title: G(q/11)α and G(s)α mediate distinct physiological responses to central melanocortins.
abstract: Activation of brain melanocortin 4 receptors (MC4Rs) leads to reduced food intake, increased energy expenditure, increased insulin sensitivity, and reduced linear growth. MC4R effects on energy expenditure and glucose metabolism are primarily mediated by the G protein G(s)α in brain regions outside of the paraventricular nucleus of the hypothalamus (PVN). However, the G protein(s) that is involved in MC4R-mediated suppression of food intake and linear growth, which are believed to be regulated primarily though action in the PVN, is unknown. Here, we show that PVN-specific loss of G(q)α and G11α, which stimulate PLC, leads to severe hyperphagic obesity, increased linear growth, and inactivation of the hypothalamic-pituitary-adrenal axis, without affecting energy expenditure or glucose metabolism. Moreover, we demonstrate that the ability of an MC4R agonist delivered to PVN to inhibit food intake is lost in mice lacking G(q/11)α in the PVN but not in animals deficient for G(s)α. The blood pressure response to the same MC4R agonist was only lost in animals lacking G(s)α specifically in the PVN. Together, our results exemplify how different physiological effects of GPCRs may be mediated by different G proteins and identify a pathway for appetite regulation that could be selectively targeted by G(q/11)α-biased MC4R agonists as a potential treatment for obesity.
authors.forename: Yong-Qi
authors.initials: YQ
authors.lastname: Li
authors.forename: Yogendra
authors.initials: Y
authors.lastname: Shrestha
authors.forename: Mritunjay
authors.initials: M
authors.lastname: Pandey
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kablan
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D007333:Insulin Resistance; D053486:Melanocortins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology; D010286:Paraventricular Hypothalamic Nucleus / Q000502:physiology*; D010913:Pituitary-Adrenal System / Q000502:physiology; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000502:physiology*
chemical_list: D053486:Melanocortins; D044105:Receptor, Melanocortin, Type 4; D002784:Cholesterol; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs