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It is unclear which mechanisms cause the age-dependent alterations in the regulation of bodyfat scales circulating leptin concentrations. In the obese (ob/ob) mouse, leptin secretion is absent due to a mutation bodyfat scales (1, 2), but as the lack of association between leptin and body fat occurring with age in humans appears to be a general phenomenon, there is little reason to suspect any specific genetic cause. More studies, including stimulation of leptin secretion, are needed to determine the nature bodyfat scales of the low leptin levels in terms of capacity of the adipocytes to secrete leptin, protein binding and composition in the circulation, and leptin clearance. Another interesting observation in our study is that there is a negative correlation between circulating levels of leptin and testosterone among the older subjects. It has been shown that leptin may be a key link between energy stores (or nutritional status) and the reproductive axis (22), and it is intriguing that our observation of a loss of correlation between leptin in the circulation and body fat stores in both men and women after middle age coincides with menopause in women and the age-related decline in testosterone in men.
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