NIH Reporter #5R01DK128477-05

Rapid hormonal modulation of feeding circuit dynamics and its disruption in obesity

This award funds research to understand how carbohydrate-rich diets affect gut-brain communication and feeding circuits in obesity, focusing on hormonal modulation and neural pathways.

Description

Obesity is a staggering public health threat associated with dysregulation of both long-acting homeostatic feedback that modulates metabolism and satiety, and fast acting signals from the gut driving meal termination. Excessive consumption of highly processed foods rich in sugar is increasingly implicated in the development of obesity and its comorbidities. A major gap in our knowledge is to understand how carbohydrate-rich diets modulate satiation via rapid gut-brain communication in normal weight and obese animals. Using a model pioneered to dissect the effects of gastrointestinal nutrient delivery on the in vivo dynamics of hypothalamic feeding circuits, previous studies showed that gastric infusion of macronutrients rapidly inhibits hunger-promoting neurons (AgRP neurons) in the hypothalamus. This inhibition is proportional to calories infused and independent of macronutrient identity, though the molecular mechanisms are macronutrient specific. Obesity induced by a high-fat diet (HFD) results in a decrease in fat-mediated AgRP neuron inhibition, supporting nutrient-specific changes along the gut-brain axis. The proposed work will define the role of rapid post-ingestive hormone release from enteroendocrine cells (EECs) in driving carbohydrate-mediated AgRP neuron inhibition, and how obesity alters these pathways.

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