Abstract
AMP-activated protein kinase (AMPK) is a known regulator of whole-body energy homeostasis, but the downstream AMPK substrates mediating these effects are not entirely clear. AMPK inhibits fatty acid synthesis and promotes fatty acid oxidation by phosphorylation of acetyl-CoA carboxylase (ACC) 1 at Ser79 and ACC2 at Ser212. Using mice with Ser79Ala/Ser212Ala knock-in mutations (ACC DKI) we find that inhibition of ACC phosphorylation leads to reduced appetite in response to fasting or cold exposure. At sub-thermoneutral temperatures, ACC DKI mice maintain normal energy expenditure and thermogenesis, but fail to increase appetite and lose weight. We demonstrate that the ACC DKI phenotype can be mimicked in wild type mice using a ghrelin receptor antagonist and that ACC DKI mice have impaired orexigenic responses to ghrelin, indicating ACC DKI mice have a ghrelin signaling defect. These data suggest that therapeutic strategies aimed at inhibiting ACC phosphorylation may suppress appetite following metabolic stress.
Highlights
There are 1.9 billion adults overweight or obese worldwide, placing them at increased risk of developing type two diabetes, cardiovascular disease, chronic kidney disease and cancer (World HealthOrganization, Fact Sheet N311, Obesity and overweight)
We report that acetyl-CoA carboxylase 1 (ACC1) Ser79/ACC2 Ser212 phosphorylation is selectively important for promoting food intake and determining fuel utilization under cold stress, while AMPK-regulated energy expenditure and capacity for thermogenesis are independent of AMPK-acetylCoA carboxylase (ACC) signaling
Our results show that inhibition of ACC1 Ser79/ACC2 Ser212 phosphorylation leads to ghrelin insensitivity and indicate that increased food intake in response to metabolic stress requires intact ghrelin receptor-mediated activation of the AMPK-ACC pathway
Summary
There are 1.9 billion adults overweight or obese worldwide, placing them at increased risk of developing type two diabetes, cardiovascular disease, chronic kidney disease and cancer (World HealthOrganization, Fact Sheet N311, Obesity and overweight). There are 1.9 billion adults overweight or obese worldwide, placing them at increased risk of developing type two diabetes, cardiovascular disease, chronic kidney disease and cancer Current weight loss strategies are typically aimed at generating a negative energy balance through calorie restriction (dieting) or increases in energy expenditure (exercise). In recent years brown fat thermogenesis has emerged as a potential alternative to exercise to increase energy expenditure in humans and has led to increased interest in the development of pharmacological activators of thermogenesis (Cypess and Kahn, 2010; Whittle et al, 2011). Weight loss strategies aimed at prolonged negative energy balance typically fail due to compensatory increases in appetite (Doucet et al, 2000; Sumithran et al, 2011).
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