Hypothalamic bile acid-TGR5 signaling protects from obesity.

Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet-induced obesity. [Display omitted] • Diet-induced obesity induces changes in the hypothalamic BA-TGR5 system • Central TGR5 agonism reduces obesity by activating the sympathetic nervous system • Hypothalamic TGR5 protects from the onset and worsening of diet-induced obesity • Hypothalamic TGR5 participates in the anti-obesity effects of BA supplementation Castellanos-Jankiewicz et al. demonstrate that activation of central TGR5 signaling counteracts diet-induced obesity, whereas genetic downregulation of hypothalamic TGR5 promotes it. These effects involve modulation of food intake and energy expenditure through the sympathetic nervous system, revealing a long-range bile acid-dependent hypothalamic mechanism contributing to weight regulation in obesity. [ABSTRACT FROM AUTHOR]