Michael Schwartz, MD

Email: mschwart@uw.edu

  • Co-Director, UW Medicine Diabetes Institute
  • Robert H. Williams Endowed Chair in Medicine
  • Professor of Medicine, Division of Metabolism, Endocrinology and Nutrition

Complete list of published work.

Dr. Schwartz received his MD from Rush Medical College in 1983 and completed his residency in Medicine at UW in 1986. His fellowship training in Endocrinology and Metabolism, undertaken in the lab of Dr. Daniel Porte, Jr., at UW, was completed in 1990. In addition to many years of clinical teaching and patient care at Harborview Medical Center in Seattle, Dr. Schwartz has been continuously funded by the NIH and other sources to study brain mechanisms governing body weight regulation, glucose homeostasis, obesity and diabetes for over 25 years, with >250 publications in these areas. He serves as Director of the UW Medicine Diabetes Institute, is a member of the American Society for Clinical Investigation and the Association of American Physicians, is the recipient of numerous awards and serves on several editorial boards. He is also former director of the Nutrition Obesity Research Center (NORC) at UW.

Research Interests

Dr. Schwartz’s research focuses on hypothalamic and neuroendocrine control of energy balance and glucose metabolism, and on CNS mechanisms involved in obesity, insulin resistance and diabetes.

Role of the Brain in the Pathogenesis of Obesity, Insulin Resistance and Type 2 Diabetes
A major focus of Dr. Schwartz’s research program is to investigate the hypothesis that the brain plays an essential role to promote homeostasis of both energy balance and glucose metabolism in response to afferent input from adiposity- and nutrient-related signals. An extension of this hypothesis is that defects in this central control system are implicated in the link between obesity, insulin resistance and type 2 diabetes. Specifically, our work centers on the concept that in times of plenty (i.e., ample fat stores and food availability), input to key brain areas from relevant afferent signals (e.g., insulin, leptin and free fatty acids) leads to inhibition of both energy intake and endogenous glucose production, while simultaneously increasing energy expenditure and mobilizing fat stores. Stated differently, when the brain senses that body energy content and nutrient availability are in sufficient supply, further increases of stored energy (in the form of fat) and circulating nutrients (e.g., glucose) are resisted. Conversely, a decrease in neuronal input from one or more of these afferent signals is proposed to alert the brain to a current or pending deficiency of stored energy or nutrient availability. In turn, the brain activates responses that promote positive energy balance (e.g., increased food intake and decreased energy expenditure) and raise circulating levels of glucose and other nutrients (e.g., increased hepatic glucose production). As body fat content and plasma glucose levels begin to rise, circulating concentrations of leptin, insulin, and free fatty acids increase as well. These humoral inputs are sensed in the brain, favoring the return of food intake and glucose production to their original values – in normal individuals. Should defects exist in the ability to mount, sense or respond to these key afferent signals, both body fat content and glucose levels are expected increase, setting in motion a vicious cycle of weight gain, insulin resistance and impaired insulin secretion that can lead to type 2 diabetes. This overarching hypothesis is supported in part by work described below.

Hypothalamic Inflammation Obesity and Type 2 Diabetes
Studies performed when Dr. Joshua Thaler was completing his training in the Schwartz lab (Dr. Thaler now runs his own independent lab at UW) revealed that in rodent models, obesity induced by switching animals from standard chow to consumption of a high-fat diet (HFD) is accompanied by inflammatory activation of two distinct subsets of glial cells – microglia and astrocytes – specifically in the hypothalamic arcuate nucleus (ARC), a key brain area for control of energy balance and glucose homeostasis. This “gliosis” reaction is characteristic of the response to neuron injury and is detectable within days of the change in diet, well in advance of increased body weight. Subsequent work by Dr. Ellen Schur has documented evidence of hypothalamic gliosis in humans (based on magnetic resonance imaging), and Dr. Thaler’s group recently reported that activation of ARC microglia is in fact required for obesity pathogenesis in mice.

Central Leptin Regulation of Peripheral Glucose Metabolism
In addition to the key role played by leptin in the control of food intake and body weight, growing evidence suggests that leptin action in the CNS is a critical determinant of glucose homeostasis. To investigate the physiological role of leptin in the control of glucose tolerance in insulin sensitivity, Drs. Schwartz and Morton first studied Koletsky (fak/fak) rats that develop severe obesity due to genetic absence of leptin receptors, and demonstrated that the marked impairment of glucose tolerance characteristic of these animals is substantially rescued by introducing functional leptin receptors selectively into the ARC. Subsequent studies showed that central leptin administration restores normal blood glucose levels to mice and rats with severe diabetes induced by the pancreatic beta cell toxin streptozotocin. The mechanisms underlying these remarkable effects of leptin are still under study, but appear to involve actions in the hypothalamic ventromedial nucleus (VMN) as well as the ARC.

Regulation of Peripheral Glucose Metabolism by the Central Actions of Fibroblast Growth Factors (FGFs)
The anti-diabetic effects of two hormonal members of the FGF family — FGF19 and FGF21 — have generated considerable research interest, and work from our laboratory helped to establish a key role for the brain in these effects. We subsequently shifted our attention to the tissue growth factor FGF1 and showed that in both rat and mouse models of T2D, a single injection of FGF1 into the brain induces diabetes remission that is sustained for weeks or months. Subsequent work showed that this effect is not mediated by changes of food intake or body weight, is elicited by doses of FGF1 that are ineffective when given systemically, and is not associated with hypoglycemia. Our ongoing work is guided by evidence that under the influence of FGF1, glucoregulatory neurocircuits are reorganized so as to defend a lower, more normal level of blood glucose in a manner that can be sustained for weeks or even months. This effect of FGF1 appears to involve pleiotropic effects on neurons, glia, and vascular elements, and ongoing work seeks both to define the details of this process and to translate these findings into a new approach to the treatment of T2D.

How can this research help people with diabetes?

By identifying the mechanisms whereby FGF1 action in the brain induces sustained remission of diabetic hyperglycemia, we hope to identify new therapeutics with the potential to improve treatment outcomes for patients with diabetes.