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 artificial activation or ablation. How AgRP neurons respond 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 was significantly impaired in KO mice and food intake was significantly lower after fasting/refeeding. KO mice exhibited lower liver glycogen, increased liver triglyceride accumulation and oxidation measured by turnover of radiolabeled 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 spectrometry 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.
In order to understand how crat deletion has affected metabolism-sensing properties in AgRP neurons, we measured protein abundances in isolated AgRP neurons using mass spectrometry. This revealed differences in metabolic and cellular communication pathways between WT versus KO AgRP neurons from fed and fasted mice.
These findings imply, Crat in AgRP neurons is required to sense negative energy balance in order to control feeding behaviour and liver function.