New method for stimulating signaling to improve metabolic health and
possibly treat obesity

Date:
February 14, 2022
Source:
University of Colorado Anschutz Medical Campus
Summary:
Following up on a 2018 study that identified an epigenetic
modifier known as histone deacetylase 11 (HDAC11) as a potential
therapeutic target for treating obesity and diabetes, researchers
have published new research that finds HDAC11 regulates G
protein-coupled receptors.



FULL STORY ========================================================================== Following up on a 2018 study that identified an epigenetic modifier known
as histone deacetylase 11 (HDAC11) as a potential therapeutic target
for treating obesity and diabetes, researchers from the University of
Colorado School of Medicine have published new research that finds HDAC11 regulates G protein- coupled receptors (GPCRs) called beta-adrenergic
receptors (b-ARs).


==========================================================================
The details of the study are published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), the official journal of the National Academy of Sciences.

Lead author of the study, Rushita Bagchi, PhD, is now a faculty member
at the University of Arkansas for Medical Sciences and was previously
a postdoctoral fellow in the laboratory of Timothy McKinsey, PhD
(on Twitter @McKinseyLab), professor of medicine in the Division of
Cardiology, who is the corresponding author of the article. Both are
part of the Consortium for Fibrosis Research & Translation, a program
funded by the CU School of Medicine to improve understanding of fibrotic diseases across various organ systems.

The scientists originally studied the biological function of HDAC11, a
lysine demyristoylase enzyme, and determined that deleting it in animal
models stimulates the formation of brown adipose tissue (BAT). The absence
of HDAC11 also triggered "beiging," turning white adipose tissue (WAT)
into brown-like adipose tissue. BAT and beige WAT are unique forms of
fat that are stimulated in response to cold temperature. BAT and beige
WAT produce heat, and in so doing, burn calories. From a therapeutic perspective, there is intense interest in developing drugs that activate
BAT or convert normal WAT into beige WAT as a means of triggering weight
loss in the context of obesity and diabetes. One approach to doing this
is to stimulate b2- and b3--ARs. However, drugs targeting these GPCRs
have underperformed as anti-obesity therapies in the clinic, perhaps due
to the high doses required, which can cause cardiovascular side effects.

"Our new research shows that inhibiting HDAC11 promotes b-AR signaling
in fat cells through a previously unrecognized mechanism called lysine myristoylation," McKinsey says. "The findings lay the foundation for
developing therapeutics for obesity and diabetes based on enhancing
GPCR signaling in adipose tissue by inhibiting HDAC11. Reversible lysine myristoylation is a very unique mechanism that has never been described
for the regulation of a GPCR.

Given the critical roles of b-ARs in various physiological
and pathophysiological processes, we think this work will be of
interest to a broad audience, and has great potential for clinical translation." "Before taking anything like this into the clinic,
there's a lot of additional work that needs to be done at the bench,"
Bagchi adds. "This paper describes only the second myristoylated
substrate of HDAC11. There are likely many more proteins that are
substrates for HDAC11, and thus, we are at the tip of the iceberg
when it comes to understanding the biological consequences and the
therapeutic potential of inhibiting this fascinating demyristoylase." ========================================================================== Story Source: Materials provided by University_of_Colorado_Anschutz_Medical_Campus. Original written by Greg Glasgow. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Rushita A. Bagchi, Emma L. Robinson, Tianjing Hu, Ji Cao, Jun
Young Hong,
Charles A. Tharp, Hanan Qasim, Kathleen M. Gavin, Julie Pires
da Silva, Jennifer L. Major, Bradley K. McConnell, Edward
Seto, Hening Lin, Timothy A. McKinsey. Reversible lysine fatty
acylation of an anchoring protein mediates adipocyte adrenergic
signaling. Proceedings of the National Academy of Sciences, 2022;
119 (7): e2119678119 DOI: 10.1073/ pnas.2119678119 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220214121248.htm

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