Objective: To investigate the importance of central Hormone-Sensitive Lipase (HSL) expression in the regulation of food intake and body weight in mice in order to clarify whether intracellular lipolysis in the mammalian hypothalamus plays a role in regulating appetite.

Methods: Using pharmacological and genetic approaches, we investigated the role of HSL in the rodent brain in the regulation of feeding and energy homeostasis, under basal conditions, during acute stress and high-fat diet feeding.

Results: We find that HSL, a key enzyme in the catabolism of cellular lipid stores, is expressed in the appetite-regulating centers of the hypothalamus and is activated by acute stress through a mechanism similar to that observed in adipose tissue and skeletal muscle. Inhibition of HSL in rodent models by a synthetic ligand, global knockout or brain-specific deletion of HSL prevents the decrease in food intake normally seen in response to acute stress and is associated with increased expression of the orexigenic peptides neuropeptide Y (NPY) and Agouti-related peptide (AgRP). The increased food intake can be reversed by adeno-associated virus-mediated reintroduction of HSL in neurons of the mediobasal hypothalamus. Importantly, metabolic stress induced by a high-fat diet also enhances the hyperphagic phenotype of HSL-deficient mice. Specific deletion of HSL in the ventromedial hypothalamic nucleus (VMH) or AgRP neurons reveals that HSL in the VMH plays a role in both acute stress-induced food intake and high-fat diet-induced obesity.

Conclusions: Our results indicate that HSL activity in the mediobasal hypothalamus is involved in the acute reduction in food intake during the acute stress response and in the sensing of high-fat diet.