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

Project: Research project

Project Details


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 carbohydrate-rich diets is increasingly implicated in the development of obesity and its comorbidities, and 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 I previously pioneered to dissect the effects of gastrointestinal (GI) nutrient delivery on the in vivo dynamics of hypothalamic feeding circuitry, I previously showed that gastric infusion of macronutrients rapidly inhibits a population of hunger-promoting neurons in the hypothalamus known as AgRP neurons. This inhibition is proportional to the total number of calories infused and independent of macronutrient identity. However, the mechanisms of this inhibition are macronutrient-specific. Moreover, preliminary data presented here suggest that diet-induced obesity (DIO) from high-fat diet (HFD) results in nutrient-specific changes in this gut-brain axis with a selective decrease in fat-mediated AgRP neuron inhibition. The molecular and circuit-based drivers of glucose-mediated AgRP neuron inhibition remain obscure. In addition, the effects of carbohydrate over-nutrition on nutrient-mediated AgRP neuron dynamics are unknown. Here we will test several hypotheses that will begin to answer these complex questions. In Aim 1, based on preliminary data collected in our lab, we will use a combination of pharmacologic and conditional genetic tools to define a role for rapid post-ingestive hormone release from enteroendocrine cells (EEC) in the duodenum in driving these dynamics. In addition to defining the GI processes and secreted signals required for carbohydrate-induced gut-brain communication, we will also determine where these hormones act to elicit ch
Effective start/end date4/1/211/31/26


  • National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK128477-04 Revised)


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