Obesity prevalence is dramatically rising in Western cultures creating devastating and costly health problems. Mutations in the melanocortin 4-receptor (MC4-R) gene are the most common monogenetic cause of severe human obesity. The central melanocortin system is a promising target for clinical drug development for the treatment of obesity and related metabolic disorders, as MC4-R agonists potently suppress food intake and body weight in animal models. This proposal is relevant to clinical drug development and public health, as experiments have potential to yield insights into the mechanisms through which MC4-R signaling contributes to food intake suppression.
The aims of this proposal are shaped by recent data showing that the nucleus tractus solitarius (NTS) of the caudal brainstem is a critical site of relevance to food intake control by MC4-R ligands, and that caudal brainstem MC4-R signaling is required for food intake suppression by exogenous cholecystokinin (CCK), the intestinally-derived satiation hormone. Experiments proposed in Specific Aim 1 will generate data that are necessary to more fully evaluate the hypothesis that caudal brainstem MC4-R signaling mediates the intake suppression triggered by various GI satiation signals. Caudal brainstem MC4-R antagonist treatment will be used to assess whether or not activation of these receptors is required for intake suppression following endogenous methods of GI satiation signaling, including intraintestinal nutrient delivery and gastric distention. Proposed research will also probe more deeply into the functional site of hindbrain MC4-R mediation of GI signals by examining the effects of parenchymal NTS MC4-R antagonist treatment on intake suppression by CCK. Adeno-associated virally-mediated knockdown of MC4-Rs in the NTS will be used as a complementary approach to antagonist treatment to assess the endogenous role of NTS MC4-Rs in mediating intake suppression by GI satiation signals. Importantly, MC4-R knockdown technology will also be used to assess the role of endogenous NTS MC4-R signaling in energy regulation more generally. Experiments proposed in Specific Aim 2 will expand consideration to the intracellular signaling pathways in the NTS contributing to intake suppression following MC4-R agonists, GI satiation signaling, and their putative combination. Proposed research will build upon our preliminary findings and other recent data by targeting the p44/42 mitogen-activated protein kinase (MAPK) signaling pathway and potential upstream kinases (protein kinase A [PKA] and phosphatidylinositol 3-kinase [PI3K]) as NTS intracellular mediators of intake suppression by MC4-R ligands and GI signals. Experiments will combine in vivo approaches using pharmacological inhibition of p44/42 MAPK, PKA, and PI3K, with in vitro approaches using activity assays and immunoblots, to assess the physiological role of these intracellular signaling pathways in the suppression of intake that follows MC4-R ligands, GI satiation signals, and potentially their combination. Research laid out in this proposal has the potential to deepen the basic science related to neurochemical mediators of food intake suppression.

Public Health Relevance

The prevalence of obese and overweight humans in Western cultures has increased dramatically, leading to devastating and costly health problems. Effective drug treatments for obesity treatment are likely to come from basic science investigating the neuronal controls of food intake behavior. Research proposed here is relevant to clinical drug development for obesity by exploring neurohormonal mediators of food intake suppression following gastrointestinal contact with ingested nutrients and the processing of these signals by the human obesity-linked melanocortin receptors in the caudal brainstem.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1-GRB-2 (M1))
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Podskalny, Judith M,
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University of Pennsylvania
Schools of Arts and Sciences
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