A molecular “trick” that kept our ancient ancestors from starving may now
be contributing to the obesity epidemic, a new study finds.
In starvation times, researchers say, animals were more likely to survive
if they could hoard and stretch out their stored energy. Even if an animal
secured a rare feast, evolution smiled on the storage of excess fuel as fat,
given the likelihood of a quick return to starvation.
“We discovered an anti-starvation mechanism that has become a curse in
times of plenty because it sees cellular stress created by overeating as
similar to stress created by starvation — and puts the brakes on our ability to
burn fat,” says lead study author Ann Marie Schmidt, MD, the Dr. Iven Young
Professor of Endocrinology at NYU School of Medicine.
Published online July 16 in Cell Reports, the current study
reveals that the natural function of a protein called RAGE on the surface of
fat cells is to stop the breakdown of stored fat in the face of stress. Its
existence may partly explain why 70 percent of American adults are overweight
or obese, according to the American Heart Association (AHA). In March 2017, the
AHA announced a grant to help researchers find the elusive “metabolic brake.”
The AHA funding followed a 2016 study that found contestants from America’s
Greatest Loser gained back their lost pounds after the show ended. Why did
their metabolisms slam to a halt in the face of weight loss, as if their bodies
were bent on returning to obesity?
A Brake on Fat Burning
According to the authors, the most efficient way for evolution to create an
anti-starvation mechanism was from ancient systems that helped animals use food
for cellular energy and recover from injury. Also wired into these primal
mechanisms was the hormone adrenalin, which signals for the conversion of fat
into energy as animals run from predators, or into body heat when they get
cold.
This convergence — through the same signaling proteins — means that RAGE
may block “fat burning” called for when we starve, freeze, get injured, panic,
or ironically, overeat.
According to the new study and experiments done elsewhere in human tissues,
RAGE is turned on by the advanced glycation endproducts (AGEs), which form when
blood sugar combines with proteins or fats — most often in aging, diabetic and
obese patients. Other molecules also activate RAGE, such as those released when
cells die and spill their contents into intracellular spaces in response to
stress.
A disturbing possibility, says Schmidt, is that many proteins and fats have
come to activate “the RAGE break” as they warp and stack up (as toxic
oligomers) in people that eat more than their ancestors did.
The current study found that removing RAGE from fat cells caused mice to
gain up to 75 percent less weight during three months of high-fat feeding,
despite equal amounts of food consumption and physical activity, than mice with
the RAGE brake on. Transplanting fatty tissue lacking RAGE into normal mice
also decreased weight gain as they were fed a high-fat diet.
In both sets of experiments, the deletion of RAGE from fat cells released
the braking mechanisms that restrained energy expenditure. Once freed up,
energy expenditure rose, contributing to the reduced body weight gain in mice
with the fatty diet.
The new study complements the team’s discovery of experimental compounds
that attach to the “tail” of RAGE. From there, they prevent RAGE from turning
down the action of protein kinase A, a key player in the chain reaction that
ends with a protein called UCP1 turning fat into body heat.
The research team plans — once they optimize the design of these “RAGE
inhibitors” — to examine whether the agents can keep bariatric surgery
patients, and patients undergoing medical weight loss regimens, from regaining
lost weight.
Importantly, RAGE is much more active during metabolic stress (e.g.
starving or overeating) than in everyday function, which suggests it can be
safely interfered with through drugs, the authors say.
“Because RAGE evolved out of the immune system, blocking it may also reduce
the inflammatory signals that contribute to insulin resistance driving
diabetes,” says Schmidt. “Further, such treatments may lessen the system-wide
inflammation linked to risk for atherosclerosis, cancer, and Alzheimer’s
disease.”
Source: https://nyulangone.org/press-releases/researchers-identify-mechanism-that-may-drive-obesity-epidemic
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