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

ABSTRACT: Obesity is a polygenic disorder with variable penetrance in the general population. Brown adipose tissue (BAT) is a major regulator of energy expenditure and metabolic physiology due to a specialized proteome that orchestrates futile metabolic cycles, which could be leveraged to treat obesity. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited understanding of generalizable mechanisms of BAT regulation over metabolism. Here we perform deep quantitative multiplexed proteomics of BAT across a cohort of 163 genetically defined Diversity Outbred (DO) mice, a model that parallels the genetic and phenotypic variation found in the human population. Leveraging the high variation afforded by this model, we define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. In doing so, we assign novel co-operative functions to 2,578 proteins with 780 established protein networks. We demonstrate that this analytic framework enables systematic discovery of regulators of BAT function, exemplified by uncovering SFXN5 and LETMD1 as modulators of UCP1-dependent thermogenesis. We also identify 638 proteins that underlie protection from, or sensitivity to, at least one parameter of metabolic disease. From this basis, we identify the Na+/K+- ATPase α2 subunit as an inhibitor of BAT energy expenditure, that increases adiposity through antagonism of calcium influx-dependent activation of thermogenic effectors. We provide this Outbred Proteomic Architecture as a resource for understanding conserved mechanisms of BAT regulation over metabolic physiology.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brown Adipose Tissue

SUBMITTER: Haopeng Xiao  

LAB HEAD: Edward Chouchani

PROVIDER: PXD036947 | Pride | 2022-11-08

REPOSITORIES: Pride