Children of mothers who had diabetes during pregnancy are at high risk for developing obesity. Some of this risk is likely to be genetic. However, studies involving siblings discordant for exposure to diabetes in utero and separate studies comparing offspring of diabetic mothers versus fathers indicate an additional effect of the intrauterine environment. Provocative studies in animal models suggest that metabolic imprinting driven by exposure to the altered intrauterine environment of maternal diabetes leads to a reorganization of brain pathways that regulate energy homeostasis. These changes promote food intake and obesity. Similar alterations in brain pathways that regulate appetite and food intake could contribute to the development of obesity in humans. However, no studies have investigated the effects of intrauterine exposure to diabetes on brain feeding circuitry in humans. The overall goal of this application is to test the hypothesis that in utero exposure to gestationa diabetes mellitus (GDM) results in alterations in brain pathways involved in the regulation of feeding behavior in humans. These studies use a combination of fMRI techniques to compare brain pathways involved in the regulation of appetite and energy homeostasis between children exposed and children not exposed to gestational diabetes in utero. Through our ongoing studies on the effects of intrauterine exposure to gestational diabetes on risk for obesity, we have an established cohort of Hispanic children of mothers with and without a documented history of GDM. Our preliminary data support findings of others demonstrating excess obesity in the offspring exposed to gestational diabetes in utero. The goal of this application is to understand potential neural mechanisms by which these intergenerational effects occur.
These studies will identify early-life markers of aberrant development that may promote obesity. These markers can be used as outcomes for short-term test-of-concept studies of potential interventions designed to mitigate obesity risks. Promising interventions can then be tested in the long term for mitigation of obesity in very high-risk children.