Resistência ao glucagon-like peptide-1 e à colecistocinina-8 em animais machos adultos superalimentados na fase neonatal

Abstract

Excessive caloric intake and rapid weight gain during the postnatal period are risk factors for the development of obesity during adulthood. This metabolic outcome that results in body weight gain may be mediated by endocrine disturbances during critical periods of development. Thus, this paper proposed to evaluate the influence of the glucagon-like peptide 1 (GLP-1) and of cholecystokinin-8 (CCK-8) on energetic homeostasis in adult young male animals (60 days) overfed on neonatal phase by reduction in the number of pups by litter (3 pups in the small litter (SL) vs 12 pups in the normal litter (NL)). The results obtained in this study demonstrated that neonatal overfeeding promoted weight gain that remained until adult phase, increase in visceral fat deposition (increase in adipocytes in number and size), dyslipidemia, hyperleptinemia and altered glycemic homeostasis, including the development of insulin resistance. Besides, small litter animals (SL) had a decreased sensitivity to noradrenalin, with lower elevation in body temperature after stimulation of brown adipose tissue (BAT) by the agonist adrenergic receptor arterenol. The SL animals were resistant to the anorexigenic, hypoglycemic, hyperinsulinemic and thermogenic action of GLP-1. To identify neural substrates that could be involved in the mediation of peripheral GLP-1, c-Fos expression was evaluated in some structures of brainstem (AP and NTS) and encephalic structures (CeA, PVN, ARC, DMH and VMH). Immunohistochemical analysis of brain areas revealed an increase in the number of neurons that express c-Fos protein (neuronal activation indicator) in NL animals after GLP-1 i.p. administration. There was no increase in c-fos expression in SL animals, indicating attenuation of central signaling to GLP-1. Similar results were found for CCK-8, i.e., SL animals showed attenuation of the anorexigenic action, thermogenic action, delayed gastric emptying and neuronal activation stimulated by this hormone. This study provides new evidence linking the overweight presented by SL animals to less responsiveness to GLP-1 and CCK-8, both in appetite suppression as energy expenditure via adaptive thermogenesis promoted by brown fat tissue, which establishes due to neurons morphofunctional rearrangement responsible for energetic homeostasis. These data reinforce that immediate post-natal period is crucial in establishment metabolic and neural control of body ingrowth and growth. Considering that overfeeding has everlasting effects, which are capable of reprogramming these regulating mechanisms, it is important to avoid excessive energy consumption during this development period.