Activation of AMP-activated protein kinase (AMPK) during increased energy demand promotes food intake and reduces brown fat thermogenesis to shift the organism to neutral energy balance. The underlying molecular interactions are not entirely understood.
The acute effects of AMPK on lipid metabolism are mediated by phosphorylation of acetyl-CoA carboxylase (ACC) 1 at Ser79 and ACC2 at Ser212, thereby inhibiting fatty acid synthesis and promoting fatty acid oxidation. To investigate the physiological impact of this regulation on whole body energy balance, we generated mice with Ser79Ala/Ser212Ala knock-in mutations (ACC double knock-in, ACC DKI). ACC DKI mice have increased ACC1/2 activity in peripheral tissues and a propensity for increased lipid synthesis. Despite deregulated lipid metabolism, ACC DKI mice do not gain more weight when compared to wild type control mice and, in contrast, show a tendency for reduced body weight from 15 weeks of age.
Food intake measurements showed that ACC DKI mice have reduced appetite in response to metabolic stress, such as overnight fasting or cold exposure. Furthermore, while ACC DKI mice are able to maintain normal body temperature under cold stress, they compensate for reduced energy intake by utilising lipids as preferred energy source. Cold exposure and overnight fasting are accompanied by increased plasma levels of the orexigenic hormone ghrelin in ACC DKI mice. Importantly, we demonstrate that feeding in response to ghrelin is attenuated and ghrelin-induced expression of the orexigenic neuropeptides NPY and AgRP is inhibited, indicating that the anorexic phenotype of ACC DKI mice may be due to ghrelin insensitivity.
These results show that AMPK regulation of ACC is an important physiological mechanism in the control of body weight regulation, whereby the lipid accumulating effects in the periphery are outweighed by anorexic effects in the hypothalamus.