Altered R-spondin 1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes.

Hyperphagia is common in diabetes and may worsen hyperglycemia and diabetic complications. The responsible mechanisms are not well understood. The hypothalamus is a key center for the control of appetite and energy homeostasis. The ventromedial nucleus (VMH) and arcuate nucleus (ARC) are two critical nuclei involved in these processes. We have reported that R-spondin 1 (Rspo1) and its receptor LGR4 in the VMH and ARC suppressed appetite, but the downstream neuronal pathways are unclear. Here we show that neurons containing cocaine and amphetamine-regulated transcript (CART) in ARC express both LGR4 and insulin receptor; intracerebroventricular (icv) injection of Rspo1 induced c-Fos expression in CART neurons of ARC; and silencing CART in ARC attenuated the anorexigenic actions of Rspo1. In diabetic and obese fa/fa rats, Rspo1 mRNA in VMH and CART mRNA in ARC were reduced; this was accompanied by increased food consumption. Insulin treatment restored Rspo1 and CART gene expressions and normalized eating behavior. Icv injection of Rspo1 or insulin increased CART mRNA in ARC. In CART neuron cell line Rspo1 and insulin potentiated each other on pERK and β-catenin, and in rats they acted synergistically to inhibit food intake. Silencing Rspo1 in VMH reduced CART expression in ARC and attenuated the inhibitory effect of insulin on food intake. In conclusion our data indicated that CART works downstream of Rspo1 and Rspo1 mediated the action of insulin centrally. Altered Rspo1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes.