What's new with ghrelin??

Since its first description in 1999 by Kojima and co-workers, ghrelin has been the subject of intense interest in the scientific community, as evidenced by the more than 2,500 published papers to date. This is good news for those with PWS, who have abnormally high levels of circulating ghrelin (in contrast, normal obese individuals have lower ghrelin levels than their lean counterparts). The more we know about ghrelin, the closer we are to understanding how elevated levels influence the PWS phenotype, and the closer we are to interrupting its appetite promoting properties.

Given the rapid pace of the field, it’s hard to keep up, but here is a smattering of recent ghrelin studies that may be important for PWS.

Evidence is mounting that ghrelin plays an important role in reproduction and fertility. In a manner similar to leptin, wherein high leptin levels are thought to signal a favorable environment and promote fertility, high ghrelin levels are generally the result of a limited food supply. In addition, ghrelin levels are known to generally decrease with puberty. Thus, it may not be surprising that Kluge and colleagues [Kluge, 2007] found that ghrelin suppresses the release of luteinizing hormone (LH, a hormone critical to proper reproductive function) in humans. Administration of ghrelin resulted in significantly lower circulating levels of LH and testosterone in healthy young men. The relationship of ghrelin with LH in adolescent girls is more complex [Kasa-Vubu, 2007 ], but the two hormones seem to be very much tied together. It may therefore be worth exploring whether some of the disturbances in puberty common in PWS (frequently, puberty is early onset, but rarely complete) might be related to abnormally elevated levels of ghrelin in the body.

Of course, targeting the appetite promoting aspect of ghrelin is also of interest to those with PWS. Ghrelin acts through a receptor, the GHSR-1a. Scientists at the Bayer Research Center [Esler, 2007 ] were interested in studying an antagonist of the the ghrelin receptor, not only for its anticipated weight loss-promoting qualities, but also because recent studies suggest that ghrelin also plays a role in maintaining optimal glucose levels in the body (i.e., regulating glucose homeostasis). These investigators examined the effects of a GHSR-1a antagonist on obese mice. Mice treated with the drug had improved glucose homeostasis, better insulin secretion and lost weight, especially fat, due to decreased food intake. Consistent with what has been understood about ghrelin to date, the weight loss promoting effects of the antagonist appeared to act largely through the brain, rather than through any effects on the peripheral organs. This is an encouraging first step towards a new pharmacological intervention for weight control, which may be particularly relevant for PWS. Look for this drug, or others like it, to move forward towards human clinical trials soon.

Topics: Research

Theresa Strong

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Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.

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