A novel therapy ameliorates obesity and Typediabetes in mice fed a
high-fat diet
This therapy, using sustained release of nitric oxide, may be a novel, efficient and safe way to prevent and treat multiple metabolic diseases.
Date:
April 29, 2022
Source:
University of Alabama at Birmingham
Summary:
A novel therapy ameliorates obesity and Type 2 diabetes in mice
fed a high-fat diet. The therapy acts through sustained release
of nitric oxide, a gaseous signaling chemical whose most important
function in the body is relaxing the inner muscles of blood vessels.
FULL STORY ==========================================================================
A novel therapy developed at the University of Alabama at Birmingham ameliorates obesity and Type 2 diabetes in mice fed a high-fat diet. The therapy acts through sustained release of nitric oxide, a gaseous
signaling chemical whose most important function in the body is relaxing
the inner muscles of blood vessels.
========================================================================== "Because reduced bioavailability of nitric oxide is the hallmark of cardiometabolic syndrome, supplying exogenous nitric oxide at a sustained
level may be an efficient way of treating the cardiometabolic syndrome,"
said Jeonga Kim, Ph.D., leader of the UAB study. "The strategy of
reducing body weight by the local delivery of nitric oxide may be a novel, efficient and safe way to prevent and treat multiple metabolic diseases."
This study, published in the journalACS Applied Materials & Interfaces,
used an ingenious self-assembling, nanomatrix gel capable of releasing a
burst of nitric oxide in the first 24 hours, followed by sustained nitric
oxide release for four weeks. The gel was developed by UAB researchers
Ho-Wook Jun, Ph.D., and Brigitta Brott, M.D., and it is licensed through
the UAB Harbert Institute for Innovation and Entrepreneurship by their
UAB spinoff company, Endomimetics LLC.
The gel was injected subcutaneously into 8-week-old mice every two weeks
for 12 weeks. Gel-injected mice and control mice were fed a high-fat diet, known to induce obesity and insulin resistance.
At the end of 12 weeks, the nitric oxide-mice had gained 17 percent less
body weight, compared to controls, and that weight difference was due
mainly to decreased fat, not lean mass or water content. The researchers
saw increased phosphorylation of the enzyme hormone-sensitive lipase and a reduction in the size of fat cells in epididymal white adipose tissue, or
eWAT. Increased lipolysis may explain the reduced body weight, Kim says.
The nitric oxide-mice also showed improved glucose tolerance, and
decreases in fasting serum insulin and leptin levels.
==========================================================================
Kim and colleagues found wide-ranging changes in measures of inflammation
and metabolism in the nitric-oxide mice, compared to controls. The
expression of four inflammatory genes, including a marker for macrophages,
was reduced in eWAT.
The nitric oxide gel also appeared to stimulate the browning of adipose
tissue, through increased gene expression of uncoupled protein 1 in
brown adipose tissue and beige adipose tissue. Nitric oxide is known
to increase mitochondrial biogenesis, a mechanism for the conversion of
white adipocytes to beige adipocytes. Brown adipose tissue, or brown fat, produces heat to maintain body temperature in cold conditions. The fat
cells in brown adipose tissue and in inguinal adipose tissue from the
nitric oxide-mice were also smaller than cells from controls.
The nitric oxide gel also protected against non-alcoholic fatty liver
disease, as seen by lower liver weight, reduced triglycerides in the
liver, and reduced triglycerides and cholesterol in blood serum. The
nitric oxide gel also improved insulin sensitivity, as measured by
increased expression of five insulin-signaling molecules in skeletal
muscle, liver or eWAT.
The mice that received the nitric oxide gel also had improved cerebral
blood flow, and they showed significantly improved spatial learning
ability, as measured by the Morris water maze test. It is unknown whether
those changes were a direct effect of nitric oxide or were mediated
through the neuroprotective effects of adipocyte beiging.
Co-authors with Kim, Jun and Brott in the study, "Subcutaneous
administration of nitric oxide-releasing nanomatrix gel ameliorates
obesity and insulin resistance in high fat diet-induced obese mice," are
Guang Ren and Sushant Bhatnagar, UAB Department of Medicine, Division
of Endocrinology, Diabetes and Metabolism; Patrick Tae Joon Hwang and
Reid Millican, Endomimetics, LLC, Birmingham, Alabama; Juhee Shin,
UAB Department of Biomedical Engineering; Brigitta C. Brott and Martin
E. Young, UAB Department of Medicine, Division of Cardiovascular Disease;
and Thomas van Groen and Craig M. Powell, UAB Department of Neurobiology.
At UAB, Kim is an associate professor in the UAB Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, and she is a scientist
in the UAB Comprehensive Diabetes Center.
Support came from UAB and from National Institutes of Health grants
DK079626, HL128695, HL163802, AG058078, DK95975-03, DK120684-01, DK109789
and NS047466.
========================================================================== Story Source: Materials provided by
University_of_Alabama_at_Birmingham. Original written by Jeff
Hansen. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Guang Ren, Patrick Tae Joon Hwang, Reid Millican, Juhee Shin,
Brigitta C.
Brott, Thomas van Groen, Craig M. Powell, Sushant Bhatnagar,
Martin E.
Young, Ho-Wook Jun, Jeong-a Kim. Subcutaneous Administration of
a Nitric Oxide-Releasing Nanomatrix Gel Ameliorates Obesity and
Insulin Resistance in High-Fat Diet-Induced Obese Mice. ACS Applied
Materials & Interfaces, 2022; DOI: 10.1021/acsami.1c24113 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220429144859.htm
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