Understanding the Brain’s Role in Metabolism and Disease
Obesity is a major public health concern linked to increased incidence of cardiovascular disease, stroke, cancer, osteoarthritis, fatty liver, and even migraine. It also is a significant risk factor for detrimental outcomes and mortality from COVID-19. The most pervasive comorbidity of obesity is diabetes, and while the underlying cause of diabetes is insulin resistance, the mechanisms through which obesity causes insulin resistance are not well understood.
Christoph Buettner, MD, PhD, professor of medicine, joined Rutgers Robert Wood Johnson Medical School in 2020 and has strengthened obesity- and diabetes-focused research in the Department of Medicine. Through collaborations with researchers within the school and across the university, his group aims to advance knowledge of the brain’s function in obesity, metabolism, and related disorders.
“Obesity has propelled diabetes into an epidemic and is a major reason for why life expectancy in the United States is not continuing to increase,” says Dr. Buettner, who also is chief of the Division of Endocrinology, Metabolism, and Nutrition. He explains that diabetes, in turn, has become a tremendous burden on healthcare systems throughout the world. According to Dr. Buettner, in the United States alone, the cost of obesity to the healthcare system is estimated to be $147 billion, and the cost of diabetes—if one includes lost productivity—is $327 billion. Combined, these healthcare costs are higher than either the cost of all heart disease or of all cancer care combined.
Dr. Buettner shares, “Diabetes and obesity are the major medical and societal challenges of the 21st century. Since I also have a family history, I have dedicated my career to investigate how obesity causes diabetes.”
Dr. Buettner’s research suggests that stress hormones, which are elevated in obesity and diabetes, are the root cause of insulin resistance. Further, inappropriate stimulation of the sympathetic nervous system drives this increase in stress hormones. The sympathic nervous system directs the body’s rapid involuntary response to dangerous or stressful situations.
“It seems that in the early stages of obesity, when a person eats too much and gains weight, insulin signaling is still normal,” Dr. Buettner says. “Rather, insulin resistance, which is the inability of insulin to lower glucose and fatty acids, is due to impaired brain control of metabolism.”
Dr. Buettner’s team found in earlier studies that the brain is one of the first organs where insulin signaling is reduced during overnutrition, even when other organs such as the liver and body fat still seem to exhibit proper insulin signaling. This insulin resistance in the brain then increases the activity of the sympathetic nervous system supplying nerves to organs like fat tissue, the liver, and the pancreas, which is the driver of increased stress hormones. This work is being conducted with Kenichi Sakamoto, MD, PhD, assistant professor of medicine, who has recently been awarded a grant from the U.S. Department of Defense.
In his lab at Icahn School of Medicine at Mount Sinai, where Dr. Buettner spent 14 years before joining Robert Wood Johnson Medical School, he found abnormal insulin action in the brain in obesity, as well in Alzheimer’s disease. Dr. Buettner explains that brain insulin resistance contributes to increases in fatty acids in the blood stream. Of note, Alzheimer’s disease is also associated with an increased risk of diabetes, possibly due to impaired brain control of metabolism and brain insulin resistance.
More recently, Dr. Buettner is studying traumatic brain injury (TBI) in animal models and its association with an increased risk of metabolic disease.
“TBI has not previously been recognized to be a risk factor for diabetes,” says Dr. Buettner. “We reasoned that even mild forms of TBI impair brain control and may increase susceptibility to diabetes, which has public health relevance, as an estimated 1.5 million Americans sustain a traumatic brain injury each year.” Similar to Alzheimer’s and obesity, TBI seems to impair the brain’s control of metabolism.
As a clinician, Dr. Buettner believes studies addressing the role of stress hormones in diabetes may also be relevant to our understanding of why people of color and financially disadvantaged persons experience much higher rates of diabetes, since social stress, similar to obesity, increases counter-regulatory hormones and induces insulin resistance.
“Our work explains why we need to avoid overnutrition, promote psychological well-being, and encourage and enable people to be physically active as important ways to restore the brain’s control of metabolism and prevent diabetes,” says Dr. Buettner.
He explains further, “In addition to promoting health measures, identifying new strategies that restore insulin action in the brain could help in the fight against many diseases, including fatty liver disease, for which there are no effective therapies.”
This year, Dr. Buettner was elected to the Association of American Physicians, an honor given to physicians with outstanding credentials in basic or translational biomedical research. His more than two decades’ worth of knowledge in metabolic disorders will help advance patient care at the medical school. Within the past year and a half, the Division of Endocrinology started two new clinics, dedicated to the care of patients with obesity and of transgender patients. He also hopes to start an interdisciplinary clinic for women’s health and dedicate a new inpatient service for the care of diabetes.