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Title page for ETD etd-07162014-230748


Type of Document Dissertation
Author Panaro, Brandon Lee
Author's Email Address brandon.panaro@gmail.com
URN etd-07162014-230748
Title Roles of the Melanocortin-4 Receptor in Gut-Brain Communication
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
Danny Winder, Ph.D. Committee Chair
Alyssa Hasty, Ph.D. Committee Member
Aurelio Galli, Ph.D. Committee Member
Louis Muglia, M.D., Ph.D. Committee Member
Mentor: Roger Cone, Ph.D. Committee Member
Keywords
  • obesity
  • melanocortin-4 receptor
  • mc4r
  • gut hormones
  • gut-brain axis
  • food preference
Date of Defense 2014-03-31
Availability unrestricted
Abstract
Loss-of-function mutations causing haploinsufficiency of the MC4R are the most common monogenic cause of severe early-onset obesity in humans. Research has primarily focused on how central MC4R contributes to energy homeostasis with the eventual goal of developing anti-obesity therapeutics. MC4R expression has been found in vago-vagal circuitry, as well as in enteroendocrine cell populations in the gastrointestinal tract. Multi-choice feeding studies in MC4R deficient mice revealed a surprising reduction in preference for palatable foods high in either fats or carbohydrates. This loss of macronutrient preference was also coupled with a homeostatic drive for hyperphagia. These complex defects in feeding behaviors were suggestive of defects in the gut-brain axis, a cascade of neural and hormonal signals which bi-directionally control feeding behaviors. Gastrointestinal expression of MC4R in L cells was shown to be functionally significant as MC4R agonism stimulated peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) secretion in vivo. These findings highlighted a complementary role for peripheral MC4R in the gut-brain axis that has implications for energy and glucose homeostasis. Furthermore, pharmacological action of melanocortin compounds at peripheral sites must now be considered when examining effects of the receptor on whole-animal physiology.
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