title: Predominant role of GIP in the development of a metabolic syndrome-like phenotype in female Wistar rats submitted to forced catch-up growth.
abstract: Catch-up growth has been associated with the appearance of metabolic dysfunctions such as obesity and type 2 diabetes in adulthood. Because the entero-insular axis is critical to glucose homeostasis control, we explored the relevance of the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the development of these pathologies. Offspring of rat dams fed ad libitum (control [C]) or 65% food-restricted during pregnancy and suckling time (undernourished [U]) were weaned onto a high-fat (HF) diet (CHF and UHF, respectively) to drive catch-up growth. Both male and female UHF rats showed an obese phenotype characterized by hyperphagy, visceral fat accumulation, and adipocyte hypertrophy. High-fat diet induced deterioration of glucose tolerance in a sex-dependent manner. Female UHF rats experienced much more severe glucose intolerance than males, which was not compensated by insulin hypersecretion, suggesting insulin resistance, as shown by homeostatic model assessment of insulin resistance values. Moreover, female, but not male, UHF rats displayed enhanced GIP but not GLP-1 secretion during oral glucose tolerance test. Administration of the GIP receptor antagonist (Pro3)GIP to UHF female rats over 21 days markedly reduced visceral fat mass and adipocyte hypertrophy without variations in food intake or body weight. These changes were accompanied by improvement of glucose tolerance and insulin sensitivity. In conclusion, the exacerbated production and secretion of GIP after the catch-up growth seems to represent the stimulus for insulin hypersecretion and insulin resistance, ultimately resulting in derangement of glucose homeostasis. Overall, these data evidence the role of GIP as a critical link between catch-up growth and the development of metabolic disturbances.
authors.affiliation: Departments of Biochemistry and Molecular Biology II (J.D.T.-M., E.L.-M., F.E., C.A.) and Physiology (E.L.-O.), Faculty of Pharmacy, University Complutense of Madrid, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (E.F.-M., E.L.-M., F.E., C.A.), Instituto de Salud Carlos III, 28029 Madrid, Spain; and Inserm Unité Mixte de Recherche S 1138 (P.S.), Centre de Recherche des Cordeliers, Sorbonne Universités, Université Pierre et Marie Curie-Paris 6, F-75006 Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: De Toro-Martín
authors.forename: E
authors.initials: E
authors.lastname: Fernández-Millán
authors.forename: E
authors.initials: E
authors.lastname: Lizárraga-Mollinedo
authors.forename: E
authors.initials: E
authors.lastname: López-Oliva
authors.forename: P
authors.initials: P
authors.lastname: Serradas
authors.forename: F
authors.initials: F
authors.lastname: Escrivá
authors.forename: C
authors.initials: C
authors.lastname: Alvarez
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D059305:Diet, High-Fat; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000502:physiology*; D006963:Hyperphagia / Q000097:blood / Q000209:etiology; D015228:Hypertriglyceridemia / Q000097:blood / Q000209:etiology; D008297:Male; D044342:Malnutrition / Q000150:complications / Q000503:physiopathology*; D024821:Metabolic Syndrome / Q000378:metabolism*; D009765:Obesity / Q000097:blood / Q000209:etiology; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D005749:Gastric Inhibitory Polypeptide