Scientists in the United States suggest how a molecular mechanism that may have helped to stop our ancestors from starving might now be contributing to the obesity epidemic. Studies headed by a team at the NYU School of Medicine found that a protein located on the surface of fat cells acts to stop the breakdown of stored fat in response to different stressors.

“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,” said Ann Marie Schmidt, MD, the Dr. Iven Young professor of endocrinology at NYU School of Medicine, who is corresponding author of the researchers’ published paper in Cell Reports, which is titled, “A Receptor of the Immunoglobulin Superfamily Regulates Adaptive Thermogenesis.”

An animal’s ability to store and use nutrients is dependent upon a precise balance between energy intake and energy expenditure, the authors wrote. “Yet, hoarding energy is a double-edged sword, albeit, salutary in nutrient deprivation; in over-feeding, excess energy storage confers susceptibility to obesity and type 2 diabetes.”

White adipose tissue (WAT, or white fat), and brown adipose tissue (BAT, or brown fat) in mammals store energy in the form of triglycerides and release fatty acids and glycerol in response to cues by the sympathetic nervous system. “Whereas WAT releases fatty acids into the circulation, BAT preferentially oxidizes fatty acids and dissipates energy through uncoupled respiration and the production of heat,” the researches further explained.

The authors suggest that evolution devised an anti-starvation mechanism that helped animals to efficiently use food to fuel their cellular activity and recover from injury. Studies now suggest that integral to this mechanism is the immunoglobulin superfamily molecule, the receptor for advanced glycation end (RAGE) products. RAGE binds to specific molecules that accumulate in metabolic stress, and which are linked with diabetes and inflammation. However, the team noted, more recent evidence suggests that these molecules, and RAGE itself, are also present in human and mouse fat tissue. The hormone mechanism also links in by signaling for the conversion of fat into energy either for flight from danger, or to generate heat when the body gets cold. The idea is that that RAGE effectively acts to block fat burning when we starve, freeze, become injured, or panic, and, potentially, when we overeat. This concept fits in with the authors’ own recent finding that mice engineered to lack Ager, the gene encoding RAGE, are protected from obesity and insulin resistance when fed a high-fat diet (HFD).

Through their newly reported studies, Schmidt and colleagues showed that mice engineered with adipose-specific deletion of Ager were also significantly protected from HFD-induced obesity and insulin resistance than control animals, and were better able to control body temperature during a cold challenge. Mice lacking RAGE in their fat cells gained up to 75% less weight after three months on a high-fat diet than mice that retained RAGE, despite equal amounts of food consumption and physical activity. Transplanting fatty tissue lacking RAGE into normal mice also led to decreased weight gain when the animals were then fed a high-fat diet. In both sets of experiments RAGE deletion from fat cells effectively released braking mechanisms that held back energy expenditure, so the animals could ramp up energy expenditure when fed a high-fat diet, which helped to reduce weight gain.

Ann Marie Schmidt, MD
Ann Marie Schmidt, MD [NYU Langone Health]
The new results complement those from the researchers’ recent experiments in which they found that small molecule RAGE antagonists suppressed RAGE ligand-stimulated signaling by dampening the activity of protein kinase A, which is integral to the pathways that control UCP1-related increases in body heat. “The present studies illustrate that recently identified inhibitors of RAGE signal transduction block the RAGE ligand-mediated reduction of phosphorylation of PKA targets in adipocytes,” they wrote. “ … we demonstrate that the immunoglolubin super family molecule, the RAGE, suppresses adaptive thermogenesis in both BATs and WATs, at least in part by reducing the effects of beta-adrenergic signaling in adipocytes, through suppression of the phosphorylation of PKA targets … This work identifies the innate role of the RAGE as a key node in the immunometabolic networks that control responses to nutrient supply and cold challenges, and it unveils opportunities to harness energy expenditure in environmental and metabolic stress.”

The researchers aim to optimize their RAGE inhibitors and test whether the molecules can help to stop weight regain in bariatric surgery patients and those undergoing medical weight loss programs. Putting lost weight back on isn’t uncommon for even the most successful dieters. A 2016 study found that contestants from America’s Greatest Loser piled the pounds back on after the show ended. “Because RAGE evolved out of the immune system, blocking it may also reduce the inflammatory signals that contribute to insulin resistance driving diabetes,” said Schmidt. “Further, such treatments may lessen the system-wide inflammation linked to risk for atherosclerosis, cancer, and Alzheimer’s disease.”


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