is a global health problem that represents a major risk factor for several
chronic diseases. In hopes to find new potential therapeutic targets for
obesity, UT Southwestern researchers have identified a pathway that plays a
critical role in regulating the creation of fat.
Sept. 17, 2019 – In work suggesting new therapeutic targets to fight obesity,
UT Southwestern researchers have identified a novel mechanism that regulates
the creation of fat in mammals.
a global health problem that represents a major risk for several chronic
diseases, including Type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular
disease, stroke, and cancer,” said Dr. Joshua Mendell, Professor of Molecular
Biology at UT Southwestern and an Investigator in the prestigious Howard Hughes
Medical Institute. Dr. Mendell is corresponding author of the study appearing
online in the journal Genes & Development.
molecular mechanisms that regulate how and where fat tissue builds up in the
body – or doesn’t – are key to understanding the development of obesity.
However, the genes and molecular pathways that influence the size and number of
fat cells in the body are not completely understood.
that loss of a family of microRNAs results in a dramatic increase in fat
formation. In addition, we showed that overexpression of the miR-26 family of
miRNAs strongly protects against weight gain in mice fed a high fat diet,” said
Dr. Asha Acharya, an Instructor of Molecular Biology and lead author of the
researchers further found that the miR-26 family controls the levels of a
protein called FBXL19 that is important for new fat cell production. “This
protein had not been linked to fat formation or obesity in the past, so this
result was unexpected,” Dr. Mendell said.
including mice and humans, a diet loaded with calories – such as the high fat
diet used in this study – can cause existing fat cells to expand. It can also
result in the creation of new fat cells from a population of stem-like
progenitor cells, he explained.
in adult mammals is a highly regulated process that involves mobilizing progenitor
cells that differentiate into fat cells,” said Dr. Mendell, a member of the
Harold C. Simmons Comprehensive Cancer Center and the Hamon Center for
Regenerative Science and Medicine at UTSW, as well as a CPRIT Scholar in Cancer
A feature of
obesity is the uncontrolled expansion of white fat tissue, which does more than
store energy in times of caloric surplus. It also plays an important role in
metabolic regulation by secreting signaling proteins and lipids that influence
pathways controlling appetite, blood sugar balance, and immune responses.
earlier studies indicated important roles for the miR-26 family as suppressors
of cancer and regulators of insulin sensitivity, the broader functions of these
miRNAs had remained a mystery. In part, that was due to the difficulty of
knocking out, or removing, all three genes that produce miR-26 family members
in mammals in order to study their functions.
this technical challenge, the researchers used the gene-editing technique
called CRISPR/Cas9 to remove all miR-26-encoding genes from the mouse genome.
They found that although mice lacking these miRNAs developed normally in early
life, they had a two- to threefold increase in white fat tissue beginning in
early adulthood, even while consuming a normal diet.
test the role of these miRNAs in regulating fat formation, the scientists used
a different genetically engineered mouse line that produces excess miR-26.
After being fed a high fat diet, normal mice exhibited dramatic weight gain and
an increase in fat content to 40 percent of their overall body mass. Mice with
increased miR-26, however, were strongly resistant to weight gain and, despite
consuming an identical diet, produced very little additional fat. Mice with
increased miR-26 also showed lower blood sugar and lipid levels compared with
reveals a new mechanism of controlling fat production in the body,” Dr. Mendell
said. “A deeper understanding of this mechanism could lead to new therapies to
treat obesity, for example by revealing strategies to increase miR-26 activity
or to inhibit the downstream targets of this microRNA.”
received support from the Cancer Prevention and Research Institute of Texas
(CPRIT), the National Institutes of Health, The Welch Foundation, and the HHMI.
co-authors include Dr. He Zhang, a Computational Biologist in the Quantitative
Biomedical Research Center and the Department of Population and Data Sciences;
Dr. Robert Hammer, a Professor of Biochemistry who holds the Graydon Heartsill
Professorship in Medical Science; Dr. Jonathan Graff, a Professor of Internal
Medicine and Molecular Biology; and Benjamin Jones, a graduate student
researcher in the Mendell lab. Researchers at Cornell University and the
University of Illinois at Chicago also participated.
Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the USA, integrates pioneering biomedical research with exceptional clinical care and education.
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