Leptin Resistance with Age-Related Obesity

Abstract

Leptin, synthesized by white adipose tissue, interacts with the appetite and 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 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. Leptin modulates a number of neuropeptides in the hypothalamus, including neuropeptide Y (NPY). NPY both stimulates feeding and suppresses thermogenesis in brown adipose tissue. Following leptin infusion, the decrease in food intake and the increase in energy expenditure were blunted in the aged rats. Moreover, leptin decreased 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 were unchanged with age, but the dose of leptin required for half maximal stimulation was 5-fold greater in the older rats, suggesting that sensitivity for leptin signal transduction is diminished with age. In summary, aged rats demonstrate a reduced responsiveness to 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 be due to either the elevated obesity and serum leptin with age or due to age itself or both.