Bile acids (BA) are cholesterol-derived molecules that are mostly known for their involvement in lipid digestion and absorption. Recent evidence recognizes them as metabolic integrators able to reduce body weight (BW), increase energy expenditure (EE) and improve glycemic control by activating their specific receptor, the Takeda G protein-coupled receptor 5 (TGR5) in peripheral organs. These outcomes have increased importance in the context of diet-induced obesity and associated metabolic alterations, implying a therapeutic role for TGR5. Here we have hypothesized that TGR5 is also present in the hypothalamus, a major brain structure involved in the regulation of energy balance and whole-body metabolic responses, and that modulation of hypothalamic TGR5 activity is relevant for the control of energy balance, particularly under diet-induced obesity. In order to investigate this hypothesis, we used a multidisciplinary approach, spanning from pharmacological activation of TGR5 to genetic strategies for the hypothalamic deletion of TGR5, associated with evaluation of changes in food intake, body weight, adiposity and other metabolic outputs. Our data demonstrate that TGR5 and BA transporters are expressed in the mediobasal hypothalamus and that diet-induced obese mice have significantly decreased circulating and hypothalamic BA levels. Acute intracerebroventricular (icv) administration of BA or synthetic TGR5 agonist significantly decreased food intake and body weight, particularly in diet-induced obese mice. Similar outcomes were observed after acute administration of TGR5 agonist directly in the mediobasal hypothalamus. Four-weeks continuous icv administration of TGR5 agonist in diet-induced obese mice significantly reduced food intake, body weight, fat mass and improved insulin sensitivity. Effects on body weight and adiposity were in large part due to increased energy expenditure, in turn driven by increased sympathetic activity. Accordingly, chemical sympathectomy or thermoneutrality were able to prevent effects of central TGR5 agonism on body weight and adiposity. Conversely, virally-mediated deletion of TGR5 in the mediobasal hypothalamus of TGR5flox/flox mice caused a rapid increase of food intake, body weight, and fat mass, accelerating the development of diet-induced obesity or worsening the phenotype of already obese mice. These changes were associated to blunted sympathetic activity, which favored the appearance of the obese phenotype. Overall, our results prove the existence of a functional BA-TGR5 hypothalamic system. We show for the first time that the activation of TGR5 in the mediobasal hypothalamus mediates a myriad of effects that improve metabolic parameters, which are particularly relevant in the presence of diet-induced obesity.
18 May 2019 - 21 May 2019