Umut Ozcan and other researchers at Harvard Medical School have used a unique computer-based drug-screening approach to discover a compound that caused up to 45% of ‘fat weight loss’ in diet-induced obese mice by sensitizing the hunger suppression hormone Leptin. Given the known enormity of obesity and its associated lifespan and life-quality reducing diseases, the compound Celastrol — shown more effective than gastric bypass surgery — is truly exciting.

When energy levels in the body are sensed to be high, fat cells release the hormone Leptin, which travels to the hypothalamus of the brain to inhibit hunger. Leptin’s historic discovery two decades ago initially generated buzz as a potential treatment of obesity; but this quickly fell flat when it was found that, counter-intuitively, obese individuals are hyperleptinemic (high levels of circulating leptin). Furthermore, administering leptin to obese mice does not reduce weight, though it does in lean mice. This led scientist to think of obesity as an “insensitivity” or “resistance” to leptin.

Ozcan found another piece to the puzzle one decade ago when he showed that, the UPR or unfolded protein response — a condition caused when the endoplasmic reticulum (ER) is under stress — causes Leptin resistance. Scientists have previously been unsuccessful in finding druggable single molecule targets in the UPR, in part due to the complexity and at times paradoxical nature of the UPR.

So instead, in this study, Ozcan used a variety interventions that reduce ER stress in mice to create a gene expression profile that represents a return to the homeostatic ER condition. He then compared his experimentally-determined expression profiles to an existing database containing expression profiles from human cells that were treated with more than one thousand small molecules. Ozcan found that Celastrol (a compound isolated from the Chinese herbal medicine Thunder God Vine) produced an expression profile most collectively similar to each of the various ER stress reducing interventions.

When testing Celastrol in diet induced obesity (DIO) mice, the results were dramatic across all measures — 80% decreased food intake and increased fat metabolism in Celastrol-treated DIO mice corresponded to 45% weight loss without lean mass loss or decreased energy expenditure. Ozcan shows Celastrol restores Leptin sensitivity in obese mice and, importantly, does not affect weight loss in already lean mice. Additionally, fatty liver was cured, and liver and glucose metabolism was improved in Celastrol-treated DIO mice, without toxic effects to either group of mice.

Celastrol needs testing to demonstrate safety (and dose ranges) in humans, but the prognosis for this compound as a powerful treatment of DIO in humans could not be brighter.

For further information

Read the Cell original research article which this summary is based on Treatment of Obesity with Celastrol (May 2015).

Visit the profile of the research ambassador, Grant Simpson, who wrote this summary.

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