Our Research: Faculty/Research Laboratories

Michael Schwartz, MD

Robert H. Williams Endowed Chair in Medicine

Director, UW Medicine Diabetes Institute

Director, Nutrition Obesity Research Center

Professor, Division of Metabolism and Endocrinology

Email Address: mschwart@u.washington.edu

Division of Metabolism, Endocrinology and Nutrition Website:  http://depts.washington.edu/metab/


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 also directs the Nutrition Obesity Research Center (NORC) at UW.


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. This effect of FGF1 appears to involve pleiotropic effects in both neurons and glia, 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.

Support the Schwartz Lab Research

Representative Publications:

Thaler JP, Yi C-X, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf SA, Izgur V, Maravilla KR, Nguyen HT, Fischer JD, Matsen ME, Wisse BE, Morton GJ, Horvath TL, Baskin DG, Tschöp MH, Schwartz MW. Obesity is associated with hypothalamic injury in rodent models and humans. J Clin Invest. 122:152-162, 2012. PMCID: PMC3248304.

Thaler JP, Guyenet SJ, Dorfman M, Wisse BE, Schwartz MW. Hypothalamic inflammation: Marker or mechanism of obesity pathogenesis? Diabetes. 62:2629-2634, 2013. PMCID: PMC3717869.

Schwartz MW, Seeley RJ, Tschöp MH, Woods SC, Morton GJ, Myers MG, D’Alessio D. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature. 503:59-66, 2013. PMCID: PMC3983910.

Schwartz MW, Baskin DG. Leptin and the brain: then and now. J Clin Invest. 123:2344-2345, 2013. PMCID: PMC3668840.

Morton G, Matsen M, Bracy D, Meek T, Nguyen H, Stefanovski D, Bergman R, Wasserman DH, Schwartz MW. FGF19 action in the brain induces insulin-independent glucose lowering. J Clin Invest. 123:4799-4808, 2014. PMCID: PMC3809800.

Morton GJ, Kaiyala KJ, Foster-Schubert KE, Cummings DE, Schwartz MW. Carbohydrate feeding dissociates the postprandial FGF19 response from circulating bile acid levels in humans. J Clin Endocrinol Metab. 99:E241-E245, 2014. PMCID: PMC3913810.

Berkseth KE, Guyenet SJ, Melhorn SJ, Lee D, Thaler JP, Schur EA, Schwartz MW. Hypothalamic gliosis associated with high fat diet feeding is reversible in mice: a combined immunohistochemical and magnetic resonance imaging study. Endocrinology. 155:2858-2567, 2014. PMCID: PMC4098007

Morton GJ, Meek TH, Schwartz MW. Neurobiology of food intake in health and disease. Nat Rev Neurosci. 15:367-378, 2014. PMCID: PMC4076116.

Morton GJ, Kaiyala KJ, Foster-Schubert KE, Cummings DE, Schwartz MW. Carbohydrate feeding dissociates the postprandial FGF19 response from circulating bile acid levels in humans. J Clin Endocrinol Metab. 99:E241-E245, 2014. PMCID: PMC3913810.

Berkseth KE, Guyenet SJ, Melhorn SJ, Lee D, Thaler JP, Schur EA, Schwartz MW. Hypothalamic gliosis associated with high fat diet feeding is reversible in mice: a combined immunohistochemical and magnetic resonance imaging study. Endocrinology. 155:2858-2867, 2014. PMCID: PMC4098007.

Laeger T, Henagan TM, Albarado DC, Redman LM, Bray GA, Noland RC, Munzberg H, Gettys TW, Schwartz MW, Morrison CD. FGF21 is an endocrine signal of protein restriction. J Clin Invest. 124:3913-3922. 2014. PMCID: PMC4153701.

O-Sullivan I, Zhang W, Wasserman DH, Liew CW, Liu J, Paik J, DePinho RA, Stolz DB, Kahn CR, Schwartz MW, Unterman TG. FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and utilization. Nat Commun. 6:7079, 2015.  PMCID: PMC4755301.

Schur EA, Melhorn SJ, Oh SK, Lacy JM, Berkseth KE, Guyenet SJ, Sonnen JA, Tyagi V, De Leon MRB, Webb MF, Gonsalves ZT, Fligner CL, Schwartz MW, Maravilla KR. Radiologic evidence that hypothalamic gliosis is associated with obesity and insulin resistance in humans. Obesity (Silver Spring). 23:2142-2148, 2015. PMCID: PMC4634110.

Scarlett JM, Schwartz MW. Gut-brain mechanisms controlling glucose homeostasis. F1000Prime Rep. 7:12, 2015. PMCID: PMC4311273.

Schwartz MW. Can the history of modern endocrinology shape the future of obesity? Mol Endocrinol. 29:155-157, 2015. PMCID: PMC4318879.

Meek TH, Nelson JT, Matsen ME, Dorfman M, Guyenet SJ, Allison MB, Damian V, Scarlett J, Nguyen HT, Thaler JP, Olson DP, Myers Jr MG, Schwartz MW, Morton GJ. Functional identification of a neurocircuit regulating blood glucose. Proc Natl Acad Sci U S A. 113:E2073-E2082, 2016. PMCID: PMC4833243.

Scarlett JM*, Rojas JM*, Matsen ME, Kaiyala KJ, Stefanovski D, Bergman RN, Nguyen HT, Dorfman MD, Lantier L, Wasserman DH, Mirzadeh Z, Unterman TG, Morton GJ, Schwartz MW. Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents. Nat Med. 22:800-806, 2016. PMCID: PMC4938755. (*contributed equally to this work)

Campos CA, Bowen AJ, Schwartz MW, Palmiter RD. Parabrachial CGRP neurons control meal termination. Cell Metab. 23:811-820, 2016. PMCID: PMC4867080.

Morton G, Muta K, Kaiyala K, Rojas J, Scarlett J, Matsen M, Nelson J, Acharya N, Piccinini F, Stefanovski D, Bergman R, Taborsky G Jr., Kahn S, Schwartz, M. Evidence that the sympathetic nervous system elicits rapid, coordinated and reciprocal adjustments of insulin secretion and insulin sensitivity during cold exposure. Diabetes. 66:823-834, 2017. PMCID: PMC5360298.

Campos CA, Bowen AJ, Han S, Wisse BE, Palmiter RD, Schwartz MW. Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus.Nat Neurosci. 20:934-942, 2017. PMC Journal – In Process.

Schwartz MW, Seeley RJ, Zeltser LM, Drenowski A, Ravussin E, Redman LM, Leibel RL. Obesity pathogenesis: An Endocrine Society scientific statement. Endocr Rev. 38:1-30, 2017. PMC Journal – In Process.

Deem JD, Muta K, Scarlett JM, Morton GJ, Schwartz MW. How should we think about the role of the brain in glucose homeostasis and diabetes? Diabetes. 66:1758-1765, 2017. PMC Journal – In Process.

Full Publication List

Current Collaborations:

Within the Diabetes and Obesity Center of Excellence and its Affiliated Members
Ernie Blevins, PhD
Jay Heinecke, MD
Steven Kahn, MB, ChB
Francis Kim, MD
Greg Morton, PhD
Joshua Thaler, MD, PhD
Brent Wisse, MD
Vincenzo Cirulli, MD

Lab Members:

Jarrad Scarlett, MD, PhD
Kenjiro Muta, PhD
Carlos Campos, PhD
Zaman Mirzadeh, MD, PhD
Kimberly Alonge, PhE
Jennifer Deem, PhD
Jenny Brown
Chelsea Kasper
Hong Nguyen
Kayoko Ogimoto, PhD
Miles Matsen
Nick Acharya
Vincent Damian
Jarrell Nelson
Loan Nguyen
Trista Harvey
Kevin Velasco
Bao Phan