Abstract
Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the responses of 23 brain regions to exogenous leptin in 4 different groups of weight- and/or diet-perturbed mice. Responses to leptin were assessed by quantifying pSTAT3 levels in brain nuclei 30 minutes following 3 mg/kg intraperitoneal leptin. HFD attenuated leptin sensing throughout the brain, but weight loss did not restore central leptin signaling to control levels in several brain regions important in energy homeostasis, including the arcuate and dorsomedial hypothalamic nuclei. Effects of diet on leptin signaling varied by brain region, with results dependent on the method of weight loss (restriction of calories of HFD, ad lib intake of standard mouse chow). High fat diet attenuates leptin signaling throughout the brain, but some brain regions maintain their ability to sense leptin. Weight loss restores leptin sensing to some degree in most (but not all) brain regions, while other brain regions display hypersensitivity to leptin following weight loss. Normal leptin sensing was restored in several brain regions, with the pattern of restoration dependent on the method of weight loss.
Highlights
Many co-morbidities associated with obesity are mitigated by long-term maintenance of even modest (10%) body weight reduction [1]
After 12 weeks of ad libitum access to low-fat diet, the body weights of previously obese HF-LF mice were indistinguishable from those of never-obese LF controls (Fig 1); the majority of the weight loss of HF-LF mice was due to a reduction in fat mass (Fig 2A)
Though both caloric restriction (CR) and HF-LF mice exhibited significant reductions in fat mass compared to HF mice, fat-free mass for each group remained significantly higher than LF mice (Fig 2A)
Summary
Many co-morbidities associated with obesity are mitigated by long-term maintenance of even modest (10%) body weight reduction [1]. Achievement and maintenance of reduced body weight in both mice [3] and humans [4] is accompanied by a significant decrease in energy expenditure that is ~15–20% greater than can be accounted for by changes in body mass and composition [3, 4]. This decrease in energy expenditure is due, at least in part, to the metabolic consequences of reductions in circulating leptin concentrations that are, in turn, the consequence of (and proportionate to) decreases in body fat. The administration of “replacement” doses of leptin to weight reduced humans [10,11,12] and rodents [13,14,15] rectifies most of these bioenergetic and behavioral phenotypes, confirming that brain sensing of leptin plays a critical role in mediating these responses to reduced body weight
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