Augmenting leptin circadian rhythm following a weight reduction in diet-induced obese rats: short- and long-term effects.

The current study sought to examine whether leptin injections following a weight reduction in diet-induced obese rats would reduce both the enhanced food intake and body weight (BW) regain observed during the refeeding phase. Female Wistar rats (n = 100, 20 per group) were divided into 5 groups: (1) LEP rats were fed a high-fat (HF) diet (35% wt/wt) for 8 weeks to induce obesity and were then food-restricted (50% ad libitum) with a fortified high-fat diet for 2 weeks to induce a 20% BW loss. These rats were then refed the HF diet ad libtum for another 11 weeks. They were given leptin injections (200 microg/kg BW, twice daily, intraperitoneally ) for 19 days concomitant with the onset of refeeding. (2) SAL rats were treated in the same manner as LEP rats except that they were given saline injections; (3) PF rats were treated like SAL rats except that they were pair-fed with the LEP rats; (4) HFC rats were fed HF diet ad libitum; and (5) LFC rats were fed a low-fat (LF) diet (AIN-93M) ad libitum. Ten rats from each group were killed after leptin treatment and at the end of the study. Food and caloric intakes were monitored, and body composition and plasma glucose, insulin, and leptin levels were assessed at death. Leptin injections after a weight reduction briefly reduced energy intake during the first week only. After 19 days of treatment and to the end of the study, LEP and SAL rats were similar in energy intake, BW (LEP: 393 +/- 11.2 g, SAL: 371 +/- 14.1; difference not significant [NS]) and total body fat percent (LEP: 19.3 +/- 1.5, SAL: 17.6 +/- 1.5; NS). Leptin treatment induced hyperinsulinemia and insulin resistance. All of the metabolic abnormalities observed at the end of treatment period disappeared at the end of the study (8 weeks post-leptin injection). We conclude that bolus leptin injections to manipulate leptin circadian rhythm in diet-induced obese rats after a weight reduction caused temporary insulin resistance and hyperinsulinemia, and were ineffective in influencing food intake, BW, and fat content. Leptin resistance was evident following 1 week of treatment in this study. Leptin treatment had no effect on body fat content both short-term and long-term. Exogenous leptin treatment may, in the long run, increase leptin resistance in diet-induced obese animals. Hence, long-term leptin treatment may not be beneficial to obese individuals consuming a HF diet.