SUN-678 - Lgr4 in ARH-Pomc Neurons Mediates Physiologic Energy Expenditure Responses Without Protecting From Diet-Induced Obesity

Lgr4 (leucine-rich repeat–containing G-protein–coupled receptor 4) is a G-protein-coupled receptor recently implicated in regulating energy balance through both energy expenditure and food intake. Whole-body Lgr4 deletion protects against diet-induced obesity, increases energy expenditure, and reduces food intake, making Lgr4 an attractive therapeutic target for obesity. However, the hypothalamic circuitry mediating these effects remains unclear. Prior work shows that intracerebroventricular (ICV) delivery of the Lgr4 ligand R-spondin-1 (Rspo1) increases food intake in a leptin-dependent manner, and that arcuate nucleus (ARH) Lgr4 loss increases energy expenditure. Here, we investigated the hypothalamic circuits through which Rspo1–Lgr4 signaling controls energy balance. ICV leptin delivery increased Rspo1 expression in leptin receptor-expressing neurons within the ventromedial nucleus of the hypothalamus (VMH). Circuit mapping showed that over 30% of VMH neurons that project to ARHPomc neurons express Rspo1, and that nearly 50% of VMH neurons projecting to ARHPomc neurons are Rspo1-positive, supporting a VMHRspo1 to ARHPomc pathway. To test the functional relevance of Lgr4 in Pomc neurons, we generated Pomc-specific Lgr4 knockout mice (Lgr4flox/flox;Pomc-Cre). On a chow diet, mutants showed reduced dark-phase food intake and energy expenditure, without changes in 24-h intake, total energy expenditure, or body weight. During fasting, mutants exhibited significantly reduced energy expenditure during the first 8 h, but normal responses after prolonged fasting and during refeeding. On a 60% high-fat diet, mutants did not differ from controls in food intake, energy expenditure, or body weight. Additionally, there was no change in liver steatosis, brown adipose tissue (BAT) whitening, or BAT thermogenic gene expression. These data indicate that Lgr4 signaling in ARHPomc neurons mediates physiological responses, such as acute fasting-induced energy expenditure, while dysfunction in other pathways likely mediates the pathophysiology of diet-induced obesity.

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