Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice


The increasing global prevalence of obesity and its associated disorders points to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules that have mRNA expression profiles similar to that of celastrol, a naturally occurring compound that we previously identified as a leptin sensitizer. Through this process, we identified another naturally occurring compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin-A treatment of mice with diet-induced obesity (DIO) resulted in a 20–25% reduction of body weight, while also decreasing obesity-associated abnormalities, including hepatic steatosis. Withaferin-A treatment marginally affected the body weight of ob/ob and db/db mice, both of which are deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism that occur independently of its leptin-sensitizing effect. Our results show that the metabolic abnormalities of DIO can be mitigated by sensitizing animals to endogenous leptin, and they indicate that withaferin A is a potential leptin sensitizer with additional antidiabetic actions.

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Figure 1: Identification of withaferin A as sharing a similar gene expression profile with celastrol.
Figure 2: Withaferin A reduces the body weight and food intake of mice with DIO but not that of lean mice.
Figure 3: Leptin-signaling-deficient mice are resistant to the weight-reducing effect of withaferin A.
Figure 4: Withaferin A increases leptin sensitivity in the hypothalamus of mice with DIO.
Figure 5: Withaferin A reduces ER stress.
Figure 6: Withaferin A's beneficial effect on metabolic homeostasis.

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We greatly appreciate M. White for his time spent on critical reading of our manuscript and for his contributions and suggestions. We thank S. Cabi and I. Cakir for their initial experimental contributions to this work. We also thank S. Mert and B. Akosman for their help on some of the experiments, and S. Huang and M. Mulcahey-Maynard for measurement of serum T3 levels. TSC+/+ and TSC−/− MEFs were kindly provided by D. Kwiatkowski (Dana-Farber Cancer Institute). This work was mainly supported by funds provided to U.O. from the Department of Medicine, Boston Children's Hospital, and also by grant R01DK098496 (U.O.) from the US National Institutes of Health and American Diabetes Association Career Development grant #7-09-CD-10 (U.O.).

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U.O. came up with the idea to investigate compounds that have similar gene expression to celastrol by using CMAP. U.O. directed this and subsequent analyses and picked withaferin A as a candidate for the treatment of type 2 diabetes and obesity. J. Lee, J. Liu, X.F., M.A.S.H., P.M., D.I. and J.W.C. performed experiments under the direction of U.O. U.O., J. Lee, J. Liu and X.F. analyzed data. U.O. wrote the manuscript, and J. Lee, J. Liu and X.F. were involved in the writing and preparation of the manuscript.

Correspondence to Umut Ozcan.

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Competing interests

U.O. is a scientific founder, shareholder, and scientific advisory board and board of directors member of ERX Pharmaceuticals.

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Lee, J., Liu, J., Feng, X. et al. Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice. Nat Med 22, 1023–1032 (2016). https://doi.org/10.1038/nm.4145

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