Bile acids signaling as a novel mechanism in the hypothalamic control of energy balance
Daniela Cota, MD, HDR
Summary: Bile acids (BA) are cholesterol-derived molecules mostly known for participating in the digestion of lipids. By activating the Takeda G protein coupled receptor 5 (TGR5) in peripheral organs, BA can also act as signaling molecules to reduce body weight, increase energy expenditure and improve glycaemia. These outcomes imply an anti-obesity function for TGR5. Since the major center of convergence of nutrient, hormonal, and environmental cues is the brain, particularly the hypothalamus, we hypothesized a role for TGR5 in this brain structure, specifically under diet-induced obesity.
Our results show that TGR5 and BAs transporters are expressed in the mediobasal hypothalamus (MBH), and that obese mice have decreased circulating and hypothalamic BA levels. Acute intracerebroventricular (ICV) or intra-MBH administration of TGR5 agonists reduced food intake and body weight in obese mice only, and improved insulin sensitivity. Accordingly, chronic ICV administration of the TGR5 agonist in obese mice reduced their body weight and adiposity, while increasing energy expenditure and markers of sympathetic activity in the adipose tissue. Indeed, experiments conducted at thermoneutrality (30°C) or chemical sympathectomy blunted these effects, demonstrating that central TGR5 effects require the engagement of the sympathetic nervous system. Conversely, by using genetic animal models, we observed that the deletion of TGR5 in the MBH rapidly increased food intake, body weight and adiposity, while blunting the sympathetic response to a cold challenge (4h at 4°C), hence worsening obesity.
Our work proves the existence of a functional hypothalamic BA – TGR5 receptor system. We show for the first time that the activation of TGR5 in the MBH decreases body weight and adiposity, while increasing energy expenditure through recruitment of the sympathetic nervous system. These results expose a new mechanism of action for potential anti-obesity therapies.
Keywords: Bile acids, TGR5, diet-induced obesity, mediobasal hypothalamus, energy balance, sympathetic activity, thermogenesis.
Date de la soutenance: 14/11/2019 - 14h00
Lieu: Neurocentre Magendie Seminar room