A signaling pathway in fat cells may one day provide the key to better treatments for obesity, according to new research by scientists at the Perelman School of Medicine at the University of Pennsylvania. They reported their findings in Genes & Development.
|This image shows adipose tissue, with fat droplets in green
and blood vessels in red. Credit: The laboratory of
Zoltan Arany, MD, PhD, Perelman School of Medicine,
University of Pennsylvania
Arany and colleagues found that the browning program in white adipocytes is normally suppressed by a protein called FLCN. It performs this function in cooperation with a major cellular signaling hub, a protein complex known as mTOR. The FLCN-mTOR interaction keeps the browning program switched off by preventing a protein called TFE3 from entering the cell nucleus.
The scientists showed that deleting the FLCN gene in the white adipocytes of mice allows TFE3 to migrate into the nucleus, where it binds to DNA and activates a key regulator of cellular metabolism called PGC-1β. It then turns on the set of genes for the browning program.
In the mice in which FLCN was deleted, white adipocytes became visibly browner as they produced more mitochondria–tiny, oxygen reactors that supply chemical energy within cells and convert energy to heat in brown adipocytes. In several other ways too, including their altered cellular structures, mitochondria’s higher capacity for consuming oxygen, and their distinctive pattern of gene expression, the cells became more like brown adipocytes.
Arany and his team showed that they could reproduce this browning effect merely by forcing the overexpression of PGC-1β in the white adipocytes of mice. “In principle, a drug that boosts the activity of PGC-1β or some of its target genes might serve as a therapeutic activator of the browning program to curb obesity and treat or prevent diabetes,” Arany said.
Aside from its potential medical relevance, the discovery is an important advance in understanding cell biology. “Cellular metabolism is regulated by major signaling pathways and with this study, we’re linking two of these major pathways, the mTOR, and the PGC-1 pathways,” Arany said. “The connection between them hasn’t been well understood, but here we’re clarifying it significantly.”
Arany and his team plan further studies of the pathway and its relation to other mTOR signaling pathways.
Citation:“The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue”. Shogo Wada, Michael Neinast, Cholsoon Jang, Yasir H. Ibrahim, Gina Lee, Apoorva Babu, Jian Li, Atsushi Hoshino, Glenn C. Rowe, James Rhee, José A. Martina, Rosa Puertollano, John Blenis, Michael Morley, Joseph A. Baur, Patrick Seale and Zoltan Arany. Genes & development 2016.
Research funding: National Institutes of Health.
Adapted from press release by Perelman School of Medicine at the University of Pennsylvania.