Analysis of the in vivo effect of carnitine palmitoyltransferase 1A deletion in AgRP neurons

Abstract

Food intake and whole-body energy balance are regulated by the brain through a sophisticated neuronal network located mostly in the hypothalamus. In particular, the hypothalamic arcuate nucleus (ARC) is a fundamental sensor for the hormones and nutrients that inform about the energy state of the organism. The ARC contains two populations of neurons with opposite functions: anorexigenic proopiomelanocortin (POMC)-expressing neurons and orexigenic Agouti-related protein (AgRP)- expressing neurons. Activation of AgRP neurons leads to an increase in food intake and a decrease in energy expenditure. It has been suggested that lipid metabolism in the ARC plays an important role in the central control of whole-body energy balance. Yet it is unclear whether lipid metabolism regulates the activity of AgRP neurons specifically. To answer this question, we studied mutant mice lacking carnitine palmitoyltransferase 1A (CPT1A) specifically in AgRP neurons (Cpt1aAgRP(-/-) mice). CPT1A regulates the rate-limiting step in the mitochondrial oxidation of fatty acids (FAs) and therefore plays a central role in the metabolism of lipids. The results presented here demonstrated that the deletion of Cpt1a in AgRP neurons induces sex- based differences on the energy metabolism. Although male and female Cpt1aAgRP(-/-) mice showed a reduction of the body weight gain, both genders afford this reduction in different way. Male Cpt1aAgRP(-/-) mice showed a reduction of food intake with no changes in the energy expenditure, while female Cpt1aAgRP(-/-) mice increased the energy expenditure with no changes in food intake. Despite these results, the AgRP neuronal activation in fasting condition or by high levels of ghrelin were impaired in both genders. At a peripheral level, the deletion of Cpt1a in AgRP had an impact on different adipose tissues. On the one hand, the lack of Cpt1a in AgRP neurons activated the brown adipose tissue (BAT) activity, on the other hand, induced a substantial reduction of white adipose tissues, specially inguinal and gonadal fat pads. Although AgRP neurons have been associated with solid food consumption, here we also reported that AgRP neurons could be involved in water homeostasis. Mice lacking CPT1A in AgRP neurons showed reduced levels of AV/ADH hormone and had impaired activation of center related with thirst. Finally, our results reveal that AgRP neurons requires Cpt1a to maintain a normal morphology and physiology. The deletion of Cpt1a in AgRP neurons does not affect the neuronal viability. However, interfered in the number of dendritic spines altering their morphology and normal state of the synapses. Altogether, our results suggest that CPT1A and FAs oxidation in AgRP neurons impact peripheral energy balance highlighting this pathway as a possible target for therapeutic strategies to decrease body weight. We also provide evidence that AgRP could be involved in the regulation of water homeostasis.