Engineered Hot Fat Implants Reduce Weight Gain in Mice

UC Berkeley scientists have discovered a new way to engineer the growth and expansion of energy-burning “good” fat. Subsequently they showed that this fat helped reduce weight gain and lower blood glucose levels in mice. According to Andreas Stahl, the senior author of this study, this technique could potentially lead to new approaches to combat obesity, diabetes and other metabolic disorders.

Stahl and his coworkers devised a specifically tailored hydrogel that acted as a scaffold for stem cells that are able to form brown fat. Implantation of this stem cell-laced scaffold could form a functional brown-fat-like tissue. White fat, which is associated with obesity, stores excess energy, but brown fat is a heat generator and burns calories in order to heat your body.

“What is truly exciting about this system is its potential to provide plentiful supplies of brown fat for therapeutic purposes,” said study lead author Kevin Tharp, a doctoral student in the Department of Nutritional Sciences and Toxicology. “The implant is made from the stem cells that reside in white fat, which could be made from tissue obtained through liposuction.”

“This is figuratively and literally a hot area of research right now,” said Stahl, who is an associate professor of nutritional sciences and toxicology. “We are the first to implant in mice an artificial brown-fat depot and show that it has the expected effects on body temperature and beneficial effects on metabolism.”

Several studies have shown that cold temperatures can increase the metabolic activity of brown fat. However, Stahl pointed out that exposure to cold usually leads to increases in food intake, as well, which potentially negating any calorie-burning benefits from brown-fat activity.

There are three basic types of fat tissue in our bodies. These include energy-storing white fat that many of us are most familiar with, and two kinds of energy-burning fat used to generate heat, which include brown fat, which arises during fetal development, and beige fat, which is brown-like fat that is formed within white fat tissue after exposure to cold and other stressful situations.

For this experiment, Stahl teamed up with Kevin Healy, a UC Berkeley professor of bioengineering. The goal was to increase brown-like beige fat without exposing the animals to cold temperatures. Stahl and Healy wanted to develop a system of physical cues to guide stem cell differentiation.

“It’s already known that for a number of organs, including the heart, the extracellular matrix in which a cell resides provides signals to guide growth and development,” said Dr. Healy. “We applied this concept to stem cells isolated from white-fat tissue.”

The specific matrix recipe for converting white-fat stem cells to brown fat was quite unclear but Stahl and Healy noted that previous studies suggested that stiffness of the surrounding environment was a factor. If white-fat stem cells are placed in a 3D environment that is soft, with little resistance, they become fat. However, if the surrounding environment is rather stiff, the stem cells grew into bone.
Healy and his postdoctoral research fellow Amit Jha generated a tightly knit 3D mesh that consisted of hydrogel, water, hyaluronic acid and short protein sequences associated with brown-fat growth and function. Hyaluronic acid is a naturally occurring acidic carbohydrate that helps make water thicker and gel-like (stiffer in other words). They then took white-fat stem cells (adipose tissue-derived multipotent stem cells or ADMSCs) from mice that had been genetically engineered to express an enzyme from fireflies that made the cells luminescent. Because these cells glowed when incubated with the right substrate, they could be easily traced.

These ADMSCs were then added to the hydrogel and, before the mixture thickened, injected them under the skin of genetically identical mice.

The gel polymerized after injection and stiffens up under the skin of the animal. These labeled cells were then monitored to determine how well they stayed put, how long they persisted in the body and whether they were metabolically functional.

Stahl and Healy and their colleagues noticed an increase in the core body temperature of the mice at ambient temperatures of 21 degrees Celsius and after 24 hours at 4 degrees Celsius. In both cases, the mice with the implanted cells were up to half a degree Celsius warmer than a control group of mice with no injection. The higher the concentration of cells, the larger the effect on temperature.

Next, they put these experimental mice on a high-fat diet. By the end of three weeks, the mice with injected beige fat gained half as much weight and had lower levels of blood glucose and circulating fatty acids compared with control mice.

“This is a feasibility study, but the results were very encouraging,” said Dr. Stahl. “It is the first time an optimized 3D environment has been created to stimulate the growth of brown-like fat. Given the negative health effects of obesity, research into the role of brown fat should continue to see if these findings would be effective in humans.”

The study was published Aug. 20 in Diabetes.

Drug Converts White Fat into Brown Fat and Induces Weight Loss

Exciting new research has determined that a variant of a drug used to treat pulmonary arterial hypertension induces weight-loss in obese mice. Among mice fed a high-fat diet, those who did not get the medication became obese while medicated mice did not.

The experimental drug used stimulates soluble guanylyl cyclase (sGC), and this drug is a member of the same class of novel drugs as the drug riociguat. The Food and Drug Administration approved riociguat in 2013 to treat high blood pressure in the lungs. Riocoguat is produced by Bayer HealthCare Pharmaceuticals, is marketed under the trade name Adempas.

In mice, the sCG stimulator stimulated a shift in fat tissue and turned stored white fat in the mice into brown fat, which burns up more energy and improves metabolic function. Beige or brown fat is a beneficial type of fat that is richly populated with mitochondria, which makes the tissue look brown under a microscope. White fat releases hormonal signals that prompt the storage of still more white fat, but brown fat burns up fat and protects against weight gain, even when caloric intake is high.

In this research, which was published in the journal Nature Communications, mice made obese by a high-fat, high-calorie diet were given the sCG stimulator. These mice not only experienced weight loss, but also showed improved glucose tolerance, reduced insulin levels and decreased the signs of fatty liver, which is a damaging consequence of established obesity. It also even shrunk white fat cells.

In plump mice on the sCG stimulator, circulating dietary fatty acids were increasingly drawn into the brown fat and burned up at high rates. Even muscle and white fat in those mice increased their use of the circulating fatty acids. These metabolic changes caused mice to burn more calories, and their abnormal metabolic function improved.

This new research was led by researchers at the University Hospital in Bonn, Germany, and it elucidated the biochemical pathway that generates brown fat. This brings potential targets into view that could shift white fat into brown fat.

The sCG stimulator used in this study, the authors concluded, “might be used to enhance weight loss induced by physical activity.”

If a drug related to riociguat is to enter broad use for obesity, however, it will need to be cheaper than its close chemical relative. At doses taken by those with pulmonary arterial hypertension, a typical month’s prescription of Adempas costs close to $2,800, or about $90,000 a year.

As a treatment for the nation’s more than 72 million obese adults, that cost could prove prohibitive, especially as obesity and its consequences are increasingly understood to be chronic conditions that will need long-term management.