Hypothalamic hormone-sensitive lipase regulates appetite and energy homeostasis

Molecular Metabolism

Rudolf Zechner¹  Søren H. Christiansen²  Aske W. Helge³  Tune H. Pers³  Petra Kotzbeck³  Cecilia Ratner⁴  Lola Torz⁴  Annette K. Serup⁴  Thomas O. Eichmann⁴  Jonatan J. Thompson⁴  Cecilie Hundahl⁴  Martin P. Madsen⁵  Birgitte Holst⁵  David P.D. Woldbye⁶  Bente Kiens⁷  Hayley B. Burm⁷  Louise J. Skov⁸  Daniele Piomelli⁸ 

[1] Center for Explorative Lipidomics, BioTechMed-Graz, Graz, Austria;Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria;Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen N, Denmark;Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark;Department of Neuroscience, University of Copenhagen, 2200 Copenhagen N, Denmark;Department of Nutrition, Exercise and Sports, University of Copenhagen, 2100 Copenhagen Ø, Denmark;Institute of Molecular Biosciences, University of Graz, Graz, Austria;Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen N, Denmark;

关键词: Appetite regulation;    Stress;    Obesity;    Hypothalamus;   

DOI  :  

来源: DOAJ

【 摘 要 】

Objective: The goal of this study was to investigate the importance of central hormone-sensitive lipase (HSL) expression in the regulation of food intake and body weight in mice 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 found that HSL, a key enzyme in the catabolism of cellular lipid stores, is expressed in the appetite-regulating centers in 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 a decrease in food intake normally seen in response to acute stress and is associated with the increased expression of orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP). 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 sensing of a high-fat diet.

【 授权许可】

Unknown