Carnitine acetyltransferase in AgRP neurons enables metabolic sensing of negative energy balance

ZB Andrews and A Reichenbach

Biomedicine Discovery Institute, Department of Physiology, Monash University

Acute activation or neonatal ablation studies show AgRP neurons are important in the control of energy homeostasis. However these studies lack physiological context due to the nature of artifical activation or ablation. How AgRP neurons repsond to physiological changes in metabolic state is unknown. We reasoned mitochondrial mechanisms act as metabolic sensors in AgRP neurons based on their ability to process glucose and fatty acids. We deleted carnitine acetyltransferase (Crat), a mitochondrial matrix enzyme regulating glucose and fat metabolism, from AgRP neurons (KO). Feeding behaviour (BioDAQ cages) was significant impaired in KO mice and food intake was significantly lower after fasting/refeeding. KO mice exhibited lower liver glycogen, increased liver TAG acculumation and oxidation measured by turnover of radiolabled oleate during fasting. The liver changes were associated with reduced sympathetic nervous system innervation as measured by norepinephrine turnover. Hepatic gene expression indicated KO mice engaged different hepatic gluconeogenic and lipolytic pathways and stable isotope mass spec analysis confirmed that KO mice use more glycerol as a substrate to maintain blood glucose during fasting. Fasting and acute stress also increased plasma corticosterone in KO mice suggesting increased counter-regulatory mechanisms to maintain plasma glucose concentrations. These findings imply Crat in AgRP neurons is required to sense negative energy balance in order to control feeding behaviour and liver function.