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What Research with Mice is Teaching Scientists About Obesity and Weight Loss

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Obesity is one of the most serious health issues in the United States. According to the Centers for Disease Control and Prevention, almost 72% of U.S. adults are overweight, more than 42% are obese, and more than 9% are severely obese. Not only does obesity increase the risk of heart disease, stroke, type 2 diabetes, and some cancers, it also costs hundreds of billions of dollars a year. Dieting and exercise alone are rarely effective for significant and permanent weight loss, so scientists working with mice are looking for other solutions.

What Research with Mice is Teaching Scientists about ObesityRare Mutation Offers Protection Against Obesity

Why do some people gain weight easily while others never seem to put on a pound? It has long been clear that genetics plays a role, and a team of researchers led by the Regeneron Genetics Center and Duke University has discovered that people with genetic mutations in the GPR75 gene (which occurs in about one in every 3,000 people) are 54% less likely to become obese.

The team did a comprehensive study of 16 gene mutations tied to body mass index (BMI) and found one—GPR75—that had the largest effect on BMI.

To confirm the discovery, researchers ran an experiment using mice that had been genetically engineered to lack copies of the GPR75 gene. When the GPR75 mutated mice were fed a high-fat diet along with a control group of normal mice, the mutated mice gained 44% less weight than the mice without the mutation.

This new understanding of how GPR75 affects weight could lead to new drugs that deactivate the GPR75 receptor in order to treat obesity.

Lowering Iron Content in Fat Cells

Researchers at UT Southwestern discovered that lowering the iron content in the fat cells of mice prevented them from gaining too much weight, even while eating a high-fat diet.

The team used mice specifically bred to have significantly lower iron content in their fat cells, which they expected would lead to the poor health normally associated with anemia. Instead, the low-iron mice were healthy, lean, and did not exhibit any negative effects from a high-fat diet that led control mice to become severely obese and develop related metabolic disorders.

What’s the connection between low iron and healthy weight? The team discovered that iron-poor mice absorbed fewer lipids in the intestines, which significantly reduced the overall calories they took in. They determined that the low-iron fat cells send a signal to intestinal cells directing them to limit lipid intake, though they are unsure what type of signal is sent or how it is communicated. Once that mystery is solved, researchers may be able to recreate the signal for use in humans.

Restricting BCAAs for Weight Loss

A new study from the University of Wisconsin-Madison found that diets high in three branched chain amino acids (BCAAs)—leucine, isoleucine, and valine—are associated with diabetes, obesity, and other metabolic illnesses.

The body can’t make these three BCAAs, so they must come through food intake. Therefore, the team determined that reducing the intake of foods high in leucine, valine, and isoleucine could reduce the incidence of obesity and related metabolic conditions.

To test the theory, mice were fed a high-fat, high-sugar diet for a few months. Once the mice were obese, the team restricted isoleucine. The mice continued to eat more food but showed a higher metabolism and did not gain any more weight.

Restricting valine in the diets of the mice showed similar, but less marked results, while reducing levels of leucine showed no benefits. Based on this discovery, researchers speculate that limiting intake of foods high in isoleucine—such as beef, chicken, pork, tuna, tofu, milk, cheese, beans, lentils, wheat, nuts, and seeds—might help humans lose weight.

A Gut Bacterium That Targets Obesity

Scientists from the Louvain Drug Research Institute discovered that a newly identified bacterium called Dysosmobacter welbionis, which is found in the gut of 63%-70% of healthy humans, may combat obesity, insulin resistance, and inflammation.

In mice on a high-fat diet, scientists gave the mice supplements of D. welbionis, which protected the mice from obesity development, fat mass gain, insulin resistance, and inflammation, leading to hopes that D. welbionis may help reduce obesity and manage diabetes in humans.

Generating Heat, Losing Weight

Preclinical research by Weill Cornell Medicine, NewYork-Presbyterian and Harvard Medical School/Beth Israel Deaconess Medical Center scientists found that a protein called Them1 prevents fat burning in cells.

When mice get cold, their bodies speed up the fat-burning process to generate heat. When temperature normalizes, the Them1 protein shuts down the process.

To better understand how Them1 works, the team engineered mice to delete the gene for Them1. The bodies of the modified mice went into metabolic overdrive—burning so much energy trying to make heat that they ate twice the normal amount and still lost weight.

Humans also produce more Them1 to generate body heat in cold conditions, so the findings may lead to a new Them1-inhibiting treatment for obesity.

Proteins to Prevent Obesity

According to a new study from Cincinnati Children’s and the University of Cincinnati, two protein molecules (BAFF and APRIL) interact with fat cells to prevent weight gain.

Researchers found that mice that produced high levels of BAFF and APRIL proteins did not gain weight, even when fed a diet that would normally cause obesity. Mice engineered to lack BAFF and APRIL proteins gained weight quickly when fed the same diet.

The result is mirrored in humans: research shows that people with higher levels of BAFF and APRIL proteins lose more weight after receiving bariatric surgery. The findings suggest that boosting BAFF/APRIL production in obese people might help prevent weight gain.

A New Obesity Drug from Lizard Venom

The venom of a Gila monster lizard contained hormones that can regulate blood sugar, a fact that led a scientist at the University of Toronto to develop a synthetic version of a venom-derived hormone that is now used to treat type 2 diabetes.

Both humans and mice taking the drug for diabetes tended to lose weight, which led to another venom-based medicine, this one to treat obesity. Called semaglutide, that drug, a once-weekly injectable, received FDA approval in June.

Semaglutide prompts people to eat less by imitating the effects of GLP-1, a hormone that stimulates the pancreas to make more insulin after a meal, which lowers blood sugar, and also sends a signal to the brain to stop eating.

In clinical trials, semaglutide helped people with obesity lose an average of 15% of their body weight.  

Supplementing Snack Foods with Fiber

Dietary fiber helps prevent obesity, heart disease, and type 2 diabetes, but most people don’t get enough of it. What we do get enough of, however, is snack foods. Now, scientists at Washington University in St. Louis are working on ways of adding more fiber to snack foods to increase fiber intake.

The team has identified several cheap and readily available sources of fiber, such as peels, rinds, and husks, that would normally be discarded. Adding these fiber sources to snack foods as a prebiotic would boost gut microbes that are in short supply in people with obesity.

The researchers tested how snacks supplemented with some of these fibers affected the gut microbiomes of mice by colonizing the guts of “gnotobiotic” mice, which lack any gut microbes of their own, with microbes from people with obesity. They then fed the mice a high-fat, low-fiber diet, and added snacks supplemented with pea fiber, orange fiber, or barley bran.

They discovered that each snack led to an increased in the enzymes needed to digest the fiber. A trial with human volunteers yielded similar results, and showed that the more different kinds of fiber were introduced into the diet via the snack foods, the more helpful, obesity-fighting bacteria proliferated in the gut.

A new study by the American Obesity Association projected that half of U.S. adults would be obese by 2025, and 60% by 2030, which makes obesity one of the fastest-growing health risks in the country. With more and more researchers focusing on ways to treat or prevent obesity, hopefully that number will start to shrink.

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