University of
California - Riverside
More than two in three
adults in the United States are considered overweight or obese, with
substantial biomedical and clinical evidence suggesting that chronic
overconsumption of a "western diet" -- foods consisting high levels
of sugars and fats -- is a major cause of this epidemic.
New research by
scientists at the University of California, Riverside now shows that chronic
consumption of a western diet leads to overeating and obesity due to elevations
in "peripheral endocannabinoid signaling."
The endocannabinoid system is located throughout the mammalian body, including the brain and all peripheral organs, and participates in the control of many physiological functions in the body, including food intake, energy balance, and reward.
It is
comprised of lipid signaling molecules called endocannabinoids -- which can be
thought of as the body's own "natural cannabis" -- that bind to
cannabinoid receptors located on cells throughout the body.
"Our research
shows that targeting cannabinoid receptors in the periphery with
pharmacological inhibitors that do not reach the brain holds promise as a safe
therapeutic approach for the treatment of overeating and diet-induced
obesity," said Nicholas V. DiPatrizio, an assistant professor of
biomedical sciences in the School of Medicine, who led the research project.
"This therapeutic approach to targeting the periphery has substantial
advantages over traditional drugs that interact with the brain and cause
psychiatric side-effects."
The work describes for
the first time that overeating associated with chronic consumption of a western
diet is driven by an enhancement in endocannabinoid signals generated in
peripheral organs.
Study results appear
in the journal Physiology & Behavior.
To examine the role
for endocannabinoids generated in peripheral organs in controlling the
overeating of western diet, DiPatrizio and coauthor Donovan A. Argueta, a
bioengineering Ph.D. student in his lab, used a mouse model of western
diet-induced obesity (chronic exposure to high levels of sugars and fats).
They found that when
compared to mice fed a standard low-fat/low-sugar diet, mice fed a western diet
for 60 days rapidly gained body weight and became obese, and displayed
"hyperphagia," that is, they consumed significantly more calories,
and consumed significantly larger meals at a much higher rate of intake
(calories per minute).
"These
hyperphagic responses to western diet were met with greatly elevated levels of
endocannabinoids in the small intestine and circulation," DiPatrizio said.
"Importantly, we found that blocking the actions of the endocannabinoids
with pharmacological inhibitors of cannabinoid receptors in the periphery
completely normalized food intake and meal patterns in western diet-induced
obese mice to levels found in control lean mice fed standard chow."
DiPatrizio and Argueta
caution that further research is necessary to identify whether similar
mechanisms drive obesity in humans.
"Importantly,
however, other research groups have reported elevations in circulating levels
of endocannabinoids in obese human subjects, which suggests that this system
may also be overactive in human obesity," DiPatrizio said.
He explained that
rimonabant, a drug which blocked endocannabinoid signaling at cannabinoid
receptors, was on the market in Europe for the treatment of human obesity.
"It worked quite
well at reducing body weight and improving metabolic profiles; however, this
drug was not restricted to the periphery and thus, led to severe psychiatric
side effects and was not given FDA approval in the United States,"
DiPatrizio said.
"Peripherally restricted inhibitors of cannabinoid
receptors, such as AM6545 used in our experiments, however, would be devoid of
these side effects given that they do not reach the brain."
DiPatrizio and Argueta
were surprised to find that inhibiting peripheral endocannabinoid signaling
with inhibitors like AM6545 completely normalized intake to that found in lean
mice maintained on a standard chow.
"This suggests
that these elevations in peripheral endocannabinoid signaling are critical in
driving hyperphagia associated with a western diet," said Argueta, the
first author of the research paper.
Next, the researchers
plan to identify critical upstream and downstream mechanisms of endocannabinoid
signaling in western diet-induced obesity, as well as the possible specific
dietary constituents in western diet (e.g., sucrose) that drive overeating as a
result of elevated peripheral endocannbinoid levels.
"In addition, we
aim to translate our work in rodents to similar studies in humans,"
DiPatrizio said.
