# Neurobiology for Lac-Phe Hypophagia

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $601,556

## Abstract

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.

## Key facts

- **NIH application ID:** 10913538
- **Project number:** 5R01DK136479-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** YONG XU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $601,556
- **Award type:** 5
- **Project period:** 2023-08-25 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913538

## Citation

> US National Institutes of Health, RePORTER application 10913538, Neurobiology for Lac-Phe Hypophagia (5R01DK136479-02). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10913538. Licensed CC0.

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