The role of leptin resistance in the lipid abnormalities of aging

Leptin resistance has been implicated in the pathogenesis of obesity-relate d complications involving abnormalities of lipid metabolism that resemble t hose of old age. To determine whether development of leptin resistance in a dvancing age might account for such abnormalities, we compared the effects of hyperleptinemia (>40 ng/ml) induced in 2-month-old and 18-month-old lean wild-type (+/+) Zucker diabetic fatty rats by adenovirus gene transfer. Th e decline in food intake, body weight, and body fat in old rats was only 25 %, 50%, and 16%, respectively, of the young rats. Whereas in young rats pla sma free fatty acids fell 44% and triacylglycerol (TG) 94%, neither changed in the rats. In hyperleptinemic young rats, adipocyte expression of preadi pocyte factor 1 increased dramatically and leptin mRNA virtually disappeare d; there was increased expression of acyl CoA oxidase, carnitine palmitoyl transferase 1, and their transcription factor peroxisome proliferator-activ ated receptor alpha, accounting for the reduction in body fat. These hyperl eptinemia-induced changes were profoundly reduced in the old rats. On a hig h-fat diet, old rats consumed 28% more calories than the young and gained 1 .5x as much fat, despite greater endogenous hyperleptinemia. Expression of a candidate leptin resistance factor, suppressor of cytokine signaling 3 (S OCS-3), was compared in the hypothalamus and white adipocytes of young and old rats before and after induction of hyperleptinemia; hypothalamic SOCS-3 mRNA was similar to 3x higher in old rats before, whereas it was 3x higher in WAT after, hyperleptinemia. We conclude that the anorexic and antilipop enic actions of leptin decline with age, possibly through increased SOCS-3 expression, and that this could account for the associated abnormalities in lipid metabolism of the elderly.