Melanocortin-4 Receptor and Obesity
- Obesity is a major risk factor in the development of the metabolic syndrome, which is characterized by hypertension, glucose intolerance, insulin resistance, dyslipidemia, and increased propensity to develop diabetes type 2.
- A likely cofactor promoting the alarming increase in obesity in the last 10 years is the availability of food with high caloric and fat content. Exposure to a hypercaloric, high-fat diet induces lipid stress in regions of the hypothalamus controlling appetite.
- Melanocortin-4 Receptor (MC4R), a G-protein coupled receptor (GPCR) expressed by neurons of the hypothalamus controls appetite and is thereby considered a relevant target for anti-obesity therapies. However, even very potent MC4R agonists do not appear to treat obesity in mice and humans. The underlying mechanisms by which such agonists are ineffective are yet unclear.
- Our research aims to discover how lipid stress, such as that induced by high fat diet, affects MC4R abundance, signaling, and intracellular traffic; whether chemical chaperones can rescue function of MC4R in lipid stressed neurons; and whether different synthetic MC4R agonists have specific effects to promote MC4R signaling.
- Our research analyzes MC4R function in cultured hypothalamic neurons, neuronal cells, and the murine hypothalamus by using state-of-the-art techniques, such as Quantitative Fluorescence Microscopy, including Förster Resonance Energy Transfer and Fluorescence Recovery After Photobleaching, Super-Resolution Microscopy, Electron Microscopy and Mass Spectrometry.
- Molden BM, Cooney KA, West K, Van Der Ploeg LH, Baldini G. Temporal cAMP signaling selectivity by natural and synthetic MC4R agonists. Mol Endocrinol. 2015 Sep 29;PubMed PMID: 26418335. |Abstract|
- Cragle FK, Baldini G. Mild lipid stress induces profound loss of MC4R protein abundance and function. Mol Endocrinol. 2014 Mar;28(3):357-67. PubMed PMID: 24506538; PubMed Central PMCID: PMC3938541. |Abstract|
- Granell S, Molden BM, Baldini G. Exposure of MC4R to agonist in the endoplasmic reticulum stabilizes an active conformation of the receptor that does not desensitize. Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):E4733-42. PubMed PMID: 24248383; PubMed Central PMCID: PMC3856822. |Abstract|
- Granell S, Serra-Juhé C, Martos-Moreno GÁ, Díaz F, Pérez-Jurado LA, Baldini G, Argente J. A novel melanocortin-4 receptor mutation MC4R-P272L associated with severe obesity has increased propensity to be ubiquitinated in the ER in the face of correct folding. PLoS One. 2012;7(12):e50894. PubMed PMID: 23251400; PubMed Central PMCID: PMC3520997. |Abstract|
- McDaniel FK, Molden BM, Mohammad S, Baldini G, McPike L, Narducci P, Granell S, Baldini G. Constitutive cholesterol-dependent endocytosis of melanocortin-4 receptor (MC4R) is essential to maintain receptor responsiveness to α-melanocyte-stimulating hormone (α-MSH). J Biol Chem. 2012 Jun 22;287(26):21873-90. PubMed PMID: 22544740; PubMed Central PMCID: PMC3381150 |Abstract|
- Granell S, Mohammad S, Ramanagoudr-Bhojappa R, Baldini G. Obesity-linked variants of melanocortin-4 receptor are misfolded in the endoplasmic reticulum and can be rescued to the cell surface by a chemical chaperone. Mol Endocrinol. 2010 Sep;24(9):1805-21. PubMed PMID: 20631012; PubMed Central PMCID: PMC2940480. |Abstract|
- Mohammad S, Baldini G, Granell S, Narducci P, Martelli AM, Baldini G. Constitutive traffic of melanocortin-4 receptor in Neuro2A cells and immortalized hypothalamic neurons. J Biol Chem. 2007 Feb 16;282(7):4963-74. PubMed PMID: 17166828. |Abstract|