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Kikukatsu Ito - One of the best experts on this subject based on the ideXlab platform.
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Thioredoxin o-mediated reduction of mitochondrial alternative oxidase in the Thermogenic skunk cabbage Symplocarpus renifolius.
Journal of biochemistry, 2018Co-Authors: Yui Umekawa, Kikukatsu ItoAbstract:Thermogenesis in plants involves significant increases in their cyanide-resistant mitochondrial alternative oxidase (AOX) capacity. Because AOX is a non-proton-motive ubiquinol oxidase, the dramatic drop in free energy between ubiquinol and oxygen is dissipated as heat. In the Thermogenic skunk cabbage (Symplocarpus renifolius), SrAOX is specifically expressed in the florets. Although SrAOX harbours conserved cysteine residues, the details of the mechanisms underlying its redox regulation are poorly understood. In our present study, the two mitochondrial thioredoxin o cDNAs SrTrxo1 and SrTrxo2, were isolated from the Thermogenic florets of S. renifolius. The deduced amino acid sequences of the protein products revealed that SrTrxo2 specifically lacks the region corresponding to the α3-helix in SrTrxo1. Expression analysis of Thermogenic and non-Thermogenic S. renifolius tissues indicated that the SrTrxo1 and SrAOX transcripts are predominantly expressed together in Thermogenic florets, whereas SrTrxo2 transcripts are almost undetectable in any tissue. Finally, functional in vitro analysis of recombinant SrTrxo1 and mitochondrial membrane fractions of Thermogenic florets indicated its reducing activity on SrAOX proteins. Taken together, these results indicate that SrTrxo1 is likely to play a role in the redox regulation of SrAOX in S. renifolius Thermogenic florets.
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In vivo redox state of the ubiquinone pool in the spadices of the Thermogenic skunk cabbage, Symplocarpus renifolius.
Journal of plant research, 2009Co-Authors: Takashi Kamata, Kazushige Matsukawa, Yusuke Kakizaki, Kikukatsu ItoAbstract:In vivo ubiquinone (UQ) reduction levels were determined in Thermogenic stigma and post-Thermogenic male stages of spadices of the skunk cabbage, Symplocarpus renifolius. In contrast to Arum maculatum, in which the UQ pool is almost fully reduced during thermogenesis, the reduction levels of UQ9 and UQ10 were not affected by the Thermogenic status or developmental stage of individual S. renifolius spadices. Moreover, these levels were controlled within the ranges 40-75% and 35-60%, respectively. These results suggest that the reduction state of the UQ pool per se is not primarily involved in thermoregulation in S. renifolius.
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Expression of uncoupling protein and alternative oxidase depends on lipid or carbohydrate substrates in Thermogenic plants.
Biology letters, 2005Co-Authors: Kikukatsu Ito, Roger S. SeymourAbstract:Thermogenesis, in which cellular respiratory activity is considerably stimulated, requires mitochondrial uncoupling protein (UCP) in mammals and an alternative oxidase (AOX) in plants. Here, we show that the genes for both proteins are expressed in Thermogenic plants, but the type correlates with the respiratory substrate. A novel gene termed PsUCPa encoding a variant of UCP was specifically expressed in Thermogenic flowers of Philodendron selloum, which uses lipids as substrates. However, a gene termed DvAOX encoding for AOX protein was expressed in Thermogenic flowers of Dracunculus vulgaris, which presumably uses carbohydrates as substrates. These findings suggest that cellular metabolism is a major determinant in selective expression of appropriate Thermogenic genes in plants.
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Changes in the composition of xylem sap during development of the spadix of skunk cabbage (Symplocarpus foetidus).
Bioscience biotechnology and biochemistry, 2005Co-Authors: Yoshihiko Onda, Kikukatsu ItoAbstract:The spadix of skunk cabbage, Symplocarpus foetidus, is Thermogenic and maintains an internal temperature of around 20 degrees C even when the ambient air temperature drops below freezing. This homeothermic heat production is observed only during the stigma stage, and thereafter ceases at the male stage when pollen is shed. To clarify the regulatory mechanism by which the stigma stage-specific heat production occurs in the spadix, sugars, organic acids, and amino acids in xylem sap were analyzed and compared with those of post-Thermogenic plants. Interestingly, no significant difference was observed in the total volume of xylem sap per fresh weight of the spadix between Thermogenic (31.2+/-24.7 microl h(-1) g(-1)) and post-Thermogenic (50.5+/-30.4 microl h(-1) g(-1)) plants. However, concentrations of sugars (sucrose, glucose, and fructose), organic acids (malate and succinate), and amino acids (Asp, Asn, Glu, Gln, Gly, and Ala) in xylem sap decreased remarkably in post-Thermogenic plants. Our results indicate that the composition of the xylem sap differs during the development of the spadix of S. foetidus.
Hei Sook Sul - One of the best experts on this subject based on the ideXlab platform.
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Dot1l interacts with Zc3h10 to activate Ucp1 and other Thermogenic genes
eLife, 2020Co-Authors: Hai P. Nguyen, Jennie Dinh, Jose A. Viscarra, Ying Xie, Frances Lin, Madeleine Zhu, Jon Dempersmier, Yuhui Wang, Hei Sook SulAbstract:Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1l, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the Ucp1 promoter and other BAT genes. Through a direct interaction, Dot1l is recruited by Zc3h10 to the promoter regions of Thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1l is induced during brown fat cell differentiation and by cold exposure and that Dot1l and its H3K79 methyltransferase activity is required for Thermogenic gene program. Furthermore, we demonstrate that Dot1l ablation in mice using Ucp1-Cre prevents activation of Ucp1 and other target genes to reduce Thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1l plays a critical role in the Thermogenic program and may present as a future target for obesity therapeutics.
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Epigenetic dynamics of the Thermogenic gene program of adipocytes.
The Biochemical journal, 2020Co-Authors: Hai P. Nguyen, Hei Sook SulAbstract:Brown adipose tissue (BAT) is a metabolically beneficial organ capable of burning fat by dissipating chemical energy into heat, thereby increasing energy expenditure. Moreover, subcutaneous white adipose tissue can undergo so-called browning/beiging. The recent recognition of the presence of brown or beige adipocytes in human adults has attracted much attention to elucidate the molecular mechanism underlying the Thermogenic adipose program. Many key transcriptional regulators critical for the Thermogenic gene program centering on activating the UCP1 promoter, have been discovered. Thermogenic gene expression in brown adipocytes rely on co-ordinated actions of a multitude of transcription factors, including EBF2, PPARγ, Zfp516 and Zc3h10. These transcription factors probably integrate into a cohesive network for BAT gene program. Moreover, these transcription factors recruit epigenetic factors, such as LSD1 and MLL3/4, for specific histone signatures to establish the favorable chromatin landscape. In this review, we discuss advances made in understanding the molecular mechanism underlying the Thermogenic gene program, particularly epigenetic regulation.
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Zc3h10 Acts as a Transcription Factor and Is Phosphorylated to Activate the Thermogenic Program.
Cell reports, 2019Co-Authors: Jon Dempersmier, Hai P. Nguyen, Jennie Dinh, Jose A. Viscarra, Yuhui Wang, Chihiro Tabuchi, Hei Sook SulAbstract:Brown adipose tissue harbors UCP1 to dissipate chemical energy as heat. However, the transcriptional network that governs the Thermogenic gene program is incompletely understood. Zc3h10, a CCCH-type zinc finger protein, has recently been reported to bind RNA. However, we report here that Zc3h10 functions as a transcription factor to activate UCP1 not through the enhancer region, but by binding to a far upstream region of the UCP1 promoter. Upon sympathetic stimulation, Zc3h10 is phosphorylated at S126 by p38 mitogen-activated protein kinase (MAPK) to increase binding to the distal region of the UCP1 promoter. Zc3h10, as well as mutant Zc3h10, which cannot bind RNA, enhances Thermogenic capacity and energy expenditure, protecting mice from diet-induced obesity. Conversely, Zc3h10 ablation in UCP1+ cells in mice impairs Thermogenic capacity and lowers oxygen consumption, leading to weight gain. Hence, Zc3h10 plays a critical role in the Thermogenic gene program and may present future targets for obesity therapeutics.
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Epigenetic Regulation of the Thermogenic Adipose Program
Trends in endocrinology and metabolism: TEM, 2016Co-Authors: Audrey Sambeat, Jon Dempersmier, Olga Gulyaeva, Hei Sook SulAbstract:In contrast to white adipose tissue (WAT), which stores energy in the form of triglycerides, brown adipose tissue (BAT) dissipates energy by producing heat to maintain body temperature by burning glucose and fatty acids in a process called adaptive thermogenesis. The presence of an inducible Thermogenic adipose tissue, and its beneficial effects for maintaining body weight and glucose and lipid homeostasis, has raised intense interest in understanding the regulation of thermogenesis. Elucidating the regulatory mechanisms underlying the Thermogenic adipose program may provide excellent targets for therapeutics against obesity and diabetes. Here we review recent research on the role of epigenetics in the Thermogenic gene program, focusing on DNA methylation and histone modifications.
Hai P. Nguyen - One of the best experts on this subject based on the ideXlab platform.
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Dot1l interacts with Zc3h10 to activate Ucp1 and other Thermogenic genes
eLife, 2020Co-Authors: Hai P. Nguyen, Jennie Dinh, Jose A. Viscarra, Ying Xie, Frances Lin, Madeleine Zhu, Jon Dempersmier, Yuhui Wang, Hei Sook SulAbstract:Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1l, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the Ucp1 promoter and other BAT genes. Through a direct interaction, Dot1l is recruited by Zc3h10 to the promoter regions of Thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1l is induced during brown fat cell differentiation and by cold exposure and that Dot1l and its H3K79 methyltransferase activity is required for Thermogenic gene program. Furthermore, we demonstrate that Dot1l ablation in mice using Ucp1-Cre prevents activation of Ucp1 and other target genes to reduce Thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1l plays a critical role in the Thermogenic program and may present as a future target for obesity therapeutics.
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Epigenetic dynamics of the Thermogenic gene program of adipocytes.
The Biochemical journal, 2020Co-Authors: Hai P. Nguyen, Hei Sook SulAbstract:Brown adipose tissue (BAT) is a metabolically beneficial organ capable of burning fat by dissipating chemical energy into heat, thereby increasing energy expenditure. Moreover, subcutaneous white adipose tissue can undergo so-called browning/beiging. The recent recognition of the presence of brown or beige adipocytes in human adults has attracted much attention to elucidate the molecular mechanism underlying the Thermogenic adipose program. Many key transcriptional regulators critical for the Thermogenic gene program centering on activating the UCP1 promoter, have been discovered. Thermogenic gene expression in brown adipocytes rely on co-ordinated actions of a multitude of transcription factors, including EBF2, PPARγ, Zfp516 and Zc3h10. These transcription factors probably integrate into a cohesive network for BAT gene program. Moreover, these transcription factors recruit epigenetic factors, such as LSD1 and MLL3/4, for specific histone signatures to establish the favorable chromatin landscape. In this review, we discuss advances made in understanding the molecular mechanism underlying the Thermogenic gene program, particularly epigenetic regulation.
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Zc3h10 Acts as a Transcription Factor and Is Phosphorylated to Activate the Thermogenic Program.
Cell reports, 2019Co-Authors: Jon Dempersmier, Hai P. Nguyen, Jennie Dinh, Jose A. Viscarra, Yuhui Wang, Chihiro Tabuchi, Hei Sook SulAbstract:Brown adipose tissue harbors UCP1 to dissipate chemical energy as heat. However, the transcriptional network that governs the Thermogenic gene program is incompletely understood. Zc3h10, a CCCH-type zinc finger protein, has recently been reported to bind RNA. However, we report here that Zc3h10 functions as a transcription factor to activate UCP1 not through the enhancer region, but by binding to a far upstream region of the UCP1 promoter. Upon sympathetic stimulation, Zc3h10 is phosphorylated at S126 by p38 mitogen-activated protein kinase (MAPK) to increase binding to the distal region of the UCP1 promoter. Zc3h10, as well as mutant Zc3h10, which cannot bind RNA, enhances Thermogenic capacity and energy expenditure, protecting mice from diet-induced obesity. Conversely, Zc3h10 ablation in UCP1+ cells in mice impairs Thermogenic capacity and lowers oxygen consumption, leading to weight gain. Hence, Zc3h10 plays a critical role in the Thermogenic gene program and may present future targets for obesity therapeutics.
Jon Dempersmier - One of the best experts on this subject based on the ideXlab platform.
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Dot1l interacts with Zc3h10 to activate Ucp1 and other Thermogenic genes
eLife, 2020Co-Authors: Hai P. Nguyen, Jennie Dinh, Jose A. Viscarra, Ying Xie, Frances Lin, Madeleine Zhu, Jon Dempersmier, Yuhui Wang, Hei Sook SulAbstract:Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1l, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the Ucp1 promoter and other BAT genes. Through a direct interaction, Dot1l is recruited by Zc3h10 to the promoter regions of Thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1l is induced during brown fat cell differentiation and by cold exposure and that Dot1l and its H3K79 methyltransferase activity is required for Thermogenic gene program. Furthermore, we demonstrate that Dot1l ablation in mice using Ucp1-Cre prevents activation of Ucp1 and other target genes to reduce Thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1l plays a critical role in the Thermogenic program and may present as a future target for obesity therapeutics.
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Zc3h10 Acts as a Transcription Factor and Is Phosphorylated to Activate the Thermogenic Program.
Cell reports, 2019Co-Authors: Jon Dempersmier, Hai P. Nguyen, Jennie Dinh, Jose A. Viscarra, Yuhui Wang, Chihiro Tabuchi, Hei Sook SulAbstract:Brown adipose tissue harbors UCP1 to dissipate chemical energy as heat. However, the transcriptional network that governs the Thermogenic gene program is incompletely understood. Zc3h10, a CCCH-type zinc finger protein, has recently been reported to bind RNA. However, we report here that Zc3h10 functions as a transcription factor to activate UCP1 not through the enhancer region, but by binding to a far upstream region of the UCP1 promoter. Upon sympathetic stimulation, Zc3h10 is phosphorylated at S126 by p38 mitogen-activated protein kinase (MAPK) to increase binding to the distal region of the UCP1 promoter. Zc3h10, as well as mutant Zc3h10, which cannot bind RNA, enhances Thermogenic capacity and energy expenditure, protecting mice from diet-induced obesity. Conversely, Zc3h10 ablation in UCP1+ cells in mice impairs Thermogenic capacity and lowers oxygen consumption, leading to weight gain. Hence, Zc3h10 plays a critical role in the Thermogenic gene program and may present future targets for obesity therapeutics.
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Epigenetic Regulation of the Thermogenic Adipose Program
Trends in endocrinology and metabolism: TEM, 2016Co-Authors: Audrey Sambeat, Jon Dempersmier, Olga Gulyaeva, Hei Sook SulAbstract:In contrast to white adipose tissue (WAT), which stores energy in the form of triglycerides, brown adipose tissue (BAT) dissipates energy by producing heat to maintain body temperature by burning glucose and fatty acids in a process called adaptive thermogenesis. The presence of an inducible Thermogenic adipose tissue, and its beneficial effects for maintaining body weight and glucose and lipid homeostasis, has raised intense interest in understanding the regulation of thermogenesis. Elucidating the regulatory mechanisms underlying the Thermogenic adipose program may provide excellent targets for therapeutics against obesity and diabetes. Here we review recent research on the role of epigenetics in the Thermogenic gene program, focusing on DNA methylation and histone modifications.
Marta Giralt - One of the best experts on this subject based on the ideXlab platform.
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FGF15/19 is required for adipose tissue plasticity in response to Thermogenic adaptations.
Molecular metabolism, 2020Co-Authors: Samantha Morón-ros, Marta Giralt, Iker Uriarte, Carmen Berasain, Matias A Avila, Francesc Villarroya, Mònica Sabater-masdeu, José María Moreno-navarrete, José Manuel Fernández-real, Aleix Gavaldà-navarroAbstract:Abstract Objective To determine the role of the enterokine, FGF15/19, in adipose tissue Thermogenic adaptations. Methods Circulating FGF19 and gene expression (qRT-PCR) levels were assessed in subcutaneous adipose tissue from human patients with obesity. Effects of experimentally increased FGF15 and FGF19 levels in vivo were determined in mice using adenoviral and adeno-associated vectors. Adipose tissues were characterized in FGF15-null mice under distinct cold-related Thermogenic challenges. The analyses performed spanned metabolic profiling, tissue characterization, histology, gene expression and immunoblot assays. Results In humans, FGF19 levels are directly associated with UCP1 gene expression in subcutaneous adipose tissue. Experimental increases of FGF15 or FGF19 induced white fat browning in mice, as evidence by the appearance of multilocular beige cells and markers indicative of a beige phenotype, including increased UCP1 protein levels. Mice lacking FGF15 showed markedly impaired white adipose tissue browning and a mild reduction in parameters indicative of BAT activity in response to cold-induced environmental Thermogenic challenges. This was concomitant with signs of altered systemic metabolism, such as reduced glucose tolerance and impaired cold-induced insulin sensitization. Conclusions The enterokine FGF15/19 is a key factor required for adipose tissue plasticity in response to Thermogenic adaptations.
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the kallikrein kinin pathway as a mechanism for auto control of brown adipose tissue activity
Nature Communications, 2020Co-Authors: Marion Peyrou, Ruben Cereijo, Tania Quesadalopez, Laura Campderros, Aleix Gavaldanavarro, Laura Linarespose, Elena Kaschina, Thomas Unger, Miguel Lopez, Marta GiraltAbstract:Brown adipose tissue (BAT) is known to secrete regulatory factors in response to Thermogenic stimuli. Components of the BAT secretome may exert local effects that contribute to BAT recruitment and activation. Here, we found that a Thermogenic stimulus leads to enhanced secretion of kininogen (Kng) by BAT, owing to induction of kininogen 2 (Kng2) gene expression. Noradrenergic, cAMP-mediated signals induce KNG2 expression and release in brown adipocytes. Conversely, the expression of kinin receptors, that are activated by the Kng products bradykinin and [Des-Arg9]-bradykinin, are repressed by Thermogenic activation of BAT in vivo and of brown adipocytes in vitro. Loss-of-function models for Kng (the circulating-Kng-deficient BN/Ka rat) and bradykinin (pharmacological inhibition of kinin receptors, kinin receptor-null mice) signaling were coincident in showing abnormal overactivation of BAT. Studies in vitro indicated that Kng and bradykinin exert repressive effects on brown adipocyte Thermogenic activity by interfering the PKA/p38 MAPK pathway of control of Ucp1 gene transcription, whereas impaired kinin receptor expression enhances it. Our findings identify the kallikrein-kinin system as a relevant component of BAT Thermogenic regulation that provides auto-regulatory inhibitory signaling to BAT.
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The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes
Nature Communications, 2016Co-Authors: Tania Quesada-lópez, Ruben Cereijo, Anna Planavila, Montserrat Cairo, Ricardo Moure, Aleix Gavaldà-navarro, Roser Iglesias, Marion Peyrou, Jean Valery Turatsinze, Marta GiraltAbstract:GPR120 is a G-protein-coupled receptor that binds polyunsaturated fatty acids. Here, the authors show that GPR120 is upregulated in brown fat in cold-exposed mice, and mediates Thermogenic activation of brown fat via a mechanism that, at least in part, depends on the release of the adipokine FGF21. The Thermogenic activity of brown adipose tissue (BAT) and browning of white adipose tissue are important components of energy expenditure. Here we show that GPR120, a receptor for polyunsaturated fatty acids, promotes brown fat activation. Using RNA-seq to analyse mouse BAT transcriptome, we find that the gene encoding GPR120 is induced by Thermogenic activation. We further show that GPR120 activation induces BAT activity and promotes the browning of white fat in mice, whereas GRP120-null mice show impaired cold-induced browning. Omega-3 polyunsaturated fatty acids induce brown and beige adipocyte differentiation and Thermogenic activation, and these effects require GPR120. GPR120 activation induces the release of fibroblast growth factor-21 (FGF21) by brown and beige adipocytes, and increases blood FGF21 levels. The effects of GPR120 activation on BAT activation and browning are impaired in FGF21-null mice and cells. Thus, the lipid sensor GPR120 activates brown fat via a mechanism that involves induction of FGF21.
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Thermogenic activation represses autophagy in brown adipose tissue.
International journal of obesity (2005), 2016Co-Authors: Montserrat Cairo, Ruben Cereijo, Marta Giralt, Laura Campderros, Joan Villarroya, Francesc VillarroyaAbstract:Background Brown adipose tissue (BAT) thermogenesis is an adaptive process, essential for energy expenditure and involved in the control of obesity. Obesity is associated with abnormally increased autophagy in white adipose tissue. Autophagy has been proposed as relevant for brown-vs-white adipocyte differentiation; however, its role in the response of BAT to Thermogenic activation is unknown. Methods The effects of Thermogenic activation on autophagy in BAT were analyzed in vivo by exposing mice to 24 h cold condition. The effects of norepinephrine (NE), cAMP and modulators of lysosomal activity were determined in differentiated brown adipocytes in the primary culture. Transcript expression was quantified by real-time PCR, and specific proteins were determined by immunoblot. Transmission electron microscopy, as well as confocal microscopy analysis after incubation with specific antibodies or reagents coupled to fluorescent emission, were performed in BAT and cultured brown adipocytes, respectively. Results Autophagy is repressed in association with cold-induced Thermogenic activation of BAT in mice. This effect was mimicked by NE action in brown adipocytes, acting mainly through a cAMP-dependent protein kinase A pathway. Inhibition of autophagy in brown adipocytes leads to an increase in UCP1 protein and uncoupled respiration, suggesting a repressing role for autophagy in relation to the activity of BAT Thermogenic machinery. Under basal conditions, brown adipocytes show signs of active lipophagy, which is suppressed by a cAMP-mediated Thermogenic stimulus. Conclusions Our results show a noradrenergic-mediated inverse relationship between autophagy and Thermogenic activity in BAT and point toward autophagy repression as a component of brown adipocyte adaptive mechanisms to activate thermogenesis.
