Hypothalamic hormone-sensitive lipase regulates appetite and energy homeostasis

Abstract

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.

Hormone-sensitive lipase is localized at synapses and is necessary for normal memory functioning in mice

“…For the first time, to our knowledge, we demonstrate here that HSL is necessary for memory performance, since the HSL −/− mouse exhibited impaired short-term and long-term memory in the Barnes maze as well as impaired spatial working memory in the Y-maze. This role of HSL in cognition adds up to previous suggestions of HSL-mediated lipolysis modulating hypothalamic function ( 30 , 31 ).…”

Central hormone-sensitive lipase is located at synapses and is necessary for normal memory performance in mice

“…For the first time to our knowledge, we demonstrate here that HSL is necessary for memory performance, since the HSL-/-mouse exhibited impaired short-and long-term memory in the Barnes maze, as well as impaired spatial working memory in the Y-maze. This role of HSL in cognition adds up to previous suggestions of HSL-mediated lipolysis modulating hypothalamic function (Sekiya et al, 2004;Hundahl et al, 2021).…”

Polygonatum cyrtonema Hua Polysaccharide Alleviates Fatigue by Modulating Osteocalcin-Mediated Crosstalk between Bones and Muscles

“…CREB was a transcription factor known to play an important role in the osteocalcin-regulated ATP production by modulating glucose uptake and myofibrillar glycolysis . HSL was a key rate-limiting enzyme, which helped to hydrolyze intracellular triglycerides into free fatty acids in muscles . Moreover, western blotting also showed that PCPY-1 apparently increased the protein levels of p-CREB and p-HSL in the BMSCs/C2C12 co-culture system, compared with the control group and the BMSCs/C2C12 co-culture system without PCPY-1 (Figure G–I).…”