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Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.

ABSTRACT: Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.

SUBMITTER: Xiao H

PROVIDER: S-EPMC10040263 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.

Xiao Haopeng H Bozi Luiz H M LHM Sun Yizhi Y Riley Christopher L CL Philip Vivek M VM Chen Mandy M Li Jiaming J Zhang Tian T Mills Evanna L EL Emont Margo P MP Sun Wenfei W Reddy Anita A Garrity Ryan R Long Jiani J Becher Tobias T Vitas Laura Potano LP Laznik-Bogoslavski Dina D Ordonez Martha M Liu Xinyue X Chen Xiong X Wang Yun Y Liu Weihai W Tran Nhien N Liu Yitong Y Zhang Yang Y Cypess Aaron M AM White Andrew P AP He Yuchen Y Deng Rebecca R Schöder Heiko H Paulo Joao A JA Jedrychowski Mark P MP Banks Alexander S AS Tseng Yu-Hua YH Cohen Paul P Tsai Linus T LT Rosen Evan D ED Klein Samuel S Chondronikola Maria M McAllister Fiona E FE Van Bruggen Nick N Huttlin Edward L EL Spiegelman Bruce M BM Churchill Gary A GA Gygi Steven P SP Chouchani Edward T ET

Cell 20221104 24

Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the f ...[more]

PMID: 36334589

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Project description:In response to cold or diet, fatty acids are dissipated into heat through uncoupling protein 1 (UCP1) in brown adipose tissue (BAT). This process is termed non-shivering thermogenesis, which is important for body temperature maintenance and contributes to obesity pathogenesis. Thermogenic enhancement has been considered a promising anti-obesity strategy. Ghrelin and its receptor Growth Hormone Secretagogue Receptor (GHS-R) have critical roles in energy intake, nutrient sensing, and lipid metabolism. We previously reported that global Ghsr-knockout mice have increased energy expenditure due to enhanced thermogenesis. To determine the site of action for GHS-R mediated thermogenesis, we generated brown adipocyte-specific Ghsr knockout mice (UCP1-CreER/Ghsrf/f) and assessed thermogenic responses under regular diet (RD) fed homeostatic metabolic state or high-fat diet (HFD) fed metabolically-impaired obese state, under normal or cold housing environment. Under a RD-feeding, UCP1-CreER/Ghsrf/f mice showed increased body fat and a slightly elevated core body temperature under cold but not under normal temperature. Consistently, the expression of thermogenic genes in BAT of RD-fed UCP1-CreER/Ghsrf/f mice was increased in reposes to cold. Under HFD feeding, HFD-fed UCP1-CreER/Ghsrf/f mice showed no difference in body fat or body temperature under either normal or cold exposure. Interestingly, the expression of thermogenic genes in BAT of HFD-fed UCP1-CreER/Ghsrf/f mice was upregulated under normal temperature but downregulated under cold exposure. Overall, our data show that GHS-R has cell-autonomous effect in brown adipocytes, and GHS-R regulates BAT thermogenic activity in a temperature- and metabolic state-dependent manner. The thermogenic effect of GHS-R in BAT is more pronounced in cold environment and differentially variable based on metabolic state; under cold exposure, GHS-R inhibition in BAT activates thermogenesis under homeostatic state but suppresses thermogenesis under obese state. Our finding collectively suggests that GHS-R in BAT, acting as a "metabolic thermostat", differentially regulates thermogenesis in response to different metabolic and thermal stimuli.

Dataset Information

Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.

Publications

Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.

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