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Principal Investigator: Patrick Sweeney
Organization: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
Fiscal Year: 2024
Award: $239,039
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Proposal Summary:
The increasing rates of obesity and associated metabolic syndrome pose a major public health concern.
Although behavioral (diet and/or exercise), surgical, and pharmacological modalities exist for weight loss, many
individuals are unable to maintain this weight loss due to behavioral and neuroendocrine adaptions in the brain
promoting weight re-gain. Therefore, pathways preventing compensatory adaptations to weight loss would
provide a wholly novel approach to the conundrum of obesity treatment. Hypothalamic agouti-related peptide
(AgRP) neurons are activated by hunger and dieting and potently engage behavioral and neuroendocrine
neural circuits to drive behaviors promoting increased food intake and rebound weight gain. Here, we show
that the melanocortin 3 receptor is densely expressed in AgRP neurons, with 97% of AgRP neurons containing
MC3R. Furthermore, pharmacological manipulation of MC3R bi-directionally regulates feeding in an AgRP
neuron dependent manner, with agonism of MC3R stimulating feeding and antagonism of MC3R suppressing
feeding. Consistently, mice with impaired MC3R function do not re-feed normally following both fasting and
caloric restriction and fail to adequately activate neuroendocrine responses to weight loss. In this proposal, we
will evaluate the utility of MC3R specific antagonists as a therapeutic strategy for preventing compensatory
responses to weight loss. We will also determine the cellular and molecular mechanism(s) mediating the
anorexigenic effects of MC3R antagonism. The principle investigator in this training grant, Dr. Patrick
Sweeney, has extensive experience in behavioral neuroscience and mouse feeding behavior. In this training
grant, Dr. Sweeney will receive additional training in metabolic physiology, neuroendocrinology, obesity
biology, and pharmacology from the primary research mentor, Dr. Roger Cone. Furthermore, under the
guidance of an expert team of collaborators, Dr. Sweeney will receive hands on training in brain slice
electrophysiology and in vivo endomicroscopic brain imaging. Together, the mentorship and training in this
K99/R00 application will provide the necessary technical and conceptual background for Dr. Sweeney to
initiate an independent research program focusing on MC3R neural circuits as therapeutic targets for obesity
and eating disorders.
Terms: <4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><American><Aminalon><Aminalone><Anorexia><Arcuate Nucleus><Behavior><Behavioral><Binding><Biology><Body Weight><Body Weight decreased><Brain><Brain Nervous System><Brain imaging><Calcium><Caloric Restriction><Cone><Data><Diet><Eating><Eating Disorders><Electrophysiology><Electrophysiology (science)><Encephalon><Evaluation><Exercise><Fasting><Feeding behaviors><Food Intake><GABA><Genetic><Grant><Hunger><Hypothalamic structure><Hypothalamus><Image><Impairment><In Situ Hybridization><Individual><Infundibular Nucleus><Ingestive Behavior><Investigators><KO mice><Kinetics><Knock-out Mice><Knockout Mice><MC3 Receptor><MC4 Receptor><Maps><Mediating><Melanocortin 3 Receptor><Melanocortin 4 Receptor><Mentors><Mentorship><Metabolic><Metabolic syndrome><Mice><Mice Mammals><Modality><Molecular><Molecular Interaction><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neuroendocrine><Neuroendocrine System><Neuroendocrinology><Neurons><Neurophysiology / Electrophysiology><Neurosciences><Neurosecretory Systems><Null Mouse><Obesity><Operative Procedures><Operative Surgical Procedures><Pathway interactions><Patients><Peptides><Pharmacology><Physiology><Public Health><Publishing><Receptor, Melanocortin, Type 3><Receptor, Melanocortin, Type 4><Reporting><Research><Research Personnel><Researchers><Role><Site><Slice><Structure of nucleus infundibularis hypothalami><Surgical><Surgical Interventions><Surgical Procedure><Testing><Therapeutic><Training><United States><Viral><Weight><Weight Gain><Weight Increase><Weight Loss><Weight Loss Agents><Weight Reduction><Weight-Loss Drugs><adiposity><antagonism><antagonist><body weight gain><body weight increase><body weight loss><brain visualization><caloric restricted><calorically restricted><calorie restricted><calorie restriction><corpulence><diet and exercise><diet restriction><dietary restriction><dieting><diets><druggable target><efficacy testing><electrophysiological><endomicroscopy><experience><experiment><experimental research><experimental study><experiments><fasted><fasts><feeding><feeding-related behaviors><gamma-Aminobutyric Acid><hypothalamic><imaging><in situ Hybridization Genetics><in situ Hybridization Staining Method><in vivo><knock-down><knockdown><liraglutide><microendoscopy><mouse model><murine model><neural circuit><neural circuitry><neural control><neural regulation><neurocircuitry><neuromodulation><neuromodulatory><neuronal><neuroregulation><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><nutrient intake activity><obesity intervention><obesity therapy><obesity treatment><pathway><pharmacologic><presynaptic><prevent><preventing><programs><response><restricted diet><social role><surgery><synaptic circuit><synaptic circuitry><therapeutic target><weight maintenance><weights><wt gain><wt-loss><γ-Aminobutyric Acid>