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Taking a WAGR on Obesity



There are over 50 syndromic forms of obesity, most of which involve some degree of mental retardation. While some of the obesity seen in these syndromes may be due to problems with mobility or cognitive control of food intake, in many cases it is assumed that the underlying genetic defect directly affects genes that are of importance in energy control. Thus, for example in the Prader-Willi syndrome, one of the most common syndromic forms of childhood-onset obesity, characterized by ravenous hunger and hyperphagia, it is assumed that the very genes that cause this syndrome are directly linked to the regulation of hunger and appetite.

Although relatively rare, these syndromic forms of obesity can be considered “natural experiments” the study of which can provide insights into the complex biology of energy homeostasis. Finding genes that can cause these rare forms of obesity may lead to new pharmacological targets that can provide novel medications that may even prove to be effective in obese individuals who do not have the stated syndrome.

In this week’s New England Journal of Medicine, Joan Han and colleagues from the National Institutes of Health, Bethesda, MD, report on the elucidation of the gene involved in severe childhood-onset obesity seen in a subset of patients who have the extremely rare WAGR syndrome (Wilms’ tumor, aniridia, genitourinary anomalies and mental retardation) caused by disruption of the WT1 and PAX6 genes located on chromosome 11. Using various techniques the researchers found that the obese individuals with this syndrome, have an additional genetic defect involving the gene for Brain-Derived Neurotrophic Factor (BDNF).

The fact that BDNF may indeed be intimately involved in energy regulation was previously suspected based on studies in mice and on previous case reports of obese children who either had a mutation of this gene or the receptor for the product of this gene (TrkB). The current study now provides conclusive evidence that a defect or insufficiency of this gene does indeed lead to hyperphagic childhood-onset obesity.

Why is this important? As pointed out in an accompanying editorial by Philippe Froguel and Alexandra Blakemore, animal studies have shown that BDNF released in the hypothalamic paraventricular nucleus is closely linked to the action of other hypothalamic factors intimately linked to ingestive behavior including a-MSH/MC4 Receptor signaling and inhibitory effects of Neuropeptide Y. Brain infusion of BDNF reduced hyperphagia in MC4R-deficient mice. It is therefore conceivable that compounds that mimic the activity of BDNF in the brain may prove effective in treating obesity.

Obviously, it is a long way from identifying a potential target to having a drug that actually works and is safe enough to use in humans. Nevertheless, new hope for treatment can only come from a better understanding of how the complex neurobiology of ingestive behavior actually works.

Given that currently our best treatment for severe obesity is surgery, any hope of a treatment that can help reduce the number of patients who will ultimately need surgery is welcome.

AMS
Edmonton, Alberta

1 Comment

  1. Kathleen G. Mountjoy, in a review article (2010) described, functions for pro-opiomelanocortin-derived peptides in obesity and diabetes the first rare human POMC-null mutation was reported around the time of the development of the Pomc-null mouse. In contrast with mice, humans are unable to exist without adrenal glands and glucocorticoid hormones. Humans with a POMC-null mutation only survive when they are supplemented with glucocortioids from birth and they can exhibit red hair, hyperphagia and obesity, a remarkably similar phenotype to that seen in Pomc-null mice, thus emphasizing the highly conserved role for the POMC gene in the regulation of energy homoeostasis. The melanocortin system, as is now known, is far more complex than most of us could have imagined in 1997, and, similarly, the importance of this system for regulating energy homoeostasis in the general human population is much greater than we would have predicted. Of the known factors that can cause human obesity, or protect against it, the melanocortin system is by far the most significant.
    As seen through the years, the brain neurotransmitter system is increasingly involved in obesity. studies show more and more involvement of POMC and MC receptors and their association with other genetic alterations, personally, I believe that by better understanding this difficult internal homeostasis and get the drug that selectively act on specific receptor then we can treat obesity without presenting undesirable side effects. In the meantime, we give to the patient the best of our knowledge to treat and offer a good quality of life.

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