Origins of Obesity − Rakyat Biologi

Much remains to be discovered about the extremely complex circuitry regulating the body's energy use and storage as well as how disruptions within it might help perpetuate existing obesity or predispose an individual to becoming obese in the first place. The discovery of leptin in mice led to the identification of a few humans whose severe obesity could be explained by a single genetic defect. Such "monogenic" obesities are quite rare but very informative. For example, a handful of patients have been identified with severe obesity attributable to mutations in the genes for leptin, the leptin receptor, or POMC, a precursor of the appetite-depressing hypothalamic peptide MSH.

Mutations that cause loss of functioning MC4 receptors--the targets of MSH--are also very important, accounting for between 3 and 5 percent of patients with severe obesity. In most of those individuals, only one of two copies of the gene is affected, leaving them with about 50 percent of normal MC4 receptor function.

The majority of people with obesity, however, have no known genetic mutations that could explain their condition. Moreover, their leptin levels are actually higher than those of lean individuals, which sounds counterintuitive if leptin is supposed to cause appetite suppression. Indeed, this discovery led to the idea that most obese patients may have leptin resistance--for some reason, leptin's signal that fat stores are abundant is not being heard by some part of the energy-regulation pathway. Consistent with this theory is the fact that attempts to administer leptin therapeutically have produced disappointingly poor responses in typical obese patients lacking specific leptin-associated gene mutations.

Finding the molecular basis for leptin resistance is therefore a matter of substantial research interest. Two proteins have been implicated strongly as contributing to leptin resistance by acting in the brain and possibly in peripheral tissues. One is called SOCS3 and is produced by hypothalamic neurons that normally respond to leptin. SOCS3 can block leptin's ability to signal to those cells. The other protein, PTP1B, squelches leptin signaling inside the cells. In mouse experiments, reducing levels of SOCS3 or PTP1B in all tissues, or even just in neurons, makes mice more sensitive to leptin and resistant to obesity. The precise role of these proteins in human leptin resistance is still unknown, but based on these observations in animals it is tempting to speculate that such molecules produced by leptin-sensitive neurons serve the purpose of modulating leptin signaling so that the cells do not become overwhelmed by it. In obese individuals, chronically high leptin levels could therefore cause these proteins to start overcompensating to protect the cells, initiating a cycle of increasing resistance to leptin signaling.

Such physiological feedback mechanisms could help perpetuate and worsen obesity, and variations in genes involved in fat-regulating pathways may have a similar role in unbalancing the system. Indeed, we believe that variations in genes that influence body weight through as yet undiscovered mechanisms are a likely source of at least some susceptibility to obesity. Whether there are many such genes whose variation affects weight to a small extent or a few dominant genes whose variation affects weight in most people remains to be seen. With powerful techniques for scanning human genes within large populations becoming more widely available, discovery of new weight-regulatory pathways and new insights into known mechanisms is bound to accelerate. At present, however, the prevalence of obesity and its complications are continuing to rise, making it clear that highly effective therapies are not yet available.