Researchers ID mechanism that may drive obesity epidemic

July 16, 2019

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."
-end-
Among with Schmidt, study authors in Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, were 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.

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

This work was supported by United States Public Health Service grants 1R01DK109675, 1PO1HL131481, 5T32HL098129-10, and 1F31AG054129-01; and by the American Diabetes Association grant 1-15-MI-14. The work was also partly funded by research funds of the Diabetes Research Program at NYU, and by the Experimental Pathology Research Laboratory's Cancer Center Support grant (P30CA016087). Additional funding came from the National Mouse Metabolic Phenotyping Center at UMass, which is funded by National Institutes of Health grant 2U2C-DK093000.

NYU Langone Health / NYU School of Medicine

Related Obesity Articles from Brightsurf:

11 years of data add to the evidence for using testosterone therapy to treat obesity, including as an alternative to obesity surgery
New research covering 11 years of data presented at this year's European and International Congress on Obesity (ECOICO 2020) show that, in obese men suffering from hypogonadism (low testosterone), treatment with testosterone injections lowers their weight and improves a wide range of other metabolic parameters.

Overlap between immunology of COVID-19 and obesity could explain the increased risk of death in people living with obesity, and also older patients
Data presented in a special COVID-19 session at the European and International Congress on Obesity (ECOICO 2020) suggests that there are overlaps between the immunological disturbances found in both COVID-19 disease and patients with obesity, which could explain the increased disease severity and mortality risk faced by obese patients, and also elderly patients, who are infected by the SARS-CoV-2 virus that causes COVID-19 disease.

New obesity guideline: Address root causes as foundation of obesity management
besity management should focus on outcomes that patients consider to be important, not weight loss alone, and include a holistic approach that addresses the root causes of obesity, according to a new clinical practice guideline published in CMAJ (Canadian Medical Association Journal) http://www.cmaj.ca/lookup/doi/10.1503/cmaj.191707.

Changing the debate around obesity
The UK's National Health Service (NHS) needs to do more to address the ingrained stigma and discrimination faced by people with obesity, says a leading health psychologist.

Study links longer exposure to obesity and earlier development of obesity to increased risk of type 2 diabetes
Cumulative exposure to obesity could be at least as important as actually being obese in terms of risk of developing type 2 diabetes (T2D), concludes new research published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]).

How much do obesity and addictions overlap?
A large analysis of personality studies has found that people with obesity behave somewhat like people with addictions to alcohol or drugs.

Should obesity be recognized as a disease?
With obesity now affecting almost a third (29%) of the population in England, and expected to rise to 35% by 2030, should we now recognize it as a disease?

Is obesity associated with risk of pediatric MS?
A single-center study of 453 children in Germany with multiple sclerosis (MS) investigated the association of obesity with pediatric MS risk and with the response of first-line therapy in children with MS.

Women with obesity prior to conception are more likely to have children with obesity
A systematic review and meta-analysis identified significantly increased odds of child obesity when mothers have obesity before conception, according to a study published June 11, 2019 in the open-access journal PLOS Medicine by Nicola Heslehurst of Newcastle University in the UK, and colleagues.

Obesity medicine association announces major updates to its adult obesity algorithm
The Obesity Medicine Association (OMA) announced the immediate availability of the 2019 OMA Adult Obesity Algorithm, with new information for clinicians including the relationship between Obesity and Cardiovascular Disease, Diabetes Mellitus, Dyslipidemia, and Cancer; information on investigational Anti-Obesity Pharmacotherapy; treatments for Lipodystrophy; and Pharmacokinetics and Obesity.

Read More: Obesity News and Obesity Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.