Withaferin-A counteracts obesity by increasing leptin sensitivity
A low dose of a steroid-like substance in the Indian plant Ashwagandha may make it easier for fat people to become slim again, suspects researchers at Harvard Medical School suspect. In their animal study, fattened mice that received withaferin-A lost a quarter of their weight in 3 weeks.
The researchers experimented with normal mice that had become obese because the researchers had given them feed with extra calories.
The researchers injected part of the test animals withaferin-A directly into their small intestine. If the mice had been 100 pounds of people and had swallowed withaferin-A in capsules, then they would have used 25 milligrams of withaferin-A roughly every day.
Administration of withaferin-A reduced the body weight of the mice [lower left]. This was mainly because withaferin-A had the animals eat less [bottom right].
Withaferin-A reduced the fat mass. Although the mice in the withaferin A group lost weight, their lean body mass remained intact.
The administration of withaferin-A normalized the concentration of leptin in the blood of the test animals.
The researchers repeated experiments with slender mice with a normal leptin level. In them, withaferin-A had no effect on body weight and body composition. The researchers also repeated their tests with ob/ob mice that do not produce leptin due to a genetic error, and with db/db mice with a defect leptin receptor does not work. Both mouse types eat so much and become fat. In those animals, withaferin-A had hardly any effect.
The body makes more leptin when the fat reserves grow. This reduces appetite. When the fat reserves shrink, the production of leptin goes down again, and the appetite increases again. However, if you eat too much for a long time, this mechanism gets disrupted. The body becomes 'deaf' for leptin. Supplementation with withaferin-A increases leptin sensitivity, the researchers think.
"More than two decades have passed since the historic discovery of leptin by Friedman and coworkers, [Dis Model Mech. 2012 Sep;5(5):576-79.] but no viable leptin-centric treatment for obesity has been developed to date", te researchers write. "Soon after the initial publications on leptin, it was suggested that obesity is a condition of leptin-resistance."
"Over the course of the last twenty years, hopes for a leptin-oriented treatment of obesity have progressively diminished, as many attempts at re-sensitizing the brains of obese individuals to endogenous leptin failed. These unsuccessful efforts to increase leptin sensitivity and utilize the hyperleptinemic state of obesity to treat the condition also contributed substantially to the debate on whether or not leptin resistance actually exists."
Treatment of high fat diet-fed obese and hyperleptinemic mice with withaferin A led to a robust reduction in food intake as well as in body weight. Both changes are dependent on high levels of circulating leptin. As the leptin levels gradually decrease over the treatment period, the effect of withaferin A also gradually diminishes. Also, no withaferin A-induced changes in food consumption or in body weight were observed in lean mice, which have low levels of circulating leptin."
"Withania somnifera extracts, which also contain withaferin A, have been used by humans for centuries, and the leptin system is strongly preserved among mammals including mice and humans. Considering all of this information, we believe that translating the use of withaferin A for the treatment of obesity in humans holds great promise for the future."
Nat Med. 2016 Sep;22(9):1023-32.
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