Low birth weight is associated with an increased incidence of obesity and the subsequent development of type 2 diabetes. Epidemiological studies reveal that prenatal and postnatal nutrition, tobacco smoke exposure, maternal alcohol consumption, infection and genetic variants contribute to low birth weight. Using a surgical intrauterine growth retardation (lUGR) rat model that develops obesity and adult onset diabetes, the Sponsor's laboratory previously demonstrated that 6 daily doses of the GLP-1 receptor agonist Exendin-4 (Ex-4) during the neonatal period prevented the later development of both obesity and diabetes. The prevention of diabetes was associated with the preservation of (J cell mass through effects on 13. cell replication and islet vascularity;however the decrease in adult body weight is likely to be mediated through extrapancreatic effects of Ex-4. Of note, even control rats treated with neonatal Ex-4 maintained a lower body weight throughout life. We recently generated a conditional allele of the GLP1 receptor on the C57BI6 genetic background that will permit a genetic dissection ofthe molecular pathways involved in this pivotal response. Further, our preliminary data demonstrate that the effect of neonatal Ex-4 on body weight and fat mass is conserved in C57BI6 mice. Therefore, we hypothesize that Ex-4 reprograms adipogenesis during neonatal development and that this will protect against diet-induced obesity. We will characterize the effect on adipose development and determine whether Ex-4 exerts its effect on adipogenesis via the GLP1 receptor expressed in the developing adipose tissue. Our studies have significant translational relevance, given the alarming and increasing rates of obesity and its associated complications. The possibility that a short-term pharmacological intervention in at risk individuals could prevent the later development of obesity and its associated comorbidities could have far reaching implications.
|Rozo, Andrea V; Babu, Daniella A; Suen, PoMan A et al. (2017) Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture. Mol Metab 6:748-759|