Abstract
Circulating leptin concentrations correlate with fat mass and signal the status of somatic energy stores to the brain. Previous studies suggest that diet-induced elevations of body weight increase body weight “set-point”. To assess whether chronic hyperleptinemia is responsible for this shift in defended body weight, we elevated circulating leptin concentrations in lean mice to those comparable to diet-induced obese mice for eighteen weeks. We hypothesized that following cessation of leptin infusion, a higher body weight would be defended. Compared to saline-infused controls, leptin-infused mice had elevated circulating leptin concentrations, gained less weight, yet had similar metabolic rates. Following cessation of leptin administration, leptin-infused mice gained some weight yet plateaued at 5–10% below controls. These results suggest that, unlike mice rendered hyperleptinemic by diet-induced weight gain, leptin-infused mice do not subsequently “defend” a higher body weight, suggesting that hyperleptinemia per se does not mimic the CNS consequences of chronic weight gain.
Highlights
In weight-stable individuals, circulating leptin concentrations are directly proportional to fat mass [1]
The WT mice that were switched to the HFD became leptin resistant, but the leptin-supplemented Lepob mice, which became comparably fat, were not leptin resistant, suggesting that hyperleptinemia per se is required to induce the leptin resistance associated with obesity [22]
We have shown that elevation of body weight for a period of 16 weeks in C57BL/6J mice results in metabolic defense of the higher body weight as manifest in reduced energy expenditure normalized to body mass/ composition following weight reduction [5]
Summary
In weight-stable individuals, circulating leptin concentrations are directly proportional to fat mass [1]. 48-h fasted male mice show starvation-induced changes in gonadal, adrenal, and thyroid axes that are all leptin-reversible without significant effect on body weight or on re-feeding after starvation [7] Taken together, these findings indicate that circulating leptin concentration is a major afferent signal of overall energy availability, and that the hypometabolic phenotype of weight-reduced individuals is the result e at least in part e of a state of perceived relative leptin insufficiency [8]. In contrast to the potent effect of leptin administration to humans or rodents with leptin insufficiency (weight-reduced, fasted, or congenitally leptin deficient), administration of physiological or supraphysiological doses of leptin to rodents or humans at usual or increased body weight has little to no effect on energy expenditure or food intake [3,9e11] Such data suggest that leptin-sensing circuitry in the CNS is “designed” to be inherently more responsive to a deficit of ambient leptin rather than an excess [7,12].
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