Drug-induced activation of a Gs-coupled designer GPCR in hypothalamic AgRP neurons stimulates chronic food intake and weight gain in mice

Monday, September 22, 2014 — Poster Session I
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NIDDK	NEURO-5

Authors

• Z Cui
• K Nakajima
• C Li
• M Krashes
• B Lowell
• J Wess

Abstract

Obesity is a worldwide health problem. Agouti-related peptide (AgRP)-expressing neurons located in the arcuate nucleus of the hypothalamus play a key role in food intake and metabolism. The activity of AgRP neurons is modulated by synaptic ion channels and G-protein coupled receptors (GPCRs). Recent evidence indicates that activation of Gq-coupled receptors at AgRP neurons leads to acute feeding in mice. This study is to examine activation of Gs-coupled GPCR at AgRP neurons on food intake and metabolism. Gs-coupled designer GPCR (Rs = Gs DREADD) were specifically activated at AgRP neurons by CNO on AgRP-ires-cre knockin mice through AAV-DIO-RseGFP injection at Arcuate Nucleus. After a single intracerebroventricular injection of CNO, we observed a robust increase in food intake that continued for several days, associated with a significant weight gain. This phenotype was not observed when CNO was co-injected with an anti-AgRP antibody. In addition, activation of Rs had not orexigenic effect in Ay mice, which is a aguti protein mutation and insensitive to AgRP. By contrast, inhibition of NPY receptor signaling did not suppress the Rs-mediated stimulation in food intake. Our Results suggest that existence of an orexigenic Gs→AgRP pathway in AgRP neurons, which leads to chronic food intake.

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