Oral Presentation The International Congress of Neuroendocrinology 2014

Carnitine metabolism through carnitine acyltransferase (crat) in POMC neurons regulates energy metabolism in response to high fat diet. (#52)

Sarah H Lockie 1 , Qunli Wu 1 , Alex Reichenbach 1 , Minh Deo 1 , Moyra Lemus 1 , Romana Stark 1 , Zane B Andrews 1
  1. Monash University, Clayton, VIC, Australia

Proopiomelanocortin (POMC) neurons are a key component of the hypothalamic melancortin system, which maintains peripheral energy balance. For example, monogenic mutations in the melanocortin system lead to obesity in mice and humans. POMC neurons sense nutrients during acute and chronic positive energy balance and engage mechanisms to control energy balance. We reasoned mitochondrial mechanisms regulating glucose metabolism are potentially important metabolic sensors that influence POMC function. We deleted carnitine acyltransferase (Crat), a mitochondrial matrix enzyme that regulates glucose metabolism, from POMC neurons and examined the effect on energy metabolism. Cre-dependent reporter expression using loxSTOPlox tdTomato mice revealed that greater than >85% of POMC neurons expressed tdTomato in POMC crat WT and KO mice. High fat diet (HFD) exposure increased body weight gain, fat pad mass and plasma leptin in KO mice relative to WT controls, whereas no difference was observed in mice fed a chow diet. Stereological investigation in WT and KO chow-fed and HFD-fed mice showed no genotypic difference in POMC cell number or volume, indicating deletion of Crat did not affect POMC neuron morphology. POMC crat KO mice exhibited significantly lower POMC gene expression relative to WT after 10 weeks on a HFD, whereas melanocortin 4 receptor mRNA was elevated in both chow and HFD KO mice relative to WT mice, suggesting MC4R expression may compensate for reduced POMC expression. Metabolic analysis using CLAMS revealed that deletion of crat in POMC neurons affected respiratory exchange ratio and heat production, which contributed to greater weight gain on a HFD. POMC crat KO on HFD mice were more glucose intolerant, although no genotypic differences in plasma insulin were observed during the oral glucose tolerance test. Collectively our results indicate that crat in POMC neurons facilitates the appropriate energy sensing during chronic positive energy balance to maintain energy balance.