M.D., University of Trieste, Italy
Ph.D, University of Trieste, Italy
Office: (501)526-7793 – Biomedical Research Center B421F
Lab: (501)603-1368 – Biomedical Research Center B423
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.
1. 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|
2. 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|
3. 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|
4. 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|
5. 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|
6. 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|
7. 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|