Developmental Stalwart Wnt Helps Keep Fat Cells Skinny
By Anette Breindl
Wnt is a signaling pathway that plays critical roles in development, and its proteins can go awry in many cancers. Now, researchers from the University of Michigan have gained new insights into the relationship between Wnt signaling, metabolism and mitochondria.
The research identifies "a new role for an old signaling pathway, the Wnt pathway," senior author Ormond MacDougald told BioWorld Today. MacDougald is a professor of molecular and integrative physiology, a professor of internal medicine and a member of the Brehm Center for Diabetes Research at the University of Michigan. His team's findings appeared in the June 25, 2012, issue of the Journal of Clinical Investigation.
Wnt activates receptors called frizzled, and that activation sets off a negative feedback loop that ultimately shuts off Wnt, via proteins that go by secreted frizzled-related proteins, or SFRPs.
MacDougald's laboratory is mainly focused on Wnt signaling in adipocyte or fat cell progenitors. SFRP5 is present at high levels in those progenitors, and part of its effect is to stimulate the development of more fat cells.
"Our expectation was that as adipocytes grow in size, they reach their capacity to store fat and recruit more fat cells" via SFRP5 signaling that inhibits Wnt, MacDougald said. The team expected that SFRP5 knockouts would be resistant to diet-induced obesity because they would lack the ability to stimulate the production of more fat cells via SFRP5 signaling. But that's not what happened.
SFRP5 knockouts were indeed resistant to the fattening effects of a high-fat diet. But not because they had fewer fat cells than their wild-type cousins.
Instead, mechanistic studies showed that the fat cell mitochondria of SFRP5 knockouts were more active at metabolizing fat. That kept the cells from accumulating as many lipids in their fat cells on a high-fat diet as wild-type animals did.
"We expected the adipose tissue to have far fewer adipocytes. Instead, they had the same number of adipocytes, but they were much smaller," MacDougald said. Activity in the mitochondria "helps keep fat cells skinny."
To make sure their results were not due to very subtle differences in energy intake or expenditure of SFRP5 knockout mice, the authors turned to transplantation experiments. They took fat tissue from both normal mice and SFRP5 knockouts, and transplanted them into what MacDougald termed "a very obesogenic environment," namely, leptin-deficient mice. Such animals, lacking the satiety signal that leptin provides, eat near constantly and have the bulk to show for it. But the transplanted tissues showed the same pattern that the whole animals had – the numbers of fat cells that had no SFRP5 were not reduced, but their size was.
A commentary that accompanied the paper said the findings "implicate local Wnt signaling as an attractive target for combating obesity." Such targets are certainly still needed. In June, the FDA approved the first new obesity drug in 13 years, Arena Pharmaceuticals Inc.'s Belviq (lorcaserin). The FDA has been conservative about safety concerns, however. Belviq had already been up once before, as has Vivus Inc.'s Qnexa (phentermine/topiramate), whose PDUFA date is July 17. And Orexigen Therapeutics Inc.'s Contrave (naltrexone/bupropion), is currently in an FDA-required cardiovascular outcomes study after receiving a complete response letter last year. (See BioWorld Today, June 28, 2012 and Feb. 1, 2011.)
But MacDougald was level-headed about how much work it would take to get there from here. He said that although the origins of obesity are certainly a public health problem as well as a scientific challenge, the work he and his colleagues have described in their paper "is very much a basic laboratory finding."
With much luck, "based on our work and that of many others, something applied may ultimately come out of this," he said. "But the Wnt signaling pathway has many functions." And particularly from a safety perspective, a straightforward silencing of SFRP5, in direct analogy to his team's studies, is unlikely to be the best approach: The protein also is silenced in certain cancers.
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