Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity

Bartelt, Alexander; Widenmaier, Scott B.; Schlein, Christian; Johann, Kornelia; Gonçalves, Renata L.S.; Eguchi, Kosei; Fischer, Alexander W.; Parlakgül, Güneş; Snyder, Nicole A.; Nguyen, Truc; Bruns, Oliver T.; Franke, Daniel; Bawendi, Moungi G.; Lynes, Matthew D.; Leiria, Luiz O.; Tseng, Yu‐Hua; Inouye, Karen; Arruda, Ana Paula; Hotamışlıgil, Gökhan S.

doi:10.1038/nm.4481

Cited by 175 publications

(246 citation statements)

References 72 publications

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“…In addition, BAT of the CLtreated group showed smaller lipid droplets (Fig. 6D), as reported previously [44,45]. These results indicate that the CL treatment had beneficial effects on HFDinduced obesity, and that the effects of the treatment were associated with the induction of UCP1 expression in BAT.…”

Section: Ucp1-mrfp1 Bac Tg Mice Can Be Used To Track Sequential Changsupporting

confidence: 89%

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A new mouse model for noninvasive fluorescence‐based monitoring of mitochondrial UCP1 expression

et al. 2019

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Mitochondrial uncoupling protein 1 (UCP1) is well known for its thermogenic function in brown adipose tissue (BAT). Since UCP1 expends energy on thermogenesis, UCP1 activation has been considered an approach to ameliorate obesity. As a tool for uncovering yet unknown mechanisms of UCP1 activation, we generated a transgenic mouse model in which UCP1 expression levels are reflected in fluorescence derived from monomeric red fluorescent protein 1 (mRFP1). In these UCP1‐mRFP1 BAC transgenic mice, fluorescence intensity mimics the change in UCP1 expression levels evoked through physiological or pharmacological stimulation. This transgenic mouse model will be useful in the search for bioactive compounds with the ability to induce UCP1 and for revealing undiscovered mechanisms of BAT activation.

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Section: Ucp1-mrfp1 Bac Tg Mice Can Be Used To Track Sequential Changsupporting

confidence: 89%

“…6A) and significantly lower plasma triglyceride concentrations (Fig. 6D), as reported previously [44,45]. In BAT, Ucp1 and mRfp1 mRNA expression levels were higher in the CL-treated group (Fig.…”

Section: Ucp1-mrfp1 Bac Tg Mice Can Be Used To Track Sequential Changsupporting

confidence: 88%

A new mouse model for noninvasive fluorescence‐based monitoring of mitochondrial UCP1 expression

et al. 2019

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“…Nrf1 is considered to play a key role in cellular responses to stress and ablation of this protein in white adipocytes leading to reduced adipose tissue mass which is in keeping with the phenotype here reported in p107‐ablated mice although they also exhibited a marked insulin resistance in contrast to our ablated p107‐mice. Indeed the overexpression of Nrf1 in BAT resulted in improved insulin sensitivity …”

Section: Discussionmentioning

confidence: 99%

p107 Deficiency Increases Energy Expenditure by Inducing Brown‐Fat Thermogenesis and Browning of White Adipose Tissue

Cuñarro

Buqué

Casado

et al. 2018

Molecular Nutrition Food Res

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Scope The tumor suppressor p107, a pocket protein member of the retinoblastoma susceptibility protein family, plays an important role in the cell cycle and cellular adipocyte differentiation. Nonetheless, the mechanism by which it influences whole body Energy homeostasis is unknown. Methods and Results The phenotype of p107 knockout (KO) mixed‐background C57BL6/129 mice phenotype is studied by focusing on the involvement of white and brown adipose tissue (WAT and BAT) in energy metabolism. It is shown that p107 KO mice are leaner and have high‐fat diet resistence. This phenomenon is explained by an increase of energy expenditure. The higher energy expenditure is caused by the activation of thermogenesis and may be mediated by both BAT and the browning of WAT. Consequently, it leads to the resistance of p107 KO mice to high‐fat diet effects, prevention of liver steatosis, and improvement of the lipid profile and glucose homeostasis. Conclusion These data allowed the unmasking of a mechanism by which a KO of p107 prevents diet‐induced obesity by increasing energy expenditure via increased thermogenesis in BAT and browning of WAT, indicating the relevance of p107 as a modulator of metabolic activity of both brown and white adipocytes. Therefore, it can be targeted for the development of new therapies to ameliorate the metabolic syndrome.

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“…Correlation between mRNA-protein pairs is less consistent in transcripts or proteins that decrease after mild or severe cold acclimation ( Fig 3C), which may suggest regulation via protein translation or degradation. Indeed, a recent study found that proteasomal activity increases in cold-adapted BAT, and is important for effective thermogenesis 17 . Unlike at the protein level, there was no increase in transcripts encoding for inner or outer mitochondrial membrane, or ETC proteins, relative to mitochondrial matrix proteins after cold acclimation ( Fig 3E).…”

Section: Overlap Between the Cold-induced Transcriptome And Proteomementioning

confidence: 99%

Cold-Induced Thermogenesis Increases Acetylation on the Brown Fat Proteome and Metabolome

Sanchez-Gurmaches

et al. 2018

Preprint

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Stimulating brown adipose tissue (BAT) energy expenditure could be a therapy for obesity and related metabolic diseases. Achieving this requires a systems-level understanding of the biochemical underpinnings of thermogenesis. To identify novel metabolic features of active BAT, we measured protein abundance, protein acetylation, and metabolite levels in BAT isolated from mice living in their thermoneutral zone or in colder environments. We find that the enzymes which synthesize lipids from cytosolic acetyl-coA are among the most robustly increased proteins after cold acclimation, consistent with recent studies highlighting the importance of anabolic de novo lipogenesis in BAT. In addition, many mitochondrial proteins are hyperacetylated by cold acclimation, including several sites on UCP1, which may have functional relevance. Metabolomics analysis further reveals cold-dependent increases to acetylated carnitine and several amino acids. This BAT multi-omics resource highlights widespread proteomic and metabolic changes linked to acetyl-CoA synthesis and utilization that may be useful in unraveling the remarkable metabolic properties of active BAT. RESULTS Cold adaptation upregulates lipid synthesis, glucose metabolism, and electron transport chain complex I-II proteinsFirst, we explored proteomic signatures of chronic cold-induced BAT activation by acclimating mice to three different temperature conditions: thermoneutrality (30°C, which is preferred by mice 14 ), room temperature (which is mildly cold for mice, 22°C) and severe cold (6°C) (Fig 1A). Following the temperature acclimation period, BAT was harvested and subjected to proteome analysis. The number of confidently detected proteins is consistent across all samples, ranging from 1857 to 2432 ( Fig 1B). Differential protein expression was determined by comparing each cold condition to thermoneutrality. We identified 60 proteins altered (~3%, 26 increasing, 34 decreasing) in response to mild cold and 232 proteins altered (~11%, 119 increasing, 113 decreasing) in response to severe cold ( Fig 1C) indicating a thermogenic proteome response that scales with cold severity.We would like to thank all members of the Villen lab for critical discussions and feedback on the project. This work was supported by NIH grants R01 CA196986 (to D.A.G.); R35 GM119536, R01 AG056359, and R01 NS098329 (to J.V.); R37 DK030898 and R01 DK103047 (to M.P.C.). S.W.E. and R.T.L were both supported by Samuel and Althea Stroum Endowed Graduate Fellowships.

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Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity

Cited by 175 publications

References 72 publications

A new mouse model for noninvasive fluorescence‐based monitoring of mitochondrial UCP1 expression

A new mouse model for noninvasive fluorescence‐based monitoring of mitochondrial UCP1 expression

p107 Deficiency Increases Energy Expenditure by Inducing Brown‐Fat Thermogenesis and Browning of White Adipose Tissue

Cold-Induced Thermogenesis Increases Acetylation on the Brown Fat Proteome and Metabolome

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