Obese mouse

by Mary E. Gearing 
figures by Shannon McArdel

35% of the adult population is obese, a condition which puts one at a high risk for many diseases, namely heart disease, high blood pressure and diabetes. Unfortunately, the treatments available for obesity are limited. Lifestyle modifications, including a healthy diet and exercise, can help reduce weight, but many individuals have trouble adhering to these changes over the long term. Bariatric surgery, including the well-known gastric bypass surgery, is highly effective but also invasive and expensive. The perfect treatment for obesity would be just as effective as surgery, but easier to administer, like a weight-loss pill. A recent study from researchers at Boston Children’s Hospital/Harvard Medical School may have gotten closer to finding that pill. This team identified a naturally occurring compound, celastrol, which helped obese mice lose up to 45% of their body weight! Celastrol appears to increase the body’s sensitivity to leptin, a molecule that regulates appetite and energy balance. So far, the compound has only been tested in mice, but it may soon be headed to clinical trials. Read on for the “skinny” on celastrol, and why you shouldn’t go trying it at home just yet!

The obesity rate in the United States has risen dramatically over the past few decades; today, 35% of the adult population is obese. Obese individuals have a very high body fat percentage, which puts them at a high risk for many diseases, namely heart disease, high blood pressure and diabetes [1]. The medical costs of obesity are also high, with an estimated $190 billion in US medical spending attributable to obesity [2].

Given the amount of research that’s gone into obesity, the available treatments are limited. Lifestyle modifications, including a healthy diet and exercise, can help reduce weight, but many individuals have trouble adhering to these changes over the long term. Bariatric surgery, including the well-known gastric bypass surgery, is highly effective but is not suitable for everyone due to its invasiveness and cost, as well as the risk of pre- and post-surgery complications [3]. The perfect treatment for obesity would be just as effective as surgery, but easier to administer, something along the lines of a “weight-loss pill.”

A recent study from researchers at Boston Children’s Hospital/Harvard Medical School may have gotten closer to finding that pill. Using tools developed by the Broad Institute, they found a naturally occurring compound, celastrol, which helped obese mice lose up to 45% of their body weight! [4-6] Celastrol appears to increase the body’s sensitivity to leptin, a molecule that regulates appetite and energy balance. So far, the compound has only been tested in mice, but it may soon be headed to clinical trials. Read on for the “skinny” on the identification of celastrol and its effects, and why you shouldn’t go trying it at home just yet!

Leptin: the thin hormone

The so-called “thin hormone,” leptin, was discovered completely by accident. In 1950, researchers at the Jackson Laboratory found that a group of their lean mice had given birth to obese offspring that ate much more than their lean ancestors. In 1960, it happened again in a second group of mice! In each of these instances, the obesity resulted from a new mutation, or a change in mice’s DNA. Subsequent studies in the 1990s identified the ob gene, which produced a previously unknown hormone [7]. This hormone was later renamed leptin after the Greek word for “thin.” In healthy mice and humans, leptin is made by the body’s fat cells and released into the blood, where it travels to a region of the brain called the hypothalamus to exert its effects. These effects are twofold: first, leptin suppresses food intake. Second, it increases energy expenditure by altering metabolic rate. It turns out that the first group of mice (now called ob/ob) had nonfunctional leptin, and the second group of mice (db/db) had a nonfunctional version of the leptin receptor, a protein that mediates the body’s response to leptin. The groups of neurons that contain leptin receptors are responsible for many important biological processes that impact how the body responds to and uses energy, which explains leptin’s effects on energy metabolism.

If leptin has such important effects on weight, why aren’t we using it to combat obesity? In fact, there’s one major problem with leptin as a treatment for obesity. Since leptin is made by fat cells, leptin levels actually increase as a person’s body fat increases. Obese patients usually have very high levels of leptin, but their brains don’t properly transport or respond to it [8]. This problem is called leptin resistance. In addition to promoting increased food intake, leptin resistance also turns down the body’s normal metabolism or basal metabolic rate so that the body burns fewer calories at rest [8]. Multiple factors can cause leptin resistance, including consistently high leptin levels or intake of certain dietary components, like fructose and saturated fats [9]. Adding in extra leptin doesn’t do anything to help these patients; instead, what we would need to do is make them more leptin-sensitive/responsive. It’s a difficult problem, and researchers haven’t had much success until just recently…

Figure 1. Functional and nonfunctional leptin signaling. In healthy humans and mice, leptin is produced by fat cells and interacts with its receptors in the hypothalamus. Leptin decreases food intake and increases energy expenditure, promoting maintenance of a normal weight. In ob/ob and db/db mice, leptin signaling is disrupted because either leptin or the leptin receptor is not present, and obesity results. In obese humans, leptin production is very high, but the brain does not respond properly to leptin. Leptin resistance contributes to the development and maintenance of obesity.

A new strategy to target leptin

Umut Ozcan’s lab decided to take another stab at leptin. His lab studies the endoplasmic reticulum (ER), a cellular element that helps make, process and fold proteins into their correct shapes. Several metabolic diseases, including diabetes and obesity, are associated with detrimental changes to the ER called ER stress [10]. Since ER stress in the brain has also been shown to cause leptin resistance, the researchers hypothesized that they could improve leptin sensitivity by reducing ER stress and improving ER function. Most drugs in use today are small molecules; if they could find a molecule to improve leptin sensitivity, it would be an important step forward towards finding an anti-obesity drug.

To find a small molecule, the group turned to the Broad Institute’s Connectivity map (CMAP.) To make CMAP, human cell lines were treated singly with over 1,000 small molecules, and the RNA “fingerprint” associated with each molecule was characterized. You may have heard that DNA is our instruction manual, but RNA shows us which genes are ON or OFF at any given time. Similar “fingerprints,” or patterns in RNA levels, mean that cells are behaving similarly. Ozcan compared the list of CMAP “fingerprints” to those from cells treated with laboratory chemicals that lower ER stress to try to find a molecule that mimicked these chemicals but would be less toxic. The best hit by far was celastrol, a compound from the thunder god vine (Tripterygium wilfordii) previously studied for its anti-cancer effects.

Figure 2. CMAP screening identifies celastrol as a potential leptin sensitizer. Cells were treated with chemicals that are known to reduce ER stress and improve leptin sensitivity in laboratory work but are also toxic to humans. The RNA fingerprint was compiled and compared to CMAP data for cells treated with >1,000 small molecules. Celastrol-treated cells RNA fingerprints were the best match, indicating that celastrol may improve leptin sensitivity.

To test celastrol, the laboratory used a mouse model of diet-induced obesity (DIO). DIO mice are fed diets very high in sugar and fat to model the effects of high-calorie diets on metabolic health. When DIO mice were treated with celastrol, they lost a large percentage of their body weight in a very short time period – up to 45% in just three weeks! Celastrol treatment not only helped obese mice lose weight, but it also prevented the development of obesity in lean mice on a high fat diet. This effect persisted for the 200-day experimental period without causing toxic effects in the mice. Celastrol does reduce food intake during the first few weeks of weight loss, but food intake soon returns to normal levels, and weight loss maintenance can be attributed to increased energy expenditure. To show that celastrol in fact does improve leptin sensitivity, researchers tested it in the ob/ob and db/db mutant mice mentioned earlier. Celastrol has no effects in these mice, showing that its effects are dependent on leptin signaling.

Figure 3. Celastrol is a potent anti-obesity agent in mice. Diet-induced obesity (DIO) is a common mouse model of obesity. DIO mice are fed diets very high in sugar and fat to model the effects of high-calorie diets on metabolic health. Celastrol induces weight gain in DIO mice. Celastrol also prevents DIO-induced weight gain, and this effect persists for at least 200 days.

Please don’t try this at home: What we don’t know about celastrol!

Based on these data, celastrol is a very exciting molecule for the treatment and prevention of obesity, but it’s important to not get too carried away. Many other studies need to be done to evaluate the safety and efficacy of this compound in humans. Compounds tested in mice may be either ineffective or toxic in humans – we just don’t know until we do the studies. Leptin also has effects on parameters other than weight, such as bone health and blood pressure, and celastrol may have related side effects. Ozcan’s laboratory is currently working on the toxicology tests necessary to move celastrol forward to clinical trials, but even if celastrol passes these hurdles, it will be years before we know if this compound could be used to treat obesity in humans.

At this moment, celastrol is a black box – we don’t know exactly how it works, or in drug speak, its mechanism of action. Again, future research is necessary to figure out which proteins interact with celastrol and mediate its effects. This information will help us better understand potential side effects of celastrol, as well as give us a deeper insight into leptin biology.

Celastrol is certainly a molecule to watch, and metabolism researchers will be following it closely. For now, if you’re looking to stave off obesity or lose weight, your best option is likely still a healthy diet and regular exercise. However, the hard work of biomedical scientists studying obesity may open up new avenues for the treatment and prevention of this increasingly prevalent disease.

Mary E. Gearing is a Ph.D. candidate in the Biological and Biomedical Sciences Program at Harvard University.

References

  1. CDC. Overweight and Obesity. (2014). http://www.cdc.gov/obesity/data/adult.html
  2. Begley S. As America’s waistline expands, costs soar. (30 April 2012). Reuters. http://www.reuters.com/article/2012/04/30/us-obesity-idUSBRE83T0C820120430
  3. Mayo Clinic. Tests and procedures: Gastic bypass surgery. (2014). http://www.mayoclinic.org/tests-procedures/bariatric-surgery/basics/definition/prc-20019138
  4. Liu J, Lee J, Salazar Hernandez MA, Mazitschek R & Ozcan U. Treatment of obesity with celastrol. (21 May 2015). Cell. http://www.cell.com/cell/abstract/S0092-8674(15)00559-0
  5. Scudellari M. Chinese medicinal plant may lead to obesity wonder drug. (29 May 2015). The Boston Globe. https://www.bostonglobe.com/lifestyle/health-wellness/2015/05/29/thunder-god-plant-could-potent-obesity-treatment/UvWEc1Ugmgmx7tUw9k6XCO/story.html#
  6. Science 2.0. Traditional medicine: Thunder god vine as potential obesity treatment. (27 May 2015). http://www.science20.com/news_articles/traditional_medicine_thunder_god_vine_as_potential_obesity_treatment-155721
  7. Leading the charge in leptin research: an interview with Jeffrey Friedman. (Sep 2012). Disease Models & Mechanisms. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3424452/
  8. Kam K. The Facts on Leptin: FAQ. (2010). WebMD. http://www.webmd.com/diet/obesity/the-facts-on-leptin-faq
  9. Vasselli JR, Scarpace PJ, Harris RBS & Banks WA. Dietary components in the development of leptin resistance. (March 2013). Advances in Nutrition. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3649097/
  10. Boden G. Endoplasmic reticulum stress: another link between obesity and insulin resistance/inflammation. (March 2009). Diabetes. http://diabetes.diabetesjournals.org/content/58/3/518.full

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