Intrinsic primary afferent neurons in regulation of intestinal nutrient sensing and obesity

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Midwestern University $710,812 on April 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate the role of intrinsic primary afferent neurons in intestinal nutrient sensing and obesity.

The research uses molecular, behavioral, and electrophysiological approaches to uncover how intestinal sensory neurons modulate glucose absorption, lipid transport, and vagal-mediated gut-brain reward reinforcement that may drive weight gain. The project employs intestine-specific chemo genetic targeting in mouse models to examine neuroplasticity mechanisms by which these neurons adapt to hormonal and neural stimuli, with the hypothesis that their hyperactivity induces obesity through altered nutrient uptake and reward-reinforcement pathways.

Work is performed in Downers Grove, Illinois, with a period of performance through January 31, 2030. Midwestern University is a private, non-profit educational institution with a tax-exempt status and established federal research portfolio in health sciences.

Two sub-recipients contribute specialized research support. Vanderbilt University Medical Center (awarded May 21, 2026) performs technical expertise, research activities, data analysis, and reporting as part of a multiple-principal-investigator project. Michigan State University (awarded May 14, 2026) supervises design and development of a high-density flexible microelectrode array for in vitro studies on the neurophysiology platform and provides data analysis and manuscript guidance for conference presentations.

Abstract

Intestinal nutrient sensing is dysregulated in obesity and associated comorbidities including type 2 diabetes (T2D) which feed into the vicious cycle of maladaptive response and nutrient excess. While enteroendocrine mediated nutrient sensing has been studied, the role of GUT's neural players in regulating this phenomenon and underlying mechanisms remain unknown. Our data demonstrate that intestinal sensory intrinsic primary afferent neurons (IPANS) modulate nutrient sensing in a manner that primes towards weight gain. IPANS are a unique class of enteric neurons that orchestrate neural reflexes for optimizing nutrient uptake and efficient processing of meals. In the guinea PIG, evidence points toward neuroplasticity mechanisms that enable IPANS to adapt to changing hormonal and neural stimuli in the GUT. Using intestine-specific chemo genetic targeting strategy, we found that ipan activation in the proximal small intestine induced obesity in lean mice on a standard chow diet. Mechanisms underlying this novel and intriguing phenomenon are unknown, but our findings point towards alterations in not just intestinal glucose and lipid uptake but vagal afferent activity influencing reward reinforcement and food seeking behavior. We hypothesize that ipan activity regulates weight gain by modulating intestinal glucose and lipid uptake, and vagal mediated GUT-brain reward reinforcement. Toward this goal, we aim to: (1) uncover the role of IPANS in modulating enterocytic glucose absorption, lymphatic lipid transport, and vagal mediated reward reinforcement, and (2) elucidate the molecular machinery driving ipan firing, to understand how hyperactivity triggers the obese phenotype. Combination of molecular, behavioral, and electrophysiological approaches will be employed to study ipan activity in the lean and obese landscape, using the recently characterized and validated neuromedin (NMU)-driven CRE mouse model that specifically targets IPANS. Our studies will reveal novel functions of a previously unknown player in nutrient sensing and absorption, and the crosstalk between enteric sensory neurons and vagal afferent terminals to influence communication of luminal signals to the brain. We will then evaluate whether targeted blunting of intestinal ipan activity slows or inhibits weight gain in diet-induced obese mice and could ameliorate metabolic outcomes, including hyperglycemia, hypertriglyceridemia, and systemic glucose and lipid handling. Completion of the proposed work will reveal direct roles of enteric neurons in nutrient sensing, contrary to the paradigm, and deepen our understanding of how the deeper layers of GUT's neuronal circuitry influence metabolism and obesity.