Obesity continues to rise despite the abundance of diets, exercise regimens, and even surgical interventions. Another obesity-suppressing possibility is anti-obesity pharmacotherapy, which has started to show promise after languishing for years. Especially encouraging are experiments showing that obesity can be curtailed by increasing the number or activity of brown-like adipocytes in white fat deposits. This approach—the conversion of “bad” white fat cells to “good” brown fat cells—has become so appealing that brown-like fat may even become the new black in anti-obesity pharmacotherapy.
Progress toward achieving white-to-black metabolic conversion of fat cells has been reported by researchers at the Harvard Stem Cell Institute (HSCI). In fact, they assert that they have taken “the first step toward a pill that can replace the treadmill” for the control of obesity.
The researchers, led by HSCI principal faculty member Chad Cowan, Ph.D., presented their findings December 8 in Nature Cell Biology, in an article entitled, “White-to-brown metabolic conversion of human adipocytes by JAK inhibition.”
“We report a screening platform for the identification of small molecules capable of promoting a white-to-brown metabolic conversion in human adipocytes,” wrote the authors. “We identified two inhibitors of Janus kinase (JAK) activity with no precedent in adipose tissue biology that stably confer brown-like metabolic activity to white adipocytes.”
The compounds identified by the researchers both targeted the same molecule to alter adipocytes, which started exhibiting elevated UCP1 expression and increased mitochondrial activity. The adipocytes became metabolically active and “thermogenic.”
“We further found that repression of interferon signaling and activation of hedgehog signaling in JAK-inactivated adipocytes contributes to the metabolic conversion observed in these cells,” the authors added.
This last point suggests that the compounds identified by the researchers with their screening system could play a role in the inflammatory response. Accordingly, as Dr. Cowan indicated, administering the compounds for a long time could cause a patient to become immunocompromised. And so the compounds may require modifications. Yet one of the compounds is already on the market, as a treatment approved by the FDA for rheumatoid arthritis.
As anti-obesity therapeutics that convert white fat to brown fat, the compounds are meant to lower triglyceride levels, reduce the insulin resistance associated with type 2 diabetes, and burn white fat. “You're constantly replenishing your fat tissue,” Dr. Cowan explained, “so if you were on a medication to convert the cells, each new fat cell would be more metabolically active and would convert to brown fat over time,” reducing the likelihood of developing type 2 diabetes or any of the other conditions related to a buildup of fat.
Dr. Cowan added that what “we were really impressed by is that there are some compounds that have this same kind of effect when they are administered to animals, but when you remove them, the effect goes away. But what we saw here was a stable conversion” of white fat cells to brown cells.
The current findings resulted from a sponsored research collaboration with drug giant Roche Pharmaceuticals, Dr. Cowan said, but “unfortunately, the collaboration with Roche has ended because the company decided, for unrelated reasons, to end its metabolic disease program.”
“We found these two compounds by screening a library of about 1,000 compounds,” Cowan said, “so we know that if we have access to the typical pharmaceutical company library of 1.5 to 2 million compounds, we will find others.” Dr. Cowan is currently in discussion with several pharmaceutical companies about continuing the work. Additionally, a collaborator in Germany has been testing the first two compounds on mice.
“The compounds appear to work the same way in mice, but we don't know what the long-term metabolic or immune system effects are,” noted Dr. Cowan. The path from these findings to a safe and effective medication may not be easy, and the findings will have to be replicated by other research groups, as well as refined, before they could lead to a clinical treatment.