OBJECTIVE: To ®nd out whether leptin can attenuate hypometabolic torpor-like states of metabolic rate (MR) in adult lean animals, as it attenuates the morning suppression of thermoregulatory thermogenesis in suckling-age rat pups. DESIGN: Leptin effects on MR and food intake were studied in mice aged 4±7 months, in which a high incidence of exaggerated circadian reductions of MR had been induced by chronic food-restriction and, for comparison, in freefeeding mice. PROTOCOL: Continuous recordings of MR, for a group of seven mice maintained at an ambient temperature of 24 C, while they were repeatedly ± with pauses of at least six days ± treated for three consecutive days with either recombinant murine leptin (20, 200 or 600 pmol Á g 71 Á d 71 ) or saline. RESULTS: Leptin treatment caused dose-dependent 5±15% increases in energy expenditure by moderating the decreases in MR during the circadian minima, without affecting either the MR during the circadian maxima or food intake. Similar treatment of free-feeding mice caused dose-dependent decreases of food intake without changing MR. CONCLUSION: Leptin controls thermoregulatory energy expenditure when food supplies are scarce and changes food intake, rather than energy expenditure, when food is abundant.

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Leptin responsiveness and gene dosage for leptin receptor mutation (fa) in newborn rats. Am. J. Physiol. 276 (Endocrinol. Metab. 39): E836-E842, 1999.-To determine the degree to which the leptin receptor mutation (fa) influences the responsiveness to leptin during the first postnatal week, we injected recombinant leptin (600 pmol · g Ϫ1 · day Ϫ1 sc from day 1 to day 7) into wild-type (ϩ/ϩ), heterozygous (ϩ/fa), and fatty (fa/fa) rat pups. Growth and final body fat content of these leptin-treated pups were compared with those of saline-treated littermates of the same genotype. The body mass of the leptin-treated ϩ/ϩ pups, but not that of the ϩ/fa and fa/fa pups, increased more slowly than that of their respective controls, and fat content at day 7 was reduced by 37% in ϩ/ϩ pups, by 22% in ϩ/fa pups, but not at all in fa/fa pups. Plasma leptin remained excessively high throughout the day under this treatment, but a 30-fold lower leptin dose, causing only moderate changes of plasma leptin, still reduced the body fat of ϩ/ϩ pups significantly. We conclude that leptin participates in the control of even the earliest stages of fat deposition and that the response to supraphysiological doses of leptin is markedly reduced in 1-wk-old pups with one fa allele and absent in pups with two fa alleles.The body mass of the leptin-treated ϩ/ϩ pups increased more slowly than that of their control litter-E837 LEPTIN RESPONSIVENESS AND RECEPTOR DEFECT IN RAT PUPS

To find out whether the most characteristic physiological traits distinguishing suckling-age fa/fa pups from lean littermates also differ between +/+ and +/fa littermates, we analyzed the body composition and cold defense of 7- and 16-day-old pups and the plasma concentrations of insulin, glucose, triglycerides, and free fatty acids in 16-day-old pups. Zucker rat x Brown Norway hybrid pups were genotyped by using a molecular marker within 0.5 cM of the fa gene. At both ages the +/fa pups had significantly more body fat than their +/+ littermates. At 7 days this difference was as large as that between +/fa and fa/fa pups, but at 16 days it was only one-seventh of the fa/fa vs. +/fa difference. In contrast, there were no heterozygote differences for three parameters that show crucial abnormalities in the fa/fa pups: thermoregulatory thermogenesis and plasma concentrations of insulin and triglycerides. The physiological mechanisms underlying the increased fat content of +/fa pups thus differ from those known to fuel most of the excessive fat deposition of their fa/fa littermates.