Mechanism for identifying researchers that may lead to the obesity epidemic

NEW YORK, July 16, 2019 / PRNewswire / – A new molecular "thing" that prevented our ancestors from starving could now contribute to the obesity epidemic, a new study reveals.

According to the researchers, in times of famine, animals were more likely to survive if they could collect and stretch stored energy. Even though an animal was getting a rare treat, Evolution smiled at storing excess fuel in the form of fat, given the likelihood of a quick return to starvation.

"We have discovered an anti-starvation mechanism that has become a curse in times of plenty because it considers that the cellular stress created by overeating is similar to the stress created by starvation – and slows down our ability to burn fat." , says the main author of the study Ann Marie Schmidt, MD, Professor of Endocrinology Dr. Iven Young at the NYU School of Medicine.

Posted online July 16th in Cell reports, The current study reveals that the natural function of a protein called RAGE on the surface of adipocytes is to stop the breakdown of stored fat in the face of stress. Its existence might partly explain why 70% of American adults are overweight or obese, according to the American Heart Association (AHA). In March 2017The AHA has announced a grant to help researchers find the elusive "metabolic brake".

The AHA funding followed a 2016 study that revealed that candidates The biggest loser of America took back their lost books after the end of the show. Why did their metabolism stop abruptly in the face of weight loss, as if their body was determined to return to obesity?

A brake on fat burning

According to the authors, the most effective way for the evolution of creating an anti-starvation mechanism was from old systems that helped animals to use food to produce cellular energy and to recover from an injury. The adrenaline hormone, also involved in these primitive mechanisms, is also related to the conversion of fat into energy when animals pbad predators or to heat the body when they are cold.

This convergence – via the same signaling proteins – means that RAGE can block the "fat burning" required when we are starving, freezing, being injured, panicking or paradoxically eating too much.

According to the new study and experiments done elsewhere in human tissues, RAGE is activated by advanced glycation products (AGEs), which are formed when blood sugar combines with proteins or fats – most often in patients elderly, diabetic and obese. Other molecules also activate RAGE, such as those released when cells die and spread into intracellular spaces in response to stress.

According to Schmidt, a disturbing possibility is that many proteins and fats came to activate the "RAGE break" as they deform and pile up (as toxic oligomers) in people who eat more than their ancestors.

The current study showed that removal of RAGE from fat cells caused the mouse to lose 75% less weight for three months of high-fat diets, despite equal consumption of food and physical activity, compared with mouse with the RAGE brake activated. Transplantation of adipose tissue devoid of RAGE in normal mice also reduced weight gain as they were fed a high fat diet.

In both sets of experiments, the removal of RAGE from the fat cells released the braking mechanisms that limited energy expenditure. Once released, energy expenditure increased, contributing to the reduction of weight gain in mice with a fat 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 slowing down the action of protein kinase A, a key player in the chain reaction that ends with a protein called UCP1 that turns fat into body heat.

The research team is considering, once optimized the design of these "RAGE Inhibitors" – to examine whether agents can prevent patients with bariatric surgery and patients on a weight loss medical regimen from regaining lost weight.

It is important to note that RAGE is much more active during metabolic stress (eg, starving or overeating) than in daily function, suggesting that it may be disrupted by drugs safely, according to the authors.

"Because RAGE has evolved out of the immune system, blocking it could also reduce the inflammatory signals that contribute to insulin resistance leading to diabetes," said Schmidt. "In addition, such treatments can reduce system-wide inflammation related to the risk of atherosclerosis, cancer and Alzheimer's disease."

Of these, the authors of the Diabetes Research Program study of the Division of Endocrinology, Diabetes and Metabolism of the Department of Medicine at the NYU School of Medicine were the first authors Carmen Hurtado del Pozo and Henry Ruiz, Lakshmi Arivazhagan, Juan Francisco Aranda, Cynthia Shim, Peter Daya, Julia Derk, Michael MacLean, Meilun he, Laura Frye, and Ravichandran Ramasamy.

The authors of the study were also Randall Friedline, Hye Lim Noh, and Jason Kim of the Molecular Medicine Program and Division of Endocrinology, Metabolism and Diabetes, Department of Medicine University of Mbadachusetts Medical School; as good as Richard Friedman Herbert Irving Comprehensive Cancer Center and the Department of Biomedical Informatics, at the College of Physicians and Surgeons, Columbia University.

This work was funded by the United States subsidies 1R01DK109675, 1PO1HL131481, 5T32HL098129-10 and 1F31AG054129-01. and through the 1-15-MI-14 grant from the American Diabetes Association. The work was also partially funded by research funds from the Canadian Diabetes Research Program. NYUand the Perlmutter Cancer Center Support Grant for the Experimental Pathology Research Laboratory (P30CA016087). Additional funding was provided by the National Center for Mouse Phenotyping at UMbad, which is funded by the National Institutes of Health grant 2U2C-DK093000.

Media contact: Gregory Williams212-404-3500, [email protected]

SOURCE NYU School of Medicine