NYU Langone Health’s rapidly growing endocrinology team is quickly expanding its research portfolio, especially in areas of translational research, in which our new recruits are fostering multidisciplinary collaborations that will lead to better care for patients here and elsewhere. Below is a look at three new faculty members who are contributing to our understanding of the molecular underpinnings behind obesity and diabetes and paving the way for more effective treatments in the future.
Reversing Beta Cell Dysfunction to Treat Metabolic Disease
Andisheh Abedini, PhD, assistant professor of medicine, came to NYU Langone in 2010 as a doctoral fellow in the lab of Ann Marie Schmidt, MD, the Dr. Iven Young Professor of Endocrinology. There, she studied insulin-producing beta cells and the molecular factors that cause the loss of their function and, in turn, the onset and progression of diabetes. Now, as a principal investigator in the Diabetes Research Program and a 2016 recipient of the American Heart Association’s Scientist Development Grant, Dr. Abedini leads a team of researchers who are continuing that work, demonstrating that the preservation of beta cells is a promising avenue for treating and preventing metabolic disease.
In healthy individuals, pancreatic beta cells secrete the hormone amylin alongside insulin to help maintain energy homeostasis. In patients with type 2 diabetes, however, amylin misfolds and aggregates to form oligomers that are toxic to the very beta cells that produce it. These proteotoxic amylin aggregates further self-associate into amyloid plaques in the pancreas. Through a series of studies that included in vitro experiments, transgenic-mouse models, and human subjects with type 2 diabetes, the team made two key discoveries: They found that these toxic amyloidogenic aggregates are surprisingly distinct from those produced by other amyloidogenic proteins, like those in Alzheimer’s disease.
“This overturned a more than 10-year-long paradigm in the field that held to the idea that toxic species derived from different amyloidogenic proteins have the same properties, and explained why drugs that effectively inhibit toxicity in one do not always work for the others,” says Dr. Abedini. Next, they discovered they could mitigate the source of the beta-cell dysfunction by inhibiting the interactions between toxic amylin molecules and RAGE (receptor for advanced glycation end products), a sugar-modified protein first identified by Dr. Schmidt nearly three decades ago. These findings, which will appear in the Journal of Clinical Investigation early this year, reveal new drug targets and provide critical information for the design of new drugs to treat or prevent not only type 2 diabetes, but other metabolic diseases as well.
In other research, Dr. Abedini is examining endocrine cell cross-talk, with novel in vitro experiments simulating the way pancreatic beta cells directly communicate with different types of adipocytes, and how that impacts insulin secretion and beta-cell fate. To understand the pathogenesis of human diabetes, her group is working to translate studies from animal models into human islet biology.
Shedding New Light on the Link between Inflammation, Obesity, and Diabetes
José Alemán, MD, PhD, assistant professor of medicine, joined NYU Langone in 2016 to establish the Laboratory of Translational Obesity Research. Prior to coming to NYU Langone, Dr. Alemán was an instructor in clinical investigation at Rockefeller University, where he initiated a translational research program. Trained as an endocrinologist and a biomedical engineer, he is studying the link between low-grade inflammation that is characteristic of fat tissue in obese patients and chronic complications like type 2 diabetes and cardiovascular disease.
Last March, Dr. Alemán’s lab joined the NYU Langone arm of the American Heart Association’s multi-institution Strategically Focused Obesity Research Network Center, a nearly $4 million, four-year research collaboration between basic, clinical, and population health groups that is under the direction of Ann Marie Schmidt, MD, the Dr. Iven Young Professor of Endocrinology. With the AHA funding, Dr. Alemán is working with Ira J. Goldberg, MD, the Clarissa and Edgar Bronfman, Jr. Professor of Endocrinology and director of the Division of Endocrinology, to figure out exactly how it is that rapid weight loss through surgery reverses inflammation in white adipose tissue and resolves the accompanying insulin resistance; a large clinical trial studying bariatric-surgery patients at NYU Langone and Bellevue Hospital Center is under way.
Meanwhile, Dr. Alemán is helping launch a new weight-management clinic at the Manhattan VA Medical Center, where he is both treating obese veterans who have complications from their weight and conducting a similar clinical trial, this one focusing on medication-induced weight loss.
The large data sets from these two trials will shed light on unexpected findings from a study of weight loss in obese women undergoing a seven-week, very-low-calorie diet. “We discovered that the macrophage immune cells in inflamed adipose tissue acted in a surprisingly non-inflammatory metabolic manner during rapid weight loss,” says Dr. Alemán. If researchers can better understand the metabolic cues mediating this process, they could potentially harness these pathways to find new adipose-centric drug targets to treat inflammation and prevent obesity complications.
Reprogramming Fat Cells to Prevent Obesity
Elisabetta Mueller, PhD, associate professor of medicine, joined NYU Langone in 2016, after spending 12 years at the National Institutes of Health studying adipose tissue biology and the role fat cells play in obesity, aging, and metabolic disease. It is widely understood that white fat stores energy and brown fat burns it, but the discovery of beige fat—a newly identified adipocyte that develops in white adipose tissue but expresses characteristics of brown—has opened the door to new therapeutic possibilities, such as inducing the “browning” of white fat.
To that end, Dr. Mueller and her team are focusing on the cascade of molecular events that determine whether fat-cell precursors become white, brown, or beige adipocytes and which transcription factors, the proteins that control gene expression, act as molecular switches for energy storage or expenditure.
Recently, Dr. Mueller and her team identified and validated in vitro and in vivo two such switches, transcription regulators HSF1 and ZNF638, and demonstrated that pharmacological activation of HSF1 in mice can protect them from the development of obesity and metabolic disease. The researchers are now testing these factors genetically in animal models to see if they can reprogram fat cells to be energy burners instead of energy hoarders.
“If we tweak or overexpress these factors in transgenic mice, can we make a leaner animal, despite their being fed a high-fat diet?” asks Dr. Mueller. She is also conducting in vitro trials to identify therapeutic compounds that target specific transcription factors.