Rapid onset and reversal of peripheral and central leptin resistance in rats offered chow, sucrose solution, and lard

We previously reported that rats offered choice diet (chow, 30% sucrose solution, lard) increase body fat by 130% within 3 weeks. We tested the effects of choice diet on the development of leptin resistance in rats. Intraperitoneal injection of 2 mg/kg leptin inhibited 14 h food intake and weight gain of all rats after 2 days and 4 days of diet. On day 8, choice rats were leptin insensitive and by day 16 they were resistant. Chow rats remained leptin responsive. A second study showed that on day 16 choice, but not chow rats, were centrally leptin resistant (1.5 μg leptin, 3rd ventricle). In both studies, rats were switched back to chow only after approximately 3 weeks on choice diet and were leptin responsive after 4 days. A third study showed that carcass fat was reduced by 30% 4 days after switching back to chow. A final experiment showed that leptin responsive chow rats, but not leptin resistant choice rats, increased energy expenditure by 12% during the 2.6 h after a central leptin injection. Thus, choice diet rapidly induces leptin resistance, but leptin responsiveness is quickly restored when choice is replaced with chow. This rapid onset and reversal of leptin resistance may be associated with changes in either substrate metabolism or adiposity.

► The choice diet induces peripheral and central leptin resistance within 16 days.
► Leptin responsiveness is restored by day 4 in choice rats switched back to chow.
► Choice rats lose ∼30% of carcass fat 4 days after switching back to chow only.
► Chow rats given leptin centrally increase heat production (kcal/h/bw0.75) by 12%.
► Choice rats given leptin centrally do not increase energy expenditure.