Thursday, August 29, 2013

A Loss of Function of a Key Protein Associated with Severe Early-Onset Mammalian Obesity

There has been a growing body of evidence to suggest an association between early-onset and severe human obesity with a protein and therefore genetic dysfunction. The actual molecular mechanism responsible for this malady has remained somewhat elusive. However, Dr. Masato Asai and his colleagues from the Division of Endocrinology, Department of Medicine at Boston Children’s Hospital at Harvard Medical School, Boston MA have helped to further clarify the biological origin for this serious condition.

One of the pivotal roles of the cell membrane in living cells is providing the medium through which individual cells communicate with their external environment. For complex organisms such as mammals this is especially critical in order for cells to successfully respond to all the chemical signals that are generated in order to maintain and sustain a state of homeostasis – the regulation of an organism’s internal environment to maintain constancy and stability – so vital for survival.

To fulfill this purpose there is a particular class of membrane-bound proteins referred to as G protein-coupled receptors (GPCRs) that modulate cellular responses to a whole host of stimuli. A sub-category of this class of proteins is represented by the melanocortin receptors (MCRs).  Within this group there exists a subset of receptors tied to specific functions as the following table demonstrates –

Receptor Type      Associated Function
MC1R                     Skin Pigmentation
MC2R                     Hypothalamic-Adrenal-Pituitary Axis – responsive to stress in the external environment MC3R, MC4R         Energy Homeostasis
MC5R                      Exocrine Function

Previous studies have implicated MCR4 in connection with mammalian obesity. Furthermore, it has been shown that there are so-called accessory proteins that play an important role in the function of the MCRs that have been described above. One of these accessory proteins, MRAP2, is associated with MCR4. Given these data, MRAP2, produced in the mammalian brain, would make an excellent candidate for further study. Dr. Asai together with his colleagues genetically modified mice to produce an organism with a dysfunctional MRAP2 protein. These animals developed severe obesity at a young age.

Finally, a study of humans with severe early-onset obesity revealed four rare and possibly pathogenic genetically-derived modifications in MRAP2 further suggesting that this protein may be the causative link to this disease. These represent very important findings in regards to this kind of severe obesity in humans. This may prove to have therapeutic value in the future.

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