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Can Changes in Plasma Insulin Concentration Explain the Variability in Leptin Response to Weight Loss in Obese Women with Normal Glucose Tolerance?¹

Stanford University School of Medicine, Stanford, California 94305; Geriatric Research, Education, and Clinical Center, Veterans Administration Palo Alto Health Care System, Palo Alto, California 94304; and Shaman Pharmaceuticals, Inc., South San Francisco, California 94080

Address all correspondence and requests for reprints to: Gerald M. Reaven, M.D., Shaman Pharmaceuticals, Inc., 213 East Grand Avenue, South San Francisco, California 94080-4812. E-mail: greaven{at}shaman.com

The aim of this study was to test the hypothesis that the fall in circulating insulin concentration associated with moderate weight loss determines the associated decrease in plasma leptin concentration. For this purpose, 12 healthy, nondiabetic, obese women were studied before and after an average weight loss of 9.5 kg (11.2% of initial body weight). Plasma leptin concentrations fell from a mean (±SE) value of 35 ± 3 to 17 ± 2 ng/mL (P < 0.001) in association with the loss of weight. However, there was no correlation between the decline in leptin concentration and the associated fall in weight, body mass index, fat mass, or percent body fat. Furthermore, no correlation was seen among changes in fasting plasma glucose or insulin concentrations, the 8-h integrated plasma glucose response to breakfast and lunch, or the estimate of insulin-mediated glucose disposal. The only measured variable that correlated with the fall in plasma leptin concentration (r = 0.78; P < 0.005) was the decline in the 8-h integrated plasma insulin response after weight loss (from 304 ± 44 to 232 ± 36 µU/8 h·mL; P < 0.001). Finally, multivariate regression analysis, using various estimates of degree of obesity, insulin resistance, integrated glucose response, and integrated insulin response as dependent variables, indicated that only the insulin response was independently related to the decrease in leptin concentration (P = 0.035). The fall in integrated insulin response accounted for 66% of the variance in leptin concentrations after weight loss, and this was true no matter what the estimate of change in degree of obesity. In addition to offering an explanation for the variance in postweight loss leptin concentrations, these data provide further evidence of the importance of ambient insulin concentrations in the regulation of plasma leptin concentrations.

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