How to Turn White Fat Brown
Penn scientists discover a molecular trigger of fat-cell “browning” program, which could lead to better treatments for obesity and diabetes.
A signaling pathway in fat cells may one day provide the key to better treatments for obesity, according to new research by scientists in the Perelman School of Medicine at the University of Pennsylvania. They reported their findings online ahead of print in Genes & Development.
Ordinary fat cells, also called white adipocytes, stuff themselves with fat molecules to store up energy. If overloaded, they lead to obesity and related conditions, including diabetes.
Brown adipocytes are prevalent in children as “baby fat,” but much less so in adults. They do virtually the opposite — they burn energy rapidly to generate heat, thereby protecting the body from cold, as well as obesity and diabetes.
The signaling pathway discovered by the Penn scientists activates a “browning program” in white adipocytes, making them more like energy-burning brown adipocytes.
“It’s conceivable that one would be able to target this pathway with a drug, to push white fat to become brown fat and thereby treat obesity,” said the study’s senior author Zoltan P. Arany, MD, PhD, an associate professor of Cardiovascular Medicine.
About 36 percent of American adults are considered obese and nearly 10 percent have type 2 diabetes.
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.
Research revealed that deleting the FLCN gene in white adipocytes of mice allows TFE3 to migrate into the nucleus. Once there TFE3 binds to DNA activating a key regulator of cellular metabolism called PGC-1β. Thus turning on the 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.”
Zoltan P. Arany, MD, PhD
Aside from its potential medical relevance, the discovery is an important advance in understanding cell biology.
“Cellular metabolism is regulated by major signaling pathways. With this study we’re linking two of these major pathways, the mTOR and the PGC-1 pathways. The connection between them hasn’t been well understood, but here we’re clarifying it significantly.”
Zoltan P. Arany, MD, PhD
and his team plan further studies of the pathway and its relation to other mTOR signaling pathways.
Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly understood. Mutations in the tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dubé syndrome, a hamartomatous disease marked by mitochondria-rich kidney tumors. FLCN functionally interacts with mTOR and is expressed in most tissues, but its role in fat has not been explored. We show here that FLCN regulates adipose tissue browning via mTOR and the transcription factor TFE3. Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. Cytoplasmic retention of TFE3 by mTOR is sensitive to ambient amino acids, is independent of growth factor and tuberous sclerosis complex (TSC) signaling, is driven by RagC/D, and is separable from canonical mTOR signaling to S6K. Codeletion of TFE3 in adipose-specific FLCN knockout animals rescues adipose tissue browning, as does codeletion of PGC-1?. Conversely, inducible expression of PGC-1? in white adipose tissue is sufficient to induce beige fat gene expression in vivo. These data thus unveil a novel FLCN–mTOR–TFE3–PGC-1? pathway—separate from the canonical TSC–mTOR–S6K pathway—that regulates browning of adipose tissue.
Co-authors of the study include first author Shogo Wada, and Michael Neinast, Cholsoon Jang, Apoorva Babu, Jian Li, Atsushi Hoshino, Michael Morley, Joseph A. Baur, and Patrick Seale, all of Penn; Yasir H. Ibrahim, Gina Lee, and John Blenis of the Weill Cornell School of Medicine; José A. Martina and Rosa Puertollano of the National Heart, Lung and Blood Institute; Glenn C. Rowe of the University of Alabama; and James Rhee of Massachusetts General Hospital.
The study was supported by grants from the National Institutes of Health (T32GM007592, GM51405, HL121266, DK098656, AG043483, DK107667, HL094499).
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania(founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center — which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report — Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital — the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.
Return to top of page
Jan 3, 2017 Fetal Timeline Maternal Timeline News News Archive
Adipose tissue, with fat droplets (GREEN) and blood vessels (RED).
Image Credit: laboratory of Zoltan Arany, MD, PhD,
Perelman School of Medicine, University of Pennsylvania