Wednesday, April 2, 2025
4/2/2025
Maternal Western diet and GLP1 system development - PROJECT SUMMARY Consumption of a diet high in fat and sugar, coined the “Western diet” (WD), has profound effects on long-term health and behavioral outcomes. Moreover, maternal consumption of a WD during gestation and lactation influences long-term health outcomes of offspring, as evidenced by decreased insulin sensitivity and increased susceptibility to obesity and diabetes. Early life exposure to high fat diet (HFD) has been reported to impair the development of neural circuits involved in the homeostatic regulation of food intake, in conjunction with altered reward responses and ingestive behavior/food preference. Glucagon-like peptide 1 (GLP1), a hormone and neuropeptide produced both peripherally and centrally, regulates many of the metabolic processes and behaviors altered by maternal WD/HFD. Peripheral and central GLP1 systems appear to display considerable diet-induced plasticity, even in adulthood. Research suggests that adulthood WD exposure in rodent models reduces the number and/or density of intestinal L-cells that produce GLP1, impairing gene expression and reducing GLP1 secretion in response to nutrient stimuli. In addition, long-term adulthood HFD exposure increases the ability of interoceptive stress to activate brainstem GLP1 neurons in mice and reduces concurrent activation of GLP1 receptor (R)-expressing neurons in the dorsal lateral septum. It is possible that development of these highly plastic systems is disrupted by early life exposure to HFD/WD, causing anatomical and functional changes which may underly long-term alterations to behavior and metabolic health, but this hypothesis remains untested. Indeed, published studies evaluating the effect of diet composition on GLP1 system structure and function in rodents (and humans) have all been conducted in adults, and whether early life WD exposure impacts L-cells and central GLP1 neural systems is unknown. This project will test the hypothesis that WD exposure during the pre-weaning neurodevelopmental period will alter the structure and function of rat central and peripheral GLP1 systems during postnatal development and in adulthood. Using our novel Gcg-Cre/tdTomato reporter rat model, we will determine whether neurodevelopmental exposure to maternally-consumed WD alters offspring central GLP1 circuit structure, neural responsiveness to a GLP1R agonist, and adult offspring preference for and intake of WD, while also documenting potential alterations to intestinal L-cell morphology, density, distribution, and secretory profile. Physiological measures closely associated with GLP1 function also will be evaluated. Data collected from this study will provide novel and foundational information regarding the development of central and peripheral GLP1 systems and will advance understanding of the connection between early life nutrition and long-term health outcomes.
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