The Debate Over the Cause of Weight Gain in Menopause
SevEαl theories have been advanced to explain the cause of weight gain at the time of menopause. Some scientists have attributed it to a decrease in thyroid function, with a subsequently decreased metabolic rate. With lowered metabolism, fewer calories are required to maintain current weight, and if caloric intake remains the same, then weight will increase. Another theory is that the weight gain is due to age-related decreases in muscle mass. Because muscle tissue burns more fuel than fat tissue, a disproportionate loss of muscle mass can result in a reduced requirement for calories. Consequently, maintenance of the same caloric intake will again result in increased body weight. However, some scientists believe the weight gain that occurs at menopause may in fact be due to the reduced production of the female sex steroid estrogen that occurs at the time of menopause.
Proponents of the "estrogen argument" point to data from clinical and animal experiments indicating that estrogen is an important modulator of food intake and body weight. Scientists, who commonly study rats that have had their ovaries removed (ovariectomized [OVX] rats) in order to mimic the decline in sex steroids that occurs at menopause, have found that OVX rats eat more and gain weight more rapidly than sham-opEαted control rats. Estrogen replacement reduces both the increased food intake and the body weight gain of the OVX rats.
The Role of Estrogen Receptors Eα and ERß
Sex steroids such as estrogen induce actions by binding to a receptor. The two subtypes of estrogen receptor are Eα and ERß. However, the role of each subtype in the effects of estrogens on and food intake and body weight gain has not been conclusively determined.
Mice with a genetic knockout of the gene for Eα show an increase in fat tissue accumulation compared to wild-type mice, suggesting a role for Eα receptor in the attenuating effects of estrogens on body weight gain. In contrast, OVX Eα knockout mice treated with the estrogen estradiol (E2) gain more weight and accumulate more fat than untreated OVX Eα knockout mice, suggesting an additional role for ERß in fat tissue accumulation. Recently, investigators have been focusing on the promise of selective estrogen receptor modulators (SERMs). These drugs have varying affinities for the two subtypes of the estrogen receptor, and whether they stimulate or inhibit activity depends on the shape of the drug-receptor complex and the tissue composition of molecules that intEαct with the receptor. One hope is that SERMs can be developed that maintain the desirable positive effects but omit the negative effects of estrogens. Researchers have been working with two SERMs: 4,4',4"-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) which selectively activates Eα and 2,3-bis(4-hyroxyphenyl)-propionitrile (DPN) which selectively activates ERß.
A New Study
Researchers at Georgetown University have conducted studies using these SERMs to determine the roles of the Eα and ERß in mediating food intake and body weight gain in OVX rats. In addition to contributing to the understanding of the mechanisms by which estrogens modulate food intake and body weight, these studies help determine the feasibility of using SERMs in the future to prevent postmenopausal weight gain. The results of one study are the topic of a presentation, "Effect of Selective Estrogen Receptor Agonists on Body Weight Gain in Ovariectomized Rats." Darren M. Roesch, Ph.D., Division of Endocrinology and Metabolism & Center for the Study of Sex Differences in Health, Aging, and Disease, Georgetown University, Washington, DC will present his findings at the American Physiological Society's (APS) (www.the-aps.org) annual scientific conference, Experimental Biology 2003, being held April 17-21, 2004, at the Washington, D.C. Convention Center. Dr. Roesch's research is funded by grants from the Center for Biological Modulators (Dr. Sung-Eun Yoo, Director), Korea Research Institute of Chemical Technology, and the National Kidney Foundation of the National Capital Area.
Methodology
Rats were OVX and treated with daily injections of control substance, or E2, or one of a range of doses of the Eα selective drug PPT or the ERß selective drug DPN for 21 days. Rats were supplied liquid diet and water throughout the study. Body weights and food intake were measured daily.
Results
Dr. Roesch found the following:
Conclusions
The results of this study indicate that the Eα receptor is the primary mediator of the attenuating effects of estrogens on body weight gain, and indicate that E2 and the Eα selective drug reduce body weight gain in rats without reducing food intake. Based on these results, the author speculates that Eα-selective drugs may prove to be useful thEαpeutically to reduce postmenopausal weight gain in women.
The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 11,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.
Editor's Note: For further information or to schedule an interview with Dr. Roesch, please contact Donna Krupa at 703-967-2751 (cell), 703-527-7357 (office) or at djkrupa1@aol.com. Or contact the APS newsroom at 202-249-4009 between 9:00 AM and 6:00 PM EDT April 17-21, 2004.