Role of Hypothalamic TRPV1‐Expressing Neurons in the Regulation of Energy Homeostasis

Abstract

Transient Receptor Potential Vanilloid type 1 (TRPV1), also known as the capsaicin receptor, is a ligand‐gated nonselective cation channel that has been associated with the regulation of energy homeostasis. Acute stimulation of TRPV1 by a single injection of capsaicin decreased food intake and lowered blood glucose by increasing insulin secretion in wild type mice. Moreover, addition of capsaicin to a high fat diet prevented the development of obesity and improved insulin sensitivity in rodents. TRPV1 is expressed in the hypothalamus, a brain area involved in the regulation of energy intake and energy expenditure. Our previous findings demonstrated that liver‐related hypothalamic neurons express TRPV1 and insulin receptor substrate 2, suggesting the involvement of TRPV1 in the regulation of glucose metabolism. However, the role of TRPV1 in the central control of energy homeostasis in vivo remained to be determined. Transgenic TRPV1‐Cre mice were used throughout the study. First, we investigated the monosynaptic inputs to hypothalamic TRPV1 neurons, using pseudo‐typed rabies virus coupled with helper viruses expressed in Cre‐dependent manner (AAV‐EF1a‐Flex‐TVA‐mCherry + AAV‐CA‐Flex‐RG.ape + EnvA‐RVdG‐GFP). Starter TRPV1 neurons were mainly found in the posterior hypothalamus (PH) and lateral hypothalamus (LH). We observed that these TRPV1‐expressing starter neurons receive monosynaptic inputs from the preoptic area (POA), the dorsomedial hypothalamus (DMH) and the LH, brain areas known for their implication in the regulation of food intake, glucose metabolism and thermogenesis. This finding corroborates the potential involvement of TRPV1 in central regulation of energy homeostasis. Then, we studied the role of hypothalamic TRPV1‐expressing neurons in vivo, using the designer receptor exclusively activated by designer drugs (DREADD) approach. DREADD was expressed in Cre‐dependent manner and located mainly in the PH and LH. Thereby, a single injection of clozapine‐N‐oxide (CNO; 1 mg/kg of body weight) triggered the stimulation (AAV‐hSyn‐DIO‐hM3D( Gq)‐mCherry) or inhibition (AAV‐hSyn‐DIO‐hM4D(Gi)‐mCherry) of TRPV1/DREADD‐expressing neurons, while food intake and glucose tolerance were evaluated. Our data showed that activation of TRPV1‐expressing neurons in the PH/LH did not affect food intake during 6h of a refeeding test, whether hypothalamic TRPV1 expressing neurons were stimulated or inhibited. Similarly, the activation of TRPV1/DREADD‐expressing neurons did not modulate glucose tolerance after an intraperitoneal injection of glucose (2 g/kg of body weight), whether hypothalamic TRPV1 expressing neurons were stimulated or inhibited. In conclusion, despite the previous evidence that TRPV1 is involved in the regulation of the whole‐body energy homeostasis, TRPV1 expressing neurons located in the PH/LH area are likely not involved in the central regulation of food intake or glucose tolerance. Further studies need to be conducted to reveal the physiological role of hypothalamic TRPV1 expressing neurons in vivo.Support or Funding InformationNational Institutes of Health R01 DK099598Core Facilities (Tulane University, School of Medicine)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.