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).
We found no differences between genotypes in body weight or blood glucose development during a nine-day 60% calorie restriction (CR) protocol, yet body composition analysis before and after CR revealed that KO lost more body fat and spare lean mass.
KO mice show significant differences in feeding behaviour, BAT temperature, and locomotor activity compared to WT mice in response to chronic calorie shortfall. Promethion metabolic cage analysis under advanced CR conditions (day 6-9 of CR) revealed that KO mice have increased average energy expenditure during this period and lower respiratory quotient compared to WT littermates. The latter indicates that KO mice are preferentially utilizing lipids as an energy substrate, underlying the greater loss of fat mass.
In order to examine rebound weight gain, WT and KO mice were ad-libitum fed for 11 days, interestingly KO took longer to reach pre-CR body fat reserves and gained more body weight due to greater food intake, showing after chronic energy deficit, analogous to diet-restricted weight loss in humans, mice defend relative body fat content rather than total body weight.
These findings have implications for weight management programs and imply, Crat in AgRP neurons is required to assess and adapt to low caloric environments.