Resistance to the anorexic and thermogenic effects of centrally administrated leptin in obese aged rats

The aim of the present study was to determine whether the anorexic and ther mogenic effects of leptin were attenuated in overweight aged rats following intracerebroventricular (i.c.v.) injection of murine leptin. Male F344/BN rats of two ages (6 months: young (n = 20) and 24 months: old (n = 18)) wer e divided into three groups (control, pair-fed and leptin) and were treated with either vehicle (artificial cerebrospinal fluid) or leptin (15.6 mug/d ay) for 3 days. There was an age-related increase in basal food intake (20/-2%), serum leptin levels (363+/-106%) and leptin (OB) mRNA (72+/-16%) in perirenal white adipose tissue (PWAT). In contrast, basal expression of hyp othalamic NPY mRNA and brown adipose tissue (BAT) uncoupling protein 1 (UCP 1) mRNA was reduced significantly (-35+/-4% and -51+/-5%, respectively) wit h age. I.c.v. leptin treatment had a significantly greater effect in reduci ng food intake (-42+/-5% vs. -23+/-4%), serum leptin levels (-55+/-7% vs. 1 0+/-2%) and PWAT OB mRNA (-46+/-2% vs. 10+/-5%) in young than in old rats. Similarly, central leptin treatment also had a greater effect in suppressin g hypothalamic NPY mRNA expression in young (-23+/-4%) than in old (-8+/-4% ) rats compared with their age-matched pair-fed treated rats. The stimulato ry effect of i.c.v. leptin treatment on BAT UCP1 mRNA expression was also s ignificantly greater in young rats (45+/-8%) than in old rats (10+/-6%) com pared with age-matched pair-fed rats. Our previous report indicated that th ese overweight aged rats were resistant to peripheral administered leptin. The present data extend those findings and demonstrate that the impaired an orexic and metabolic effects of leptin are centrally mediated. This leptin resistance may be due to either the elevated obesity and serum leptin with age or due to age itself or both. The development of leptin resistance with age may contribute to the hyperphagia, hyperleptinemia and impaired energy balance with age. (C) Published by Elsevier Science B.V.