�ٺ���Ƶ

Within days of bariatric surgery, long before weight loss occurs, patients who are obese are seeing dramatic improvements in insulin resistance and chronic inflammation. Now, researchers at �ٺ���Ƶ are investigating exactly how bariatric surgery can remodel adipose tissue, reshape the microbiome, and, most remarkably, put diabetes into remission.

Delving Deeper into the Benefits of Surgery

Over the past decade, the number of patients undergoing bariatric surgery has been steadily rising, but the percentage of adults who are obese and seek this treatment is still very small, despite the promising outcomes.

“In addition to significant and sustained weight loss, most patients who have bariatric surgery experience almost immediate improvement in nearly all metabolic indicators, including insulin, glucose, and cholesterol, as well as resolution of the chronic low-grade inflammation that is linked to obesity complications like diabetes and cardiovascular disease,” says José O. Alemán, MD, PhD, assistant professor in the  and head of �ٺ���Ƶ’s Laboratory of Translational Obesity Research. While the association between surgery and these benefits is clear, the mechanisms driving these outcomes is less so.

Quantifying Microbiome Shifts After Surgery

In early 2017, Dr. Alemán’s lab joined the �ٺ���Ƶ arm of the American Heart Association’s multi-institution Strategically Focused Obesity Research Network Center, a nearly $4-million, 4-year research collaboration among basic, clinical, and population health groups that is under the direction of , the Dr. Iven Young Professor of Endocrinology. With the American Heart Associtaion funding, Dr. Alemán’s lab has been working alongside Ira J. Goldberg, MD, the Clarissa and Edgar Bronfman, Jr. Professor of Endocrinology and director of the , to study the bariatric populations at Tisch Hospital and NYC Health + Hospitals/Bellevue as part of a longitudinal trial on surgery outcomes.

Specifically, his team is focused on identifying the factors in adipose tissue that are linked to increased inflammation and insulin resistance, and learning how these factors are altered by the hormonal and microbiome changes that follow bariatric surgery.

“Bariatric surgery changes the hormonal profile of the patient in a way that is very different from diet-induced changes.”—José O. Alemán, MD 

“We know that a large component of the early metabolic improvement that happens with bariatric surgery is strictly related to caloric restriction. For instance, the diabetes remission we are seeing after surgery is comparable to what we saw in a recent trial of patients undergoing weight loss by a very low-calorie diet,” says Dr. Alemán.

Yet while people who are obese have a gut microbiome that differs from that of people who are lean, undergoing weight loss by very low-calorie diet produced only modest functional changes, at best, in the gut microbiome and fecal bile acids. “On the other hand, bariatric surgery changes the hormonal profile of the patient in a way that is very different from diet-induced changes, in large part because when we rearrange the gut we drastically change the profile of gut hormone secretion and induce big shifts in the microbiome,” says Dr. Alemán.

Dr. Alemán’s team is targeting these changes in the current bariatric surgery study, which is halfway through enrolling normoglycemic and diabetic patients undergoing sleeve gastrectomy. For each subject, the team conducts a metabolic characterization, tracks energy expenditure, and profiles hormones impacted by surgery, then repeats these tests six weeks after surgery. Investigators also collect and biobank adipose tissue at both time points and measure the microbiome changes from fecal samples. Because of the variability in the human population, the large data sets of genetic, metabolic, and histologic information generated for each subject are compared against his or her history.

“We believe this unbiased approach will uncover factors that differ between patients and will define how individual patients respond to weight-reduction surgery,” says Dr. Alemán.

Inflammatory Response Could Help Predict Outcomes

To that end, the team is looking for specific markers in adipose-tissue formation that predict which patients will experience weight loss and diabetes remission. One marker the team is paying particular attention to is receptor for advanced glycation end products, or RAGE, a protein discovered by Dr. Schmidt two decades ago that promotes inflammation and is a key player in diabetic complications. In mouse models, Dr. Schmidt has shown that inhibiting RAGE protected mice from developing obesity and insulin resistance.

“We’re working to translate those mice models to a real-world setting and uncover how rapid weight loss from bariatric surgery impacts RAGE-signaling pathways—and the associated inflammatory and metabolic effects,” says Dr. Alemán. “We hope to provide a tool to help clinicians determine who will respond best to various surgeries versus other treatment options.”

Tracking Down Targets Behind Immune-Based Inflammation

If researchers can better understand the metabolic cues mediating adipose tissue inflammation and resolution, they could potentially harness these pathways to find new adipose-centric drug targets to treat inflammation and prevent obesity complications.

In an earlier trial of weight loss in women who are obese and undergoing a seven-week, very low-calorie diet, Dr. Alemán found that every indicator of metabolic disease improved. To his surprise, however, he saw a histological increase in the macrophage immune cells in adipose tissue, which would typically signal increased inflammation. Here, though, despite the increase, the researchers did not detect any inflammatory gene expression, and circulating biomarkers of inflammation decreased.

“We discovered that during diet-induced rapid weight loss, macrophage immune cells in inflamed adipose tissue act in a metabolic rather than an inflammatory manner,” says Dr. Alemán. It’s not yet clear if he will see this same dynamic in the inflammation resolution following surgery, given the increased hormonal and microbiome changes that go along with it. “We just don’t know, but either case is interesting,” he says.