Leptin resistance with age-related obesity

Leptin, synthesized by white adipose tissue, interacts with the appetite an d satiety centers to regulate body weight, and this hormone contributes to the regulation of both food intake and energy expenditure. Serum leptin is elevated in most obese humans, and that obesity persists in spite of the el evated leptin, suggesting leptin resistance. The F-344xBn rat strain, simil ar to humans, demonstrates a steady increase in body fat and serum leptin i nto early senescence. Thus, these aged rats become obese in spite of the el evated leptin, suggesting the relationship between leptin, adiposity, and f ood intake is altered with age. Leptin modulates a number of neuropeptides in the hypothalamus, including neuropeptide Y I(NPY). NPY both stimulates f eeding and suppresses thermogenesis in brown adipose tissue. Following lept in infusion, the decrease in food intake and the increase in energy expendi ture were blunted in the aged rats. Moreover, leptin decreased NPY mRNA in young but not senescent rats, suggesting that leptin signal transduction ma y be impaired. Leptin receptor signal transduction involves phosphorylation of cytosolic signal transducer and activator of transcription (STAT) prote ins, specifically phosphorylation of STAT3 (P-STAT3). Leptin-induced P-STAT 3 levels were unchanged with age, but the dose of leptin required for half maximal stimulation was 5-fold greater in the older rats, suggesting that s ensitivity for leptin signal transduction is diminished with age. In summar y, aged rats demonstrate a reduced responsiveness to leptin, and the mechan ism may involve impaired suppression of hypothalamic NPY mRNA that may be a consequence of impaired leptin signal transduction. This leptin:resistance may be due to either the elevated obesity and serum leptin with age or due to age itself or both.