When our bodies don’t work properly, we say we’re sick. A study published in the September issue of Diabetes finds that the same could be said for fat tissue found in obese patients. The cells in their fat tissue aren’t working properly and as a result, are sicker than cells found in lean patients’ fat tissue.

Lead author Guenther Boden, M.D. theorizes that “sick fat” could more fully explain the link between obesity and higher risk of diabetes, heart disease and stroke.

Researchers from the departments of endocrinology, biochemistry and surgery at the Temple University School of Medicine took fat biopsies from the upper thighs of six lean and six obese patients and found significant differences at the cellular level.

“The fat cells we found in our obese patients were deficient in several areas,” said Boden, Laura H. Carnell Professor of Medicine and chief of endocrinology. “They showed significant stress on the endoplasmic reticulum, and the tissue itself was more inflamed than in our lean patients.”

Endoplasmic reticulum (ER) is found in every cell and helps synthesize proteins and monitor how they’re folded. The stress that Boden describes causes the ER in fat cells to produce several proteins that ultimately lead to insulin resistance, which has been found to play a major role in the development and progression of obesity-related conditions.

The National Institutes of Health recently reported that each time a body mass index (BMI) over 25 is raised by one point, the risk for diabetes increases 25 percent and the risk for heart disease increases 10 percent.

Reducing weight can help reduce stress on the ER, which can lower the risk of insulin resistance and the resulting conditions. Currently Boden and his team are looking at whether free fatty acids are a potential cause for this ER stress.

Source: Temple University

Reporting in the Aug. 21 issue of the journal Nature, the researchers demonstrated that brown fat, which is known as the “good” form of fat — so called because it burns calories and releases energy, unlike “bad” white fat that simply stores extra calories — can be generated from unspecialized precursors that routinely spawn skeletal muscle.

The team led by Dana-Farber’s Bruce Spiegelman, PhD, showed that a previously known molecular switch, PRDM16, regulates the creation of brown fat from immature muscle cells. They also determined that the process is a two-way street: Knocking out PRDM16 in brown fat cells can convert them into muscle cells. However, Spiegelman called the latter an “experimental lab trick” for which he currently envisions no practical applications.

The “huge surprise” of the study results, he said, was that muscle precursor cells known as “satellite cells” are able to give birth to brown fat cells under the control of PRDM16.

Spiegelman said the finding confirms that PRDM16 is the “master regulator” of brown fat development. The confirmation will spur ongoing research in his laboratory, he said, to see if drugs that rev up PRDM16 in mice — and potentially, in people — could convert white fat into brown fat and thereby treat obesity. Another strategy, he said, might be to transplant brown fat cells into an overweight person to turn on the calorie-burning process.

“I think we now have very convincing evidence that PRDM16 can turn cells into brown fat cells, with the possibility of combating obesity,” said Spiegelman, the senior author of the paper. The lead author is Patrick Seale, PhD, a postdoctoral fellow in the Spiegelman lab.

Another paper in the same issue of Nature described a different trigger of brown fat production, a molecule called BMP7. A commentary in the journal by Barbara Cannon, an internationally recognized researcher in the biology of fat cells at the University of Stockholm, said that the two reports “take us a step closer to the ultimate goal of promoting the brown fat lineage as a potential way of counteracting obesity.”

The Spiegelman group has long studied fat cells both as a model for normal and abnormal cell development, which relates to cancer, and also because fat cells play such a key role in the growing epidemics of obesity and diabetes.

There is much interest in brown fat’s role in regulating metabolism. Rodents and human infants have abundant brown fat that dissipates food energy as heat to protect against the cold. Though human adults have little brown fat, it apparently does have a metabolic function, including the potential to be amplified in some way to combat obesity.

In 2007, Spiegelman and colleagues reported they had inserted PRDM16 genes into white fat precursors, which they implanted under the skin of mice. The PRDM16 switch coaxed the white fat precursors to produce brown fat cells instead of white. To Spiegelman, this suggested the possibility of transplanting PRDM16-equipped white fat precursors into people who are at high risk of becoming obese, to shift their metabolism slightly into a calorie-burning mode.

The new research adds another potential source of brown fat — the muscle cell progenitors, or myoblasts, that exist in the body to replace mature muscle cells as needed. The progenitors, which can be thought of as “adult stem cells,” are committed to becoming specialized muscle cells when activated by appropriate signals, or, as the study revealed, brown fat cells when PDRM16 is turned on. The PRDM16 trigger “is very powerful at what it does,” said Spiegelman, who is also a professor of cell biology at Harvard Medical School.

Source: Dana-Farber Cancer Institute