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Principal Investigator: YONG XU
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $601,556
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <Acute><Address><Adult-Onset Diabetes Mellitus><Animal Feed><Anti-Obesity Agents><Anti-Obesity Drugs><Appetite Stimulants><Appetite-Stimulating Drugs><Arcuate Nucleus><BBB crossing><Blood Plasma><Body Weight><Body Weight decreased><Brain region><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Chronic><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><DNA Recombination><Data><Eating><Electrophysiology><Electrophysiology (science)><Endocrine Gland Secretion><Energy Expenditure><Energy Metabolism><Exercise><FOS gene><Feeding behaviors><Food Intake><Frequencies><G0S7><Genetic><Genetic Recombination><High Fat Diet><Hormones><Hypothalamic structure><Hypothalamus><Infundibular Nucleus><Ingestive Behavior><Intervention><Intervention Strategies><K element><Ketosis-Resistant Diabetes Mellitus><Lateral><Leanness><Maps><Maturity-Onset Diabetes Mellitus><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Modeling><Murine><Mus><NIDDM><Nerve Cells><Nerve Unit><Neural Cell><Neurobiology><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nucleus Tractus Solitarii><Nucleus solitarius><Obese Mice><Obesity><Output><Paraventricular Hypothalamic Nucleus><Pathway interactions><Peptides><Permeability><Phenylalanine><Physical activity><Pilot Projects><Plasma><Plasma Serum><Population><Potassium><Protooncogene FOS><Recombination><Regimen><Reticuloendothelial System, Serum, Plasma><Slow-Onset Diabetes Mellitus><Solitary Nucleus><Stable Diabetes Mellitus><Strenuous Exercise><Structure of nucleus infundibularis hypothalami><Synapses><Synaptic><Synaptic plasticity><T2 DM><T2D><T2DM><Testing><Therapeutic Hormone><Thesaurismosis><Thinness><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Weight Loss><Weight Reduction><Weight maintenance regimen><adiposity><adult onset diabetes><animal food><blood-brain barrier crossing><bloodbrain barrier crossing><body weight loss><c fos><c-fos Gene><c-fos Proto-Oncogenes><corpulence><eat less><electrophysiological><exercise training><experiment><experimental research><experimental study><experiments><feeding><feeding-related behaviors><glucose tolerance><hypothalamic><improved><insight><intense exercise><interventional strategy><ketosis resistant diabetes><lack of physical activity><maturity onset diabetes><metabolism disorder><neural><neurobiological><neurobiological mechanism><neurochemical><neurochemistry><neuronal><nutrient intake activity><ob/ob mouse><obesity risk><orexigenic><parabrachial nucleus><paraventricular nucleus><pathway><pharmacologic><physical inactivity><pilot study><reduced eating><reduced food intake><response><risk for obesity><risk of obesity><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><solitary tract nucleus><strenuous activity><strenuous physical activity><synapse><type 2 DM><type II DM><type two diabetes><v-FOS FBJ Murine Osteosarcoma Viral Oncogene Homolog><vigorous exercise><vigorous physical activity><weight control><weight management><wt-loss>