Molecular switch regulates fat burning in mice

Date:
August 2, 2021
Source:
Beth Israel Deaconess Medical Center
Summary:
New research demonstrates a metabolic regulatory molecule called
Them1 prevents fat burning in cells by blocking access to their
fuel source.

The study may contribute to the development of a new type of
obesity treatment.



FULL STORY ========================================================================== Linked to serious health problems including cancer, diabetes and
cardiovascular disease, obesity affects more than a third of adults in
the United States.

Presently, there are few safe and effective nonsurgical therapeutic interventions available to patients with obesity.


==========================================================================
Now, a multi-disciplinary team of researchers has demonstrated that a
metabolic regulatory molecule called Them1 prevents fat burning in cells
by blocking access to their fuel source. Led by microscopy experts at Beth Israel Deaconess Medical Center (BIDMC) and metabolism experts at Weill
Cornell Medicine and NewYork-Presbyterian, the study may contribute to
the development of a new type of obesity treatment. The team's findings
were published June 9 in Nature Communications.

To help explain how the protein Them1 turns off heat production, BIDMC's
cell biology and microscopy expert, Susan Hagen, PhD, associate vice-chair
for research in the Department of Surgery at BIDMC, and Yue Li, PhD,
a postdoctoral researcher in her laboratory, used light and electron
microscopy to observe Them1 in action in mouse brown fat cells grown in
the laboratory.

"Them1 is an interesting molecule," said Hagen. "If you inhibit or block
its expression, metabolism increases and that reduces body weight."
The experiments showed that when the cells are stimulated to burn
fat, a chemical modification causes Them1 molecules to spread out, or
diffuse, throughout the cell. This frees the cellular powerhouses called mitochondria to efficiently turn the cell's fat stores into energy. But
when the stimulation stops, Them1 molecules quickly reorganize into
a structure called a biomolecular condensate. Situated between the
mitochondria and the fats they use as fuel, the condensed Them1 molecules
limit energy production.

"It turned out to be so incredibly interesting," said Hagen, who is
also director of Microscopy and Histology Core Facilities at BIDMC and associate professor of surgery at Harvard Medical School. "We asked
other microscopy experts whether they had ever seen anything like the
unusual images we found in resting cells. Using very sophisticated
electron microscopy techniques, we were able to show -- for the first
time, as far as we know -- what the bimolecular condensate looks like in electron microscopy." "The study explains a new mechanism that regulates metabolism," said David Cohen, chief of the Division of Gastroenterology
and Hepatology at Weill Cornell Medicine and NewYork-Presbyterian/Weill
Cornell Medical Center and the Vincent Astor Distinguished Professor of Medicine at Weill Cornell Medicine.

"Them1 hacks the energy pipeline and cuts off the fuel supply to the
energy- burning mitochondria. Humans also have brown fat and produce more
Them1 in cold conditions, so the findings may have exciting implications
for the treatment of obesity." Cohen and Hagen, both members of the
Harvard Digestive Diseases Center, have been collaborators since 1983. The current study -- supported in part by a five-year, multi-PI grant from
the National Institutes of Health -- also included collaborators with
expertise in structural biology from Emory University.

"This was the most fun I have ever had in science in my life," Hagen
added.

"Including multiple primary investigators with different expertise gives
you the power of doing things that you could never do on your own."
Co-authors included Yue Li, Samaksh Goyal, Lay-Hong Ang, and Mahnoor
Baqai of BIDMC; Norihiro Imai, Hayley T. Nichols, Tibor I. Krisko of
Weill Cornell; Blaine R. Roberts, Matthew C. Tillman, Anne M. Roberts,
and Eric A. Ortlund of Emory University.

This work was supported by the National Institutes of Health (R01
DK 103046, R01 DK0488730 and NIHT32DK007533), the Harvard Digestive
Disease Center (P30 DK034854) and the National Institutes of Health shared-instrumentation grant program for the High Pressure Freezer (S10 OD019988-01), the Pinnacle Research Award from the AAASLD Foundation,
Weill Cornell Department of Medicine Pre- Career Award, and an American
Heart Association Postdoctoral Fellowship, and a Research Science Institute/Center for Excellence in Education Summer Research Fellowship.

========================================================================== Story Source: Materials provided by
Beth_Israel_Deaconess_Medical_Center. Original written by Terri
Janos. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yue Li, Norihiro Imai, Hayley T. Nicholls, Blaine R. Roberts,
Samaksh
Goyal, Tibor I. Krisko, Lay-Hong Ang, Matthew C. Tillman, Anne M.

Roberts, Mahnoor Baqai, Eric A. Ortlund, David E. Cohen, Susan
J. Hagen.

Thioesterase superfamily member 1 undergoes stimulus-coupled
conformational reorganization to regulate metabolism in mice. Nature
Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-23595-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210802140132.htm

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