Finding the molecular key that turns fat tissue from white to brown holds huge potential for the treatment of obesity and the entire weight loss process. However, the cellular code has been difficult to crack. Now, scientists believe they have come a step closer, demonstrating how by inhibiting histone deacetylase 11 (HDAC11), which controls fat tissue function, white fat cells are forced to consume energy under the accelerated activity of uncoupling protein 1 (UCP1).
White adipose tissue is responsible for storing fat and retaining energy in the form of triglycerides, while brown adipose tissue and its abundant mitochondria are aided by specialized UCP1 to convert chemical energy into heat through the process of non-shivering thermogenesis. Making these white fat cells more responsive to mechanisms that deplete energy stores could be the breakthrough scientists have been hoping to achieve in tackling obesity.
Researchers at the University of Colorado (UC) School of Medicine believe their findings in the fat tissue of mice and obese patients undergoing bariatric surgery may hold the key.
"There's a third type of fat called beige fat," said Timothy McKinsey of the University of California School of Medicine. "Beige fat is a white fat that's not usually that good of a fat, but it can turn into something more like brown fat. By inhibiting HDAC11, we stimulate the browning of white fat. HDAC11 inhibition is changing the phenotype of adipose tissue in a favorable way."
For some time, researchers have been seeking to manipulate natural mechanisms in cells to allow them to focus on energy expenditure in white adipose tissue, or to "behave" like brown adipose tissue.
Previous research by the UC team looked at stimulating b3-adrenergic receptors (b3-AR) with drugs such as mirabegron, which was approved by the U.S. Food and Drug Administration in 2012 to treat overactive bladder syndrome. But the drug caused fat tissue catecholamine resistance due to reduced receptors on target cells. This essentially means that people with obesity have a harder time getting the correct energy expenditure from their fat cells.
By inhibiting HDAC11, UCP1 is in turn stimulated even in the presence of catecholamine resistance, thereby increasing the activity of brown adipose tissue, which in turn begins to affect white adipose tissue. When white tissue begins to turn white, drugs that stimulate b3-AR have a better target, a larger receptor to attach to and work.
This will help patients with comorbidities such as insulin resistance, inflammation and fibrosis. The researchers plan to continue studying HDAC11, specifically focusing on how it can help improve the efficacy of existing obesity drugs and address treatment issues such as muscle loss and weight regain.
The findings were published in the Journal of Clinical Investigation.