Peripheral and hypothalamic leptin resistance with age-related obesity.

Leptin 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 elevated leptin, suggesting leptin resistance. The F-344xBN rat strain, similar to humans, demonstrates a steady increase in body fat and serum leptin into early senescence. Thus, these aged rats become obese in spite of the elevated leptin, suggesting the relationship between leptin, adiposity, and food intake is altered with age. Following both peripheral and central leptin administration, the decrease in food intake and the increase in energy expenditure are blunted in the older obese rats, The extent of the blunting is greater following peripheral leptin, suggesting both peripheral and hypothalamic components to the leptin resistance. Moreover, leptin decreased neuropeptide Y (NPY) mRNA in young but not senescent rats, suggesting that leptin signal transduction may be impaired. Leptin receptor signal transduction involves phosphorylation of cytosolic signal transducer and activator of transcription (STAT) proteins, specifically phosphorylation of STAT3 (P-STAT3). Leptin-induced P-STAT3 levels and P-STAT3 transcription factor binding were diminished with age. In summary, aged rats demonstrate a reduced responsiveness to peripheral and central leptin, and the mechanism may involve impaired suppression of hypothalamic NPY mRNA that may be a consequence of impaired leptin signal transduction. This leptin resistance may have both a peripheral and central component and may be due to either the elevated obesity and serum leptin with age or due to age itself or both.