100-OR: Defective Mitochondrial Gene Expression in Brown Adipocytes Suppresses Food Intake by Batkine GDF15

Abstract

Adaptive thermogenesis fueled by mitochondrial respiration in brown adipose tissue (BAT) contributes to thermoregulation and energy expenditure. However, whether BAT can regulate energy balance beyond thermogenesis remains unknown. Here, we describe that the Leucine-rich PPR motif-containing protein (Lrpprc) specifically regulated mtDNA-encoded gene expression in brown adipocytes. Brown adipocyte-specific Lrpprc knockout mice (LrpprcBKO) exhibited electron transport chain proteome imbalance and defective β-adrenergic-stimulated adaptive thermogenesis at room temperature and thermoneutrality. Paradoxically, LrpprcBKO mice were lean at normal chow and were protected against high-fat-diet (HFD)-induced metabolic abnormalities at both ambient temperatures. Lrpprc-deficient brown adipocytes exhibited enhanced Atf4-mediated integrated stress response and GDF15 secretion. Blocking GDF15 partially reversed the food intake and adiposity phenotypes in HFD-fed LrpprcBKO mice at thermoneutrality. Collectively, our results reveal that specific reduction of mtDNA gene expression in brown adipocytes induces a trade-off between BAT thermogenic capacity and systemic metabolism, which is in part through a GDF15-mediated BAT-to-brain crosstalk. These new findings may provide new therapeutic strategies for combating metabolic disorders. Disclosure B. Wang: None. Funding National Institutes of Health; Larry L. Hillblom Foundation