Potential strategy for fighting obesity
Lab safely replicates weight-loss benefits of plant linked to harmful
side effects

Date:
November 2, 2021
Source:
UT Southwestern Medical Center
Summary:
Scientists may have identified a method of safely mimicking
the weight- loss benefits of a plant compound that -- despite
its harmful side effects -- hold critical answers to developing
therapies for obesity.



FULL STORY ==========================================================================
UT Southwestern scientists may have identified a method of safely
mimicking the weight-loss benefits of a plant compound that -- despite
its harmful side effects -- hold critical answers to developing therapies
for obesity.


========================================================================== Celastrol, derived from the root extracts of a white-flowered plant
in China, has drawn increased attention in recent years after studies
showed it can both prevent and reverse obesity in mice. However, because celastrol can cause reactions such as high blood pressure and lethargy
in mice, researchers have sought to understand how the compound works
and use that knowledge to develop safe weight-loss treatments for people.

UT Southwestern may have solved part of the puzzle in a new study that
shows celastrol requires a specific protein in a type of neuron that
influences metabolism. Scientists found they can mimic a "fed" signal
to mouse brains by deleting this protein from the neurons, resulting
in mice losing 7% of their body weight in two weeks despite being a fed high-fat diet.

Key to the findings: The mice did not appear to endure the same
physical ailments documented in previous research in which celastrol
was administered.

"This new understanding of how celastrol works on the cellular level
opens more possibilities for targeting pathways that can improve our
metabolism without the negative health impact," said study author Kevin
W. Williams, Ph.D., an investigator at UT Southwestern's Center for Hypothalamic Research. "We haven't uncovered all the cell populations
that influence weight loss, but each of these findings brings us closer
to developing effective, safe therapies for obesity." The study,
published in JCI Insight, is the latest research from Dr. Williams that
may someday help improve glucose metabolism in patients with obesity-
driven conditions such as diabetes. More than 30 million Americans have diabetes, accounting for nearly 10% of the population, according to the
Centers for Disease Control and Prevention.



==========================================================================
The new research focused on a class of cells in the brain called POMC
neurons, which are associated with reduced appetite, lower blood glucose levels, and higher energy burning when activated. A 2019 study from
Dr. Williams showed a single bout of exercise can boost the activity of
POMC for up to two days.

In the latest research, the Williams lab found this neuron also plays
a critical part in how celastrol impacts weight loss. Mice given the
compound saw decreased activity of a protein called PERK within the
region of the brain where POMC neurons reside. The lab further found that deleting PERK from these neurons can replicate much of the weight-loss
effects of celastrol, and appears to do so without causing harmful side
effects often associated with anti- obesity drugs.

"The mice were leaner and had the same activity levels; they didn't
appear lethargic, sickly or ill," Dr. Williams said. "But this is
through observation only. Further study is needed to verify how targeting
this pathway may be influencing their cardiovascular systems and other functions." The Food and Drug Administration cautions people against
the use of celastrol, a substance also known as thunder god vine used
in traditional Chinese medicine. Although extracts from the plant are
sold as supplements, the National Institutes of Health (NIH) has posted cautionary statements saying scientists do not yet have enough data
about celastrol's safety and effectiveness.

But the compound has already given scientists important insight into how
safer strategies for weight loss may be developed in the lab. In the new
study, for instance, deleting PERK from the POMC neurons blocked about
half the food intake-reducing effect of celastrol.

"This indicates there are other cell populations for celastrol's effects
on metabolism besides POMC," said Dr. Williams, Associate Professor of
Internal Medicine at UT Southwestern and an investigator in the Peter
O'Donnell Jr.

Brain Institute. "We'll continue mapping the roles of these cell types
until we have a fuller picture of the complex network of pathways. One
day, perhaps, this knowledge may contribute to the development of
more effective therapeutics in the treatment of obesity and diabetes."
Funding for the study was provided from NIH grants R01 DK100699, R01
DK119169, and DK119130-5830.

========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Zhenyan He, Linh Lieu, Yanbin Dong, Sadia Afrin, Dominic Chau, Anita
Kabahizi, Briana Wallace, Jianhong Cao, Eun-Sang Hwang, Ting Yao,
Yiru Huang, Jennifer Okolo, Bo Cheng, Yong Gao, Ling Hu, Kevin
W. Williams.

PERK in POMC neurons connects celastrol with metabolism. JCI
Insight, 2021; 6 (18) DOI: 10.1172/jci.insight.145306 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211102125506.htm

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