Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

AMPK control of hypothalamic lipid metabolism: regulation of appetite and body weight. (#165)

Sandra Galic 1 , Lisa Murray-Segal 1 , Bruce Kemp 1
  1. St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia

The AMP-activated protein kinase (AMPK) is a cellular energy sensor that coordinates metabolic pathways to maintain cellular energy balance in response to nutrient supply and energy demand. Within the hypothalamus, activation of AMPK in response to peripheral hormones that signal negative energy balance promotes food intake by increasing the expression of orexigenic neuropeptides. The underlying molecular interactions are not fully understood, but recent studies have suggested a number of potential mechanisms, including regulation of hypothalamic lipid metabolism, interactions with the mammalian target of rapamycin or the dacetylase sirtuin-1 as possible mediators of AMPK’s effect on whole-body energy balance.
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 specifically investigate the physiological impact of this regulation, we generated mice with alanine knock-in mutations in both ACC1 (Ser79Ala) and ACC2 (Ser212Ala) (ACC double knock-in, ACC DKI). Compared with wild type mice, these mice showed reduced body weight from 12 weeks of age concomitant with decreased white fat pad weights and adipocyte size. Furthermore, ACC DKI mice had reduced appetite after overnight fast and significantly lower accumulated food intake over a 72h period. Importantly, we demonstrate that feeding in response to the orexigenic hormone ghrelin is attenuated and ghrelin-induced expression of orexigenic neupopeptides NPY and AgRP is inhibited ACC DKI mice. These results show that AMPK regulation of ACC is an important physiological mechanism in the control of feeding behaviour and body weight regulation.