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The Novel Role of Guanylyl Cyclase C Signaling in Appetite Suppression and Body Weight Regulation
Author(s) -
Valentino Michael,
Lin Jieru,
Li Peng,
Snook Adam,
Pitari Giovanni,
Schulz Stephanie,
Waldman Scott
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.lb365
Subject(s) - appetite , endocrinology , medicine , cholecystokinin , enteroendocrine cell , biology , hormone , adipocyte , hyperinsulinemia , adipose tissue , receptor , obesity , endocrine system , insulin resistance
Guanylyl cyclase C (GCC) is an intestine‐specific transmembrane receptor that synthesizes cGMP as its proximal effector. Recently, GCC has emerged as an important intermediary in signaling programs controlling appetite and body weight. C57/BL6 mice in which GCC signaling was eliminated exhibited excess body weight which was associated with adipocyte hypertrophy, an increase in subcutaneous and visceral adipose mass, and obesity‐related co‐morbidities including hepatic steatosis, hyperinsulinemia, and glucose intolerance. Furthermore, GCC‐deficient mice exhibited hyperphagia, and their excess weight gain was eliminated by restricting food intake to levels consumed by wild‐type mice. The observed hyperphagia correlates with a defect in gut pathways regulating food intake, as GCC‐deficient mice exhibit ~50% reduction in the enteroendocrine satiety hormones cholecystokinin and glucagon‐like peptide within the jejunum and ileum, respectively. These observations demonstrate a previously unrecognized role for GCC signaling in regulating appetite and body weight by modulating the function of enteroendocrine cells. This highlights a novel therapeutic paradigm in which oral hormone supplementation with GCC ligands could enhance enteroendocrine hormone levels and amplify nutrient satiety responses, thereby restricting appetite and defending against obesity. Supported by the PhRMA Foundation