Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis

Sanchez-Gurmaches, Joan; Tang, Yun‐Chi; Jespersen, Naja Zenius; Wallace, Martina; Calejman, Camila Martínez; Gujja, Sharvari; Li, Huawei; Edwards, Yvonne J. K.; Wolfrum, Christian; Metallo, Christian M.; Nielsen, Søren; Schéele, Camilla; Guertin, David A.

doi:10.1016/j.cmet.2017.10.008

Cited by 169 publications

(197 citation statements)

References 85 publications

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“…Mild cold acclimation already caused significant increases to de novo lipogenesis proteins including ATP citrate lyase (ACLY, 5.2-fold), the two acetyl-CoA carboxylase isoforms (ACACA, 3.5-fold; and ACACB, 3.2fold), and fatty acid synthase (FASN, 8.5-fold increase) (Figs 1D, 1F, Table S1). This is consistent with previous results indicating that de novo lipogenesis is a central feature of thermogenesis in BAT 15,16 . UCP1 increases 3.7-fold, and the mitochondrial pyruvate carrier 2 (MPC2) increases 3.1-fold after mild cold acclimation ( Fig S1A, Table S1).…”

Section: Introductionsupporting

confidence: 94%

“…Compared to the thermogenic proteome, the RNA-seq transcriptome analyses of these BAT samples, reported in 15 , contains a similar distribution of fold-changes between conditions ( Fig 3A), but a greater percentage of significant changes at a 5% FDR threshold ( Fig 3B). 88% of proteins that significantly increase (q ≤ 0.05) in room temperature acclimation, and 68% of those that significantly increase in severe cold acclimation, also increase at the mRNA level ( Fig 3C).…”

Section: Overlap Between the Cold-induced Transcriptome And Proteomementioning

confidence: 84%

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

Sanchez-Gurmaches

et al. 2018

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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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Section: Introductionsupporting

confidence: 94%

Section: Overlap Between the Cold-induced Transcriptome And Proteomementioning

confidence: 84%

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

Sanchez-Gurmaches

et al. 2018

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“…How BMAL1 regulates the ChREBP transcriptional activity via AKT remains to be determined in future study. A recent study suggests AKT can activate ChREBP in brown adipose tissue upon cold exposure . It is intriguing to speculate that a similar pathway is conserved in hepatocytes in the context of ethanol feeding.…”

Section: Discussionmentioning

confidence: 99%

The hepatic BMAL1/AKT/lipogenesis axis protects against alcoholic liver disease in mice via promoting PPARα pathway

et al. 2018

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“…Thus, it seems plausible that at least part of the beneficial changes in glucose metabolism of the current study are attributed to the reduction in energy intake. However, recent findings in BAT suggest that cold exposure activates the transcription factor carbohydrate-responsive element-binding protein, leading to increased de novo lipogenesis (47). It seems likely that dietary ketones could lead to an increase in glucose disposal within BAT to fuel de novo lipogenesis leading to improvements in glucose metabolism.…”

Section: Discussionmentioning

confidence: 99%

DietaryR, S‐1,3‐butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high‐fat diet

et al. 2018

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The dietary R‐3‐hydroxybutyrate‐R‐1,3‐butanediol monoester increases resting energy expenditure (REE) and markers of brown and white adipose thermogenesis in lean mice. The purpose of this investigation was to determine whether the ketone ester, R,S‐1,3‐butanediol diacetoacetate (BD‐AcAc2), increases energy expenditure and markers of adipose tissue thermogenesis in the context of high‐fat diet (HFD)‐induced obesity. Thirty‐five‐week‐old male C57BL/ 6J mice were placed on an ad libitum HFD (45% kcal) for 10 wk. The mice were then randomized to 1 of 3 groups (n = 10 per group) for an additional 12 wk: 1) control (Con), continuous HFD, 2) pair‐fed (PF) to ketone ester (KE); and 3) KE: HFD +30% energy from BD‐AcAc2. Mean energy intake throughout the study was ∼26% lower in the KE compared to the Con group (8.2 ± 0.5 vs. 11.2 ± 0.7 kcal/d; P < 0.05). Final body weight (26.8 ± 3.6 vs. 34.9 ± 4.8 g; P < 0.001) and fat mass (5.2 ± 1.2 vs. 11.3 ± 4.5 g; P < 0.001) of the KE group was significantly lower than PF, despite being matched for energy provisions. Differences in body weight and adiposity were accompanied by higher REE and total energy expenditure in the KE group compared to PF after adjustment for lean body mass and fat‐mass (P = 0.001 and 0.007, respectively). Coupled or uncoupled mitochondrial respiratory rates in skeletal muscle were not different among groups, but markers of mitochondrial uncoupling and thermogenesis (uncoupling protein‐1, deiodinase‐2, and peroxisome proliferator‐activated receptor y coactivator‐1α) were higher in interscapular brown adipose tissue (BAT) of mice receiving the KE diet. The absence of mitochondrial uncoupling in skeletal muscle and increased markers of mitochondrial uncoupling in BAT suggest that BD‐AcAc2 initiates a transcriptional signature consistent with BAT thermogenesis in the context of HFD‐induced obesity.—Davis, R. A. H., Deemer, S. E., Bergeron, J. M., Little, J. T., Warren, J. L., Fisher, G., Smith, D. L., Jr., Fontaine, K. R., Dickinson, S. L., Allison, D. B., Plaisance, E. P. Dietary R,S‐1,3‐butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high‐fat diet. FASEB J. 33, 2409–2421 (2019). http://www.fasebj.org

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Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis

Cited by 169 publications

References 85 publications

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

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

The hepatic BMAL1/AKT/lipogenesis axis protects against alcoholic liver disease in mice via promoting PPARα pathway

DietaryR, S‐1,3‐butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high‐fat diet

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