Neurobiology for Lac-Phe Hypophagia

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PROJECT SUMMARY Regular physical activity is a powerful intervention that reduces obesity and confers protection against obesity-associated metabolic diseases. The mechanisms responsible are incompletely understood but are likely to extend beyond activity-associated increases in energy expenditure alone. We recently identified a lactate-derived metabolite called N-lactoyl-phenylalanine (“Lac-Phe”) as the most significantly elevated metabolite in blood plasma after an intense exercise bout. We further demonstrated that pharmacological elevation of plasma Lac-Phe to mimic exercise training can robustly suppress feeding in obese mice, and repeated Lac-Phe regimen results in chronic hypophagia, weight loss, and reduced adiposity, associated with improved glucose tolerance. While these findings raise the possibility that Lac-Phe could be used as an anti-obesity agent, the neurobiological mechanisms underlying Lac-Phe hypophagia remains unknown. Our preliminary studies identified Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus of the hypothalamus (ARH) as one direct target of Lac-Phe action and mediate its hypophagic response. One objective is to examine effects of Lac-Phe and exercise on afferent synaptic inputs to AgRP neurons, and efferent outputs from AgRP neurons to their synaptic targets. Our data also suggest that Lac-Phe inhibits orexigenic AgRP neurons via increasing an outward potassium current, namely KATP current. Thus, the second objective is to use the CRISPR-Cas9 approach to genetically disrupt the expression of KATP channel subunits in AgRP neurons, and use these models to determine the functional relevance of KATP channel in Lac-Phe-induced AgRP inhibition and hypophagia. Finally, we also observed that Lac-Phe activates neurons in four other brain regions, the lateral septum (LS), the paraventricular nucleus of the hypothalamus (PVH), the parabrachial nucleus (PBN), and the nucleus of solitary tract (NTS). Thus, we will combine the Targeted Recombination in Active Populations (TRAP) approach with electrophysiology, chemogenetics and scRNA-Seq to determine whether Lac-Phe stimulates these neurons directly or indirectly, whether these neurons functionally participate in the Lac-Phe-induced hypophagia, and what are neurochemical identities of these Lac-Phe-activated neurons. These proposed experiments will reveal the neurobiological basis for Lac-Phe hypophagia, which may identify Lac-Phe or the associated pathways as targets for weight management.