The natural product rotundic acid treats both aging and obesity by inhibiting PTP1B
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Jie Zhu1,2, Yongpan An1, Xin Wang1
1Peking University International Cancer Institute and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
Abstract:
The occurrence of obesity is associated with age. But their interplay remains mysterious. Here, we discovered that rotundic acid (RA), a plant-derived pentacyclic triterpene, was a powerful agent for both anti-aging and treating obesity. Considering that obese individuals decrease the appetite-suppressing and energy-expenditure-enhancing functions of leptin leading to obesity, we found RA was a leptin sensitizer, evidenced by observations that RA enhanced the leptin sensitivity to normal diet-induced obese (DIO) mice, and had minimal or no use to normal lean mice, leptin receptor-deficient (db/db) mice, and leptin-deficient (ob/ob) mice. Simultaneously, RA significantly increased energy expenditure, BAT thermogenesis, and glucose metabolism in DIO mice, as the results of enhancing leptin sensitivity. Regarding mode of action, we demonstrated that RA is a noncompetitive inhibitor of leptin negative regulators protein tyrosine phosphatase 1B (PTP1B) and T-cell PTP through interaction with their C-terminus, thus leading to weight loss through enhancing leptin sensitivity. Besides, we showed that deletion of yPTP1 in yeast completely abolished the lifespan extension effect of RA, celstrol, and withaferin A, while these compounds exhibited PTP1B inhibition activity. Furthermore, PTP1B knockdown extend lifespan in yeast and human cells, indicating PTP1B is an important factor regulating cellular aging.
Insights
Rotundic acid (RA) is a plant compound that combats obesity and aging by enhancing leptin sensitivity. It works by inhibiting protein tyrosine phosphatase 1B (PTP1B), a key regulator of cellular aging and metabolism.
Area of Science:
- Biochemistry
- Metabolism
- Aging Research
Background:
- Obesity is linked to aging, but the interaction is poorly understood.
- Leptin resistance contributes to obesity by impairing appetite suppression and energy expenditure.
- Protein tyrosine phosphatase 1B (PTP1B) is implicated in metabolic disorders and aging.
Purpose of the Study:
- To investigate the effects of rotundic acid (RA) on obesity and aging.
- To determine if RA can improve leptin sensitivity.
- To elucidate the mechanism by which RA exerts its effects.
Main Methods:
- Administered RA to diet-induced obese (DIO) mice, leptin receptor-deficient (db/db) mice, and leptin-deficient (ob/ob) mice.
- Assessed leptin sensitivity, energy expenditure, BAT thermogenesis, and glucose metabolism.
- Investigated RA's interaction with PTP1B and T-cell PTP in vitro and in yeast models.
- Examined the role of PTP1B in aging using yeast and human cell models.
Main Results:
- RA enhanced leptin sensitivity and improved metabolic parameters in DIO mice.
- RA increased energy expenditure, BAT thermogenesis, and glucose metabolism in DIO mice.
- RA noncompetitively inhibited PTP1B and T-cell PTP by interacting with their C-terminus.
- PTP1B inhibition by RA and other compounds extended lifespan in yeast, and PTP1B knockdown extended lifespan in yeast and human cells.
Conclusions:
- Rotundic acid is a potent leptin sensitizer with anti-aging and anti-obesity properties.
- RA's mechanism involves the inhibition of PTP1B, a regulator of both metabolism and cellular aging.
- PTP1B is a critical factor in regulating lifespan and represents a potential therapeutic target for age-related metabolic diseases.
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