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

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PROJECT SUMMARY 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 I pioneered to dissect the effects of gastrointestinal nutrient delivery on the in vivo dynamics of hypothalamic feeding circuits, 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, though the molecular mechanisms are macronutrient specific. More recent data show that obesity induced by a high-fat diet (HFD) results in a selective decrease in fat-mediated AgRP neuron inhibition, supporting the idea that over-nutrition induces nutrient-specific changes along the gut-brain axis. However, the molecular mechanisms of AgRP neuron inhibition induced by carbohydrate ingestion remain largely unknown. The work proposed here will test several hypotheses to begin addressing this question. Aim 1 uses a combination of pharmacologic and conditional genetic tools to define a role for rapid post-ingestive hormone release from a specialized population of gastrointestinal tract-lining cells known as enteroendocrine cells (EECs) in driving carbohydrate-mediated AgRP neuron inhibition. In addition to defining the specific secreted signals required for glucose-induced gut-brain communication, we will determine in which tissues and cell types these hormones act to elicit changes in neural activity. In Aim 2, based upon our results in mice fed a HFD, we will test the hypothesis that obesity induced by high-carbohydrate diets results in unique changes in the dynamics of gut-brain communication compared to HFD due to nutrient-specific changes in the transcriptional landscape of EECs. These studies will close several gaps in our understanding of how carbohydrate intake rapidly modulates feeding circuit activity. It will clarify the role of key glucose-released gut hormones in mediating these dynamics, demonstrate where critical hormone signaling is required, and reveal how carbohydrate overconsumption changes the gut-brain axis at the levels of both neural activity and EEC function. Collectively, the integration of these data will significantly advance our understanding of how over-nutrition leads to nutrient-specific changes in critical homeostatic processes. This will ultimately yield novel insights into the treatment and prevention of obesity.