EFFECTS OF INTRACEREBROVENTRICULAR INFUSION OF LEPTIN IN OBESE ZUCKERRATS

The obese Zucker rat (OZR) exhibits a missense mutation in the cDNA fo r the leptin receptor, producing a single amino acid substitution in t he extracellular domain of the receptor, A mutation in the leptin rece ptor gene of the db/db mouse prevents the synthesis of the long splice variant of the receptor, The possibility that the OZR, like the db/db mouse, is refractory to the actions of murine leptin was tested by in fusing the protein intracerebroventricularly via a minipump for 7 days , Lean Zucker rats (LZR) infused with leptin acted as positive control s, and other groups of OZR and LZR were infused with vehicle. In LZR, leptin reduced bodyweight and food intake and increased brown adipose tissue (BAT) temperature, Plasma corticosterone increased (61%) in the se rats, and plasma triglycerides fell (78%), Leptin treatment improve d tolerance to an oral glucose load (16% reduction in the area under t he blood glucose curve) while lowering plasma insulin. In OZR, the act ions of leptin were blunted, Food intake was slightly, but not signifi cantly, reduced, Although there was a reduction in the rate of increas e in body mass, the effect of leptin was about half that seen in LZR, BAT temperature and glucose tolerance were unchanged, In contrast to t he elevated plasma corticosterone seen in LZR, leptin reduced the leve l of this hormone (27%) in OZR, In OZR and LZR treated with leptin, th e plasma leptin levels were increased 24-fold and 47-fold, respectivel y, The results suggest that leptin retains some efficacy in OZR, altho ugh these rats are less responsive than LZR.