Researchers at University of Michigan have
illuminated an aspect of how the metabolic system breaks down in obesity. The
findings provide additional evidence that a drug entering clinical trials at
the university could reverse obesity, Type 2 diabetes and fatty liver disease
In a paper scheduled for online publication
in the journal eLife on Dec. 24, Alan Saltiel, the Mary Sue Coleman Director of
the Life Sciences Institute, explains how, in obesity, fat cells stop
responding to hormones known as catecholamines that trigger them to expend more
energy. However, the fat cells of obese mice treated with a drug called
amlexanox regained sensitivity to catecholamines, burned the excess energy and
returned to normal size.
Next month, scientists at U-M will begin a
placebo-controlled clinical trial of amlexanox to test its efficacy as a drug
for treating obesity and diabetes in humans. Formulations of amlexanox are
prescribed in different international markets to treat asthma and canker sores.
links to obesity
Obesity leads to a state of chronic,
low-grade inflammation in liver and fat tissue. Scientists believe that
inflammation links obesity and insulin resistance via a pathway called NFkB,
which is involved in the regulation of a range of cellular processes and
activated in obesity.
Activation of NFkB increases the levels of
a pair of genes, IKKe and TBK1, which in turn reduce the ability of certain
receptors in the fat cells of obese mice to respond to catecholamines like
adrenaline, "fat-burning" hormones generated by the sympathetic
nervous system in response to stress.
"We've suspected that in obesity, fat
cells become less sensitive to catecholamines such as adrenaline, and that this
reduced sensitivity in turn reduces energy expenditure, but the details of this
haven't been fully understood," Saltiel said.
High levels of IKKe and TBK1 also resulted
in lower levels of a second messenger molecule called cAMP, which increases
energy expenditure by elevating fat burning.
Amlexanox interfered with the two enzymes
and restored sensitivity to catecholamine, allowing the fat cells to burn
In research published in February 2013,
Saltiel found that amlexanox reversed obesity, diabetes and fatty liver in
mice. The forthcoming eLifepaper explains in part how amlexanox works.
"There is considerable evidence to
suggest that in states of obesity, adipose tissue becomes less sensitive to
catecholamines because IKKe and TBK1 act as a sort of brake on metabolism, and
that this reduced sensitivity in turn reduces energy expenditure," Saltiel
"By releasing the brake, amlexanox seems to free the metabolic
system of mice to burn more and possibly store less energy in response to
What is: Metabolic syndrome
Obesity and its diseases
The obese personality