M. Rosenbaum, M. Nicolson, J. Hirsch, S.B. Heymsfield, D. Gallagher, F. Chu, R.L. Leibel, "Effects of Gender, Body Composition, and Menopause on Plasma Concentrations of Leptin,"

July 6, 1998

M. Rosenbaum, M. Nicolson, J. Hirsch, S.B. Heymsfield, D. Gallagher, F. Chu, R.L. Leibel, "Effects of Gender, Body Composition, and Menopause on Plasma Concentrations of Leptin," Journal of Clinical Endocrinology and Metabolism, 81:3424-7, 1996. (Cited more than 85 times since publication)

Comments by Michael Rosenbaum, associate professor of pediatrics and medicine at Columbia University.

The discovery of the obese (ob) gene by a group of investigators led by Jeffrey Friedman and Rudolph L. Leibel at Rockefeller University gave hope to millions of people struggling to lose weight. Early studies showed that leptin administration, as expected, corrected the increased food intake and low energy output of ob mutant animals. Higher doses of leptin produced weight loss in wild mice. When it was shown that most obese humans have high concentrations of circulating leptin and no evidence of mutations in their leptin genes, scientists began to wonder if some instances of obesity might be caused by insensitivity to leptin.

"In our model, leptin functions more like an emergency switch than a rheostat."
Michael Rosenbaum

Scientists also had not yet considered whether levels of leptin were best correlated with fat mass (FM), relative body fatness, or lean mass (LM) in subjects; and they were still unsure if higher levels of leptin observed in women were due solely to the fact that women generally have a higher percentage of body fat than men. A Rockefeller University research team led by Leibel and Michael Rosenbaum, now professors of pediatrics and medicine at Columbia University, considered these questions in a highly cited paper published two years ago. In the process, they gave other scientists a new model for understanding the complex workings of leptin.

Michael Rosenbaum
The Rockefeller team and investigators from the New York Obesity Research Center compared several body fat indices with concentrations of circulating leptin. Body mass index (BMI)--height ÷ weight2--percent body fat, FM, and LM were measured in 67 subjects (26 men, 20 premenopausal women, and 21 postmenopausal women). All study recruits were at their maximal lifetime weight and had maintained this weight within two kg for at least six months prior to examination. Females classified as postmenopausal had not menstruated for at least seven years. Although some subjects were classified as obese, all were considered healthy.

The research team found that FM was highly correlated with leptin in all subjects; leptin was best correlated with absolute body fat mass rather than indicators of relative body fatness such as BMI. Leptin, however, showed no relationship to age, LM, or abdominal or gluteal adipocyte volume. Most significantly, the research team observed that at equal fat masses, pre- and post-menopausal women had circulating leptin concentrations that were two- to threefold higher than men.

To consider the possibility that higher levels of leptin in women were due to lower overall lean mass--hence a lower volume of distribution for this adipocyte-derived protein, compared to men--the research team examined the effect of gender on leptin when adjusted for FM and indices of body fatness. "Even when adjusted for variation in FM, leptin was significantly higher in women than in men," Rosenbaum says. "This finding is important because it suggests that there are gender-based, hormonal, or genetic differences in circulating concentrations of leptin."

Rosenbaum also says the study has attracted the attention of researchers because it provided a new model for describing and understanding the effects of leptin on systems of energy homeostasis. For example, the research team found no significant differences in fat-mass-adjusted concentrations of circulating leptin between obese and never-obese subjects. "This clearly suggested that obesity is not due to a defect in the production of leptin, as was widely thought at the time," Rosenbaum says. "In our model, leptin functions more like an emergency switch than a rheostat. When leptin falls below a very individualized level ['set-point'] due to reduced fat mass, it will provoke changes in energy expenditure and food intake."

Since the study, Rosenbaum and Leibel have continued to focus on the effects of leptin on body composition. In one recent paper, they considered the effects of weight change on leptin concentrations and energy expenditure (M. Rosenbaum et al., Journal of Clinical Endocrinology and Metabolism, 82:3647-53, 1997). They found that leptin concentrations (adjusted for fat mass) were significantly lower during weight loss than during weight maintenance at the same weight and fat mass. Additionally, circulating leptin was significantly lower during maintenance of reduced weight in women and significantly higher during weight-gain maintenance in men. Rosenbaum says, "These data suggest that leptin's most promising therapeutic use may be to help a person maintain a reduced amount of body fat after losing weight. Exogenous leptin might replace the signal that would have been generated by the lost adipose tissue."

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