Finding the molecular key that will see fat tissue turn from white to brown has huge potential for obesity treatments, and for weight loss in general. Yet the cellular code has been a hard one to crack. Now, scientists believe they’ve edged a step closer, demonstrating how by inhibiting the histone decetylase 11 (HDAC11) enzyme, which controls adipose (fat) tissue function, white fat cells are forced to churn through energy due to the ramped-up activity of the uncoupling protein 1 (UCP1).
White adipose tissue, responsible for our stored fat, retains energy as trigcerides, while its brown counterpart and its plentiful mitochondria get the help from the specialized UCP1 to turn chemical energy into heat through the process of non-shivering thermogenesis. Making those white adipose cells more responsive to mechanisms that use up energy stores could be the breakthrough scientists have been hoping for in tackling obesity.
Researchers from the University of Colorado (UC) School of Medicine believe their findings, demonstrated in mice and in fat tissue from obese patients that underwent bariatric surgery, may be just the key.
"There's a third type of fat called beige," said Timothy McKinsey, of the UC School of Medicine. "It's when you take white fat, which normally isn't all that good, and turn it into something that looks more like brown fat. By inhibiting HDAC11, we are stimulating the beiging of white fat. HDAC11 inhibition is changing the phenotype of fat tissue in a favorable way."
Research has for some time looked to manipulate natural mechanisms in cells so they can instead focus on energy expenditure in the white adipose tissue, or 'behave' like brown adipose tissue.
Prior research by the UC team looked at stimulating the b3-adrenergic receptors (b3-AR) with drugs such as mirabegron, which was approved by the US Food and Drug Administration for the treatment of overactive bladder syndrome back in 2012. But due to a decrease in receptors on target cells, the drug has resulted in adipose tissue catecholamine resistance. This essentially means it’s much more difficult for those with obesity to target the right kind of fat cell energy expenditure.
By inhibiting HDAC11, in turn stimulating UCP1 even in catecholamine resistance, brown adipose tissue activity is boosted and in turns starts affecting white adipose tissue. When then white tissue begins to beige, b3-AR-stimulating drugs have a much better target with larger receptors to cling to and get to work.
This could help those with comorbidities such as insulin resistance, inflammation, and fibrosis.
The researchers plan to continue their work on HDAC11, particularly focusing on how it may help both improve the efficacy of current obesity drugs and counter treatment issues such as muscle loss and rebound weight gain.
The research was published in The Journal of Clinical Investigation.
