bims-mimeim 2021-05-23 papers

Issue of 2021–05–23
four papers selected by
Matthew C. Sinton, University of Glasgow

Nat Metab. 2021 May 17.

UCP1 governs liver extracellular succinate and inflammatory pathogenesis.

Evanna L Mills, Cathal Harmon, Mark P Jedrychowski, Haopeng Xiao, Ryan Garrity, Nhien V Tran, Gary A Bradshaw, Accalia Fu, John Szpyt, Anita Reddy, Hannah Prendeville, Nika N Danial, Steven P Gygi, Lydia Lynch, Edward T Chouchani.

Non-alcoholic fatty liver disease (NAFLD), the most prevalent liver pathology worldwide, is intimately linked with obesity and type 2 diabetes. Liver inflammation is a hallmark of NAFLD and is thought to contribute to tissue fibrosis and disease pathogenesis. Uncoupling protein 1 (UCP1) is exclusively expressed in brown and beige adipocytes, and has been extensively studied for its capacity to elevate thermogenesis and reverse obesity. Here we identify an endocrine pathway regulated by UCP1 that antagonizes liver inflammation and pathology, independent of effects on obesity. We show that, without UCP1, brown and beige fat exhibit a diminished capacity to clear succinate from the circulation. Moreover, UCP1KO mice exhibit elevated extracellular succinate in liver tissue that drives inflammation through ligation of its cognate receptor succinate receptor 1 (SUCNR1) in liver-resident stellate cell and macrophage populations. Conversely, increasing brown and beige adipocyte content in mice antagonizes SUCNR1-dependent inflammatory signalling in the liver. We show that this UCP1-succinate-SUCNR1 axis is necessary to regulate liver immune cell infiltration and pathology, and systemic glucose intolerance in an obesogenic environment. As such, the therapeutic use of brown and beige adipocytes and UCP1 extends beyond thermogenesis and may be leveraged to antagonize NAFLD and SUCNR1-dependent liver inflammation.

DOI: https://doi.org/10.1038/s42255-021-00389-5

Cell Rep. 2021 May 18. pii: S2211-1247(21)00467-8. [Epub ahead of print]35(7): 109128

Hepatic AKT orchestrates adipose tissue thermogenesis via FGF21-dependent and -independent mechanisms.

Jaimarie Sostre-Colón, Kahealani Uehara, Anna E Garcia Whitlock, Matthew J Gavin, Jeff Ishibashi, Matthew J Potthoff, Patrick Seale, Paul M Titchenell.

Organismal stressors such as cold exposure require a systemic response to maintain body temperature. Brown adipose tissue (BAT) is a key thermogenic tissue in mammals that protects against hypothermia in response to cold exposure. Defining the complex interplay of multiple organ systems in this response is fundamental to our understanding of adipose tissue thermogenesis. In this study, we identify a role for hepatic insulin signaling via AKT in the adaptive response to cold stress and show that liver AKT is an essential cell-nonautonomous regulator of adipocyte lipolysis and BAT function. Mechanistically, inhibition of forkhead box O1 (FOXO1) by AKT controls BAT thermogenesis by enhancing catecholamine-induced lipolysis in the white adipose tissue (WAT) and increasing circulating fibroblast growth factor 21 (FGF21). Our data identify a role for hepatic insulin signaling via the AKT-FOXO1 axis in regulating WAT lipolysis, promoting BAT thermogenic capacity, and ensuring a proper thermogenic response to acute cold exposure.

Keywords: FGF21; FOXO1; cold sensitivity; lipolysis; liver insulin signaling; thermogenesis

DOI: https://doi.org/10.1016/j.celrep.2021.109128

Mitochondrion. 2021 May 16. pii: S1567-7249(21)00072-6. [Epub ahead of print]

Mitochondrial dynamics keep balance of nutrient combustion in thermogenic adipocytes.

S S Michurina, I S Stafeev, M Y Menshikov, Ye V Parfyonova.

Non-shivering thermogenesis takes place in brown and beige adipocytes and facilitates cold tolerance and acclimation. However, thermogenesis in adipose tissue also was found to be activated in metabolic overload states for fast utilization of nutrients excess. This observation spurred research interest in mechanisms of thermogenesis regulation for metabolic overload and obesity prevention. One of proposed regulators of thermogenic efficiency in adipocytes is the dynamics of mitochondria, where thermogenesis takes place. Indeed, brown and beige adipocytes exhibit fragmented round-shaped mitochondria, while white adipocytes have elongated organelles with high ATP synthesis. Mitochondrial morphology can determine uncoupling protein 1 (UCP1) content, efficiency of catabolic pathways and electron transport chain, supplying thermogenesis. This review will highlight the co-regulation of mitochondrial dynamics and thermogenesis and formulate hypothetical ways for excessive nutrients burning in response to mitochondrial morphology manipulation .

Keywords: Mitochondrial dynamics; beige fat; brown fat; metabolism; thermogenesis

DOI: https://doi.org/10.1016/j.mito.2021.05.001

Biochim Biophys Acta Mol Cell Biol Lipids. 2021 May 15. pii: S1388-1981(21)00095-0. [Epub ahead of print] 158967

PPARγ-induced upregulation of subcutaneous fat adiponectin secretion, glyceroneogenesis and BCAA oxidation requires mTORC1 activity.

The nutrient sensors peroxisome proliferator-activated receptor γ (PPARγ) and mechanistic target of rapamycin complex 1 (mTORC1) closely interact in the regulation of adipocyte lipid storage. The precise mechanisms underlying this interaction and whether this extends to other metabolic processes and the endocrine function of adipocytes are still unknown. We investigated herein the involvement of mTORC1 as a mediator of the actions of the PPARγ ligand rosiglitazone in subcutaneous inguinal white adipose tissue (iWAT) mass, endocrine function, lipidome, transcriptome and branched-chain amino acid (BCAA) metabolism. Mice bearing regulatory associated protein of mTOR (Raptor) deletion and therefore mTORC1 deficiency exclusively in adipocytes and littermate controls were fed a high-fat diet supplemented or not with the PPARγ agonist rosiglitazone (30 mg/kg/day) for 8 weeks and evaluated for iWAT mass, lipidome, transcriptome (Rnaseq), respiration and BCAA metabolism. Adipocyte mTORC1 deficiency not only impaired iWAT adiponectin transcription, synthesis and secretion, PEPCK mRNA levels, triacylglycerol synthesis and BCAA oxidation and mRNA levels of related proteins but also completely blocked the upregulation in these processes induced by pharmacological PPARγ activation with rosiglitazone. Mechanistically, adipocyte mTORC1 deficiency impairs PPARγ transcriptional activity by reducing PPARγ protein content, as well as by downregulating C/EBPα, a co-partner and facilitator of PPARγ. In conclusion, mTORC1 and PPARγ are essential partners involved in the regulation of subcutaneous adipose tissue adiponectin production and secretion and BCAA oxidative metabolism.

Keywords: Adiponectin secretion; BCAA oxidation; C/EBPα; Glyceroneogenesis; PPARγ; Subcutaneous adipose tissue; mTORC1

DOI: https://doi.org/10.1016/j.bbalip.2021.158967