Abstract
The prevalence of obesity increases with age in humans and in rodents. Age‐related obesity is characterized by leptin resistance and associated with heightened risk of metabolic disorders. However, the effect of leptin resistance per se has been difficult to disentangle from other effects of aging. Here we demonstrate that celastrol, a natural phytochemical that was previously shown to act as a leptin sensitizer, induces weight loss in aged animals, but not in young controls. Celastrol reduces food intake and lowers fasting glucose without affecting energy expenditure. Unexpectedly, administration of celastrol just before the dark period disrupted circadian rhythms of sleep and activity. This regimen was also associated with loss of lean mass an outcome that would not be desirable in elderly patients. Adjusting the timing of celastrol administration by 12 hr, to the beginning of the light period, avoided interference with circadian rhythms while retaining the reductions in body weight and adiposity. Thus, targeting leptin signaling is an effective strategy to ameliorate age‐associated weight gain, and can profoundly impact circadian rhythms.
Highlights
The aging population is rising worldwide, with aged individuals 65 years or older projected to represent more than 20% of the population in the United States by 2035 (Mathus‐Vliegen, 2012)
We report that celastrol ameliorates leptin resistance in aged mice and decreases body weight, but unexpectedly had adverse effects on the circadian rhythms of locomotor activity and sleep when administered prior to the lights off active period
We found that 2 days of celastrol pre‐treatment sensitized aged mice to leptin's action on food intake and body weight (Figure 1e,f)
Summary
The aging population is rising worldwide, with aged individuals 65 years or older projected to represent more than 20% of the population in the United States by 2035 (Mathus‐Vliegen, 2012). Aging in humans and rodents is characterized by an expansion of adipose mass in middle age that is not resolved, despite increased circulating leptin. We hypothesized that celastrol might be an effective strategy to restore leptin sensitivity and body weight homeostasis in aged mice, which, like obese mice, display hyperleptinemia and leptin resistance. We report that celastrol ameliorates leptin resistance in aged mice and decreases body weight, but unexpectedly had adverse effects on the circadian rhythms of locomotor activity and sleep when administered prior to the lights off active period. Celastrol is effective in treating age‐related obesity, but the time of delivery has a profound impact on the outcome of treatment
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