The leptin sensitizer celastrol reduces age‐associated obesity and modulates behavioral rhythms
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....
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| Veröffentlicht in: | Aging cell 2019-06, Vol.18 (3), p.e12874-n/a |
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| creator | Chellappa, Karthikeyani Perron, Isaac J. Naidoo, Nirinjini Baur, Joseph A. |
| description | 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. |
| doi_str_mv | 10.1111/acel.12874 |
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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. 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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. 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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.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>30821426</pmid><doi>10.1111/acel.12874</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adipose tissue Age Aging Aging - drug effects Animals Behavior, Animal - drug effects Body weight Body Weight - drug effects Body weight gain Body weight loss Circadian Rhythm - drug effects Circadian rhythms Eating - drug effects Energy expenditure Energy Metabolism - drug effects Food intake Geriatrics Glucose Tolerance Test Government finance Injections, Intraperitoneal Leptin Leptin - administration & dosage Leptin - antagonists & inhibitors Leptin - pharmacology Male Metabolic disorders Mice Obesity Obesity - drug therapy Obesity - metabolism Original Paper Original Papers Rodents Sleep Triterpenes - administration & dosage Triterpenes - pharmacology Weight control Weight loss Weight Loss - drug effects |
| title | The leptin sensitizer celastrol reduces age‐associated obesity and modulates behavioral rhythms |
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