Results from this research will be presented in an abstract at the 2008 Society for Gynecologic Investigation (SGI) Annual Scientific Meeting held March 26-29 in San Diego, California.

Ghrelin, the so-called hunger hormone, is produced in the stomach and brain, induces food intake, and operates through a brain region that controls cravings for food and other energy sources. Ghrelin decreases the HOXA 10 gene that is involved in developmental programming of the uterus. The HOXA 10 gene determines how the uterus will develop in adulthood.

When you're obese, ghrelin levels are lower, and based on these preliminary findings, they may result in lower fertility, said lead author on the abstract, Hugh S. Taylor, M.D., professor in the Department of Obstetrics, Gynecology & Reproductive Sciences and section chief of Reproductive Endocrinology and Infertility at Yale School of Medicine.

The researchers bred mice designed to be deficient in ghrelin production. These mice had offspring with decreased fertility and that produced smaller litter sizes. These offspring also had lower expression of the HOXA 10 gene, which is important for proper development of the uterus in the embryo. In the adult uterus, it maintains the ability of the uterus to provide an optimal environment for proper development of the embryo.

Obesity may have an effect on pregnancy in the next generation, said Taylor, adding that the findings underscore the importance of nutrition, energy utilization and appropriate ghrelin levels on normal uterine development. Taylor and his team will next study the effects of lower ghrelin levels on humans.

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"These new variants, along with other recent genetic findings, provide a window into disease causation that may be our best hope for the next generation of therapeutics. By pinpointing particular pathways involved in diabetes risk, these discoveries can empower new approaches to understanding environmental influences and to the development of new, more precisely targeted drugs," said NHGRI Director Francis S. Collins, M.D., Ph.D., who is a co-author of the study. Dr. Collins' laboratory is a participant in the Finrisk 2002 and Finland-United States Investigation of NIDDM Genetics (FUSION), which were among the studies that contributed data to the new analysis. FUSION is funded by NHGRI?s Division of Intramural Research and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Researchers said more work is needed to understand the impact of their discovery that a genetic variant called JAZF1 appears to be involved in diabetes as well as prostate cancer. One of the study?s lead authors, Eleftheria Zeggini, Ph.D., of the University of Oxford, said, "This is now the second example of a gene which affects both type 2 diabetes and prostate cancer. We don?t yet know what the connections are, but this may have important implications for the future design of drugs for both of these conditions."

The research was conducted by the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, which brought together many groups active in the field of diabetes research. In the Nature Genetics paper, DIAGRAM researchers combined the data from three previously published genome-wide association studies in an effort to boost the statistical power of their searches ” an approach that scientists refer to as meta-analysis. The strategy paid off, enabling researchers to identify six genetic variants associated with type 2 diabetes that had gone undetected in the smaller, individual studies.

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