In 2019, a surprising study by a team of researchers at NYU Langone Health suggested that a molecular mechanism thought to have once protected humans from starvation might be contributing to the current obesity epidemic. Led by Ann Marie Schmidt, MD, the Dr. Iven Young Professor of Endocrinology, the study in Cell Reports suggested that a protein called the receptor for advanced glycation end products (RAGE) can put the brakes on metabolic activity in response to cellular stress.
Starvation and cold can trigger the kind of cellular stress that prompts RAGE’s metabolism-lowering, energy-saving strategy. But so can over-nutrition, Dr. Schmidt and colleagues found, potentially explaining why many people with obesity struggle to lose weight and suggesting how a mechanism that releases the RAGE-mediated brakes might act as a preventive or therapeutic intervention.
Based on the devastating lung inflammation and thrombosis seen in some patients with coronavirus disease (COVID-19), Dr. Schmidt and colleagues are now investigating whether the same RAGE pathway might play a role in worsening the course of the viral disease as well, especially in patients with obesity. The common link, Dr. Schmidt says, may be the receptor’s role in spurring low-grade inflammation in multiple organs as part of an only partially understood pathway that includes a growing cast of binding partners.
Releasing the Metabolic Brake
The exciting new lines of research have built upon a series of discoveries about RAGE. As part of their research into obesity, Dr. Schmidt’s team previously reported that a family of pro-inflammatory ligands tends to accumulate during times of metabolic stress. When they bind to RAGE, the ligands spur a slowdown in metabolic activity. In lean times with little incoming nutrition, she says, “It would be very helpful to be able to have a mechanism like this where you could put the brakes on energy expenditure and metabolism.” Being able to slowly mete out the stored energy in fat cells over time could provide a means to stay alive.
If RAGE’s general function has persisted over time, though, it may act like a low-grade brake on energy expenditure that is triggered by the cellular stress of over-nutrition as well. In fact, Dr. Schmidt’s group found that a high-fat diet likewise generates more ligands to RAGE within the adipose tissue of mice and humans with obesity. Other research suggests that the pro-inflammatory ligands can increase insulin resistance too.
In their 2019 study, Dr. Schmidt and colleagues discovered that RAGE-deficient mice fed a high-fat diet were more protected from obesity and cold stress than their RAGE-expressing counterparts. In addition, the RAGE-deficient animals were less insulin resistant, likely due to a decrease in the insulin resistance–promoting inflammation.
To understand the potential basis of this protective response, the researchers knocked out the RAGE receptor globally in some mice and only within the adipocytes (or fat cells) of others. In vitro experiments had suggested that RAGE ligands could suppress the energy expenditure needed to counter a high-calorie diet. A RAGE knockout, though, whether global or adipocyte-specific, released the brake by increasing the ability of the mice to respond to excess nutrition through adaptive thermogenesis. “They’re able to rev up the energy expenditure and use that to prevent the weight gain,” Dr. Schmidt says.
Even more astonishing, when the lab transplanted adipose tissue lacking the RAGE receptor into normal mice, the recipients increased their fat-burning thermogenic response, both within the transplanted adipocytes and within their own native fat cells. “The protection is presumably being transferred through something in the circulation and we don’t know what that factor is, but we want to discover that,” Dr. Schmidt says.
Potential Link to Lung Inflammation
As for the many potential ways in which RAGE might be involved with COVID-19, Dr. Schmidt says, the most proximal might be directly through the lungs. Intriguingly, RAGE is highly expressed in the same lung cells that express the ACE-2 receptor identified as the initial binding site for the SARS-CoV-2 virus. “It’s known that the virus can bind to other cell types, like endothelial cells and neurons, but what really caught our attention was the fact that it is important in these AT1 cells, as they’re called,” Dr. Schmidt says. “RAGE is highly expressed there, and so we would like to study how that might be related to COVID interactions.”
Some patients with COVID-19 develop a hypercoagulable state and subsequent pulmonary thrombosis. Research also suggests that the prothrombotic potential of endothelial cells can be increased by generating inflammatory mediators. Given Dr. Schmidt’s finding that the pro-inflammatory, RAGE-binding ligands are up-regulated in humans and mice with obesity, she hypothesizes that more ligand in the circulation and RAGE binding could set the stage for low-grade inflammation in multiple organs, including the lungs. Other studies have suggested that the RAGE pathway can exacerbate pneumonia and acute respiratory distress syndrome in animals. “That’s not surprising because of the general understanding that RAGE is involved in mainly chronic inflammation,” Dr. Schmidt says.
The evidence, she says, raises the possibility that some of the severe inflammation seen in the lungs of patients with COVID-19 could be attributable in part to the RAGE pathway. A superimposed COVID-19 infection, for its part, could exacerbate any preexisting lung inflammation through the production of pro-inflammatory cytokines or other pathways. “The bottom line is that it could be a multiple-injuries model,” Dr. Schmidt says.
Furthermore, bronchoscopies that have collected bronchoalveolar lavage fluid specimens from lung tissue in human patients have detected soluble RAGE protein and suggested a prognostic role linked to its relative levels. “What they have shown is that, remarkably, these levels of soluble RAGE are really biomarkers for the degree of injury in this acute respiratory distress syndrome,” Dr. Schmidt says. Those soluble RAGE levels, in turn, seem to correlate to the levels detected in blood plasma.
A new line of research, in collaboration with Leopoldo N. Segal, MD, associate professor of medicine, will test whether a higher elevation of soluble RAGE levels, either in blood plasma or in lung fluid, might help predict a worse prognosis. The Schmidt lab is seeking funding for experiments to explicitly test this idea in blood plasma and bronchoalveolar lavage fluid collected from patients with COVID-19 by NYU Langone’s Center for Biospecimen Research and Development, and in a mouse model within a secure Biosafety Level 3 Lab setting.
New Progress Toward a Therapy
In separate studies presented at a recent conference and conducted as part of a multi-investigator American Heart Association grant aimed at clarifying the mechanisms of obesity, the Schmidt lab first fed mice a high-fat diet until the animals became obese and insulin resistant. When the researchers subsequently knocked out the RAGE receptor in the animals’ adipocytes only, the mice lost weight better and faster and became less insulin resistant than their RAGE-expressing counterparts. If replicated, Dr. Schmidt says, the experiments would suggest that even after the RAGE receptor initially applies the brakes to energy expenditure, its loss can reverse the block and allow the body to up-regulate its metabolism in response to excess nutrition. Down-regulating RAGE, then, might be useful in not only preventing obesity but also treating it.
As one therapeutic approach to blocking the cell signaling linked to obesity, inflammation and other negative consequences, Dr. Schmidt’s team is working toward developing small molecules that might interfere with RAGE’s ability to link up with its critical binding partners. If it works, she says, the approach might mimic the benefits of an outright RAGE deletion. Dr. Schmidt says she’s excited by the challenge and potential of teasing apart the many connections seemingly mediated by the RAGE pathway. “Certainly, fat is in communication with the circulation, and obviously the lung is highly vascularized, so there’s a lot to discover,” she says.