26 publications

Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species

Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species

Role of forkhead box protein A3 in age-associated metabolic decline

Exercise-induced adaptations to white and brown adipose tissue

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