Michael Schwartz, MD
Title:
Professor, Department of Medicine, Division of Metabolism and Director, Diabetes & Obesity Center of Excellence
Email Address:
Background:
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 clinical teaching and patient care responsibilities at Harborview Medical Center in Seattle, Dr. Schwartz has been continuously funded by the NIH and other sources to study body weight regulatory systems, obesity and diabetes for over 19 years with >150 publications in this area. He serves as Director of the UW Medicine Diabetes & Obesity Center of Excellence, is a member of the American Society for Clinical Investigation and the Association of American Physicians, and serves on numerous editorial boards. He is also Associate Director of both the Clinical Nutrition Research Unit (CNRU) and Mouse Metabolic Phenotyping Center (MMPC) at UW, and is Principle Investigator on an NIH T32 Fellowship Training grant and two ADA Fellowship Training grants, as well as two NIH R01 awards and an NIH Program Project grant.
Focus:
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. Accordingly, defects in this control system may play an important role in the link between obesity, insulin resistance and type 2 diabetes. The overarching hypothesis is that in times of plenty (i.e., ample fat stores and food availability), input to key brain areas from these afferent signals (e.g., insulin, leptin and long-chain free fatty acids) leads to inhibition of both energy intake and endogenous glucose production, while simultaneously increasing energy expenditure and mobilizing fat stores. The net effect is that 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 nutrient levels (i.e., increased hepatic glucose production). As body fat content and plasma glucose levels begin to increase, circulating concentrations of leptin, insulin and free fatty acids increase as well. The latter are sensed in the brain, favoring the return of food intake and glucose production to their original values. Should defects arise in either the secretion of or the CNS response to these signals, elevated levels of both body fat content and hepatic glucose production are expected consequences. Reduced secretion of, sensing of, or responsiveness to afferent hormonal or nutrient-related signals can therefore be predicted to set in motion a vicious cycle of weight gain and insulin resistance.
Since convergent signal transduction (e.g., via the insulin receptor substrate (IRS)-phosphatidylinositide 3-OH kinase (PI3K) signaling pathway) and termination (e.g., SOCS3) mechanisms mediate neuronal actions of insulin and leptin, defects within a single biochemical pathway can potentially cause resistance to the central actions of both hormones. This, in turn, can be predicted to induce hyperphagia, weight gain, hepatic insulin resistance and glucose intolerance. The feasibility of this concept is strengthened by evidence implicating impaired IRS-PI3K signal transduction in the insulin resistance of peripheral tissues in diabetic humans and animal models. When combined with a b-cell defect, a feed-forward mechanism is again set in motion whereby reduced insulin and leptin action in the brain and periphery initially favor weight gain and insulin resistance, progressing to glucose intolerance and ultimately, diabetes. Since functional resistance to both leptin and insulin is common among the obese, this hypothesis warrants careful consideration. This concept was recently introduced formally (Science 21: 375-9, 2005) and discussed in greater detail (Diabetes 54:1264-76, 2005) by the PI. To test this hypothesis, our lab is actively investigating the mechanism whereby hypothalamic actions of insulin and leptin regulate insulin sensitivity in peripheral tissues. The main goals are to identify the specific neuronal subsets that mediate these effects and the underlying intracellular signal transduction molecules involved, using adenoviral gene therapy and transgenic strategies in mouse and rat models.
Hypothalamic Inflammation and Energy Homeostasis
This research focus, developed collaboratively with Drs. Brent Wisse and Jay Heinecke, seeks to investigate mechanisms underlying hypothalamic inflammation and clarify how this response affects brain systems that govern energy balance. A key hypothesis is that changes in the function of microglia (the resident macrophage of the brain) contribute to the link between systemic inflammatory signals and the onset and maintenance of hypothalamic inflammation. Major goals of this project are to identify the cellular mechanisms that drive hypothalamic inflammation in response to both acute inflammatory stress and to obesity, and to determine the consequences of this response for the control of energy homeostasis and peripheral glucose metabolism.
PI3K as a mediator of insulin and leptin action in the hypothalamus
PI3K is a major mediator of insulin action in peripheral tissues, and published evidence from our lab and elsewhere suggests that it is involved in signaling by both leptin and insulin in the hypothalamus. Ongoing studies seek to determine if interruption of PI3K signaling or downstream signal transduction molecules in discrete hypothalamic areas causes hyperphagia, obesity and insulin resistance. In addition, we will determine the extent to which such interventions attenuate the weight-reducing effects of intracerebroventricular (icv) insulin or leptin administration, and whether diet-induced obesity impairs hypothalamic PI3K signaling.
Leptin Action in the Forebrain Regulates Insulin Sensitivity in Peripheral Tissues
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 insulin action in peripheral tissues. To investigate the physiological role of leptin in the control of glucose tolerance in insulin sensitivity, Drs. Schwartz and Morton are studying Koletsky (fak/fak) rats that develop severe obesity due to genetic absence of leptin receptors. To date, we have demonstrated a marked impairment of glucose tolerance in these animals that is substantially rescued by adenoviral gene therapy to introduce functional leptin receptors selectively into the hypothalamic arcuate nucleus (ARC, a key forebrain site of leptin action) of fak/fak rats. Moreover, these effects cannot be explained by reductions of food intake or body weight, but they are blocked by icv infusion of a PI3K inhibitor. Conversely, the use of adenoviral gene therapy to express a constitutively active mutant of Akt, a key enzyme downstream of PI3K, in the ARC recapitulated the ability of leptin receptor gene therapy to improve insulin sensitivity when directed to this brain area. Thus, leptin signaling via the IRS-PI3K pathway in ARC neurons appears to play a key role to regulate insulin action in peripheral tissues. Dr. Morton has taken on a leadership role in developing this area of study.
Leptin Action in the Forebrain Regulates the Hindbrain Response to Satiety Signals
The capacity to adjust energy intake in response to changing energy requirements is a defining feature of energy homeostasis. In collaboration with Dr. Greg Morton, we found markedly increased meal size and reduced satiety in response to the gut peptide cholecystokinin (CCK) in Koletsky rats that lack functional leptin receptors. This observation suggests a critical role for leptin signaling in the response to endogenous signals that promote meal termination. To identify the brain area involved in this action of leptin, we used adenoviral gene therapy to introduce either functional leptin receptors or a reporter gene selectively into the ARC. We found that restoration of leptin signaling to this brain area normalizes the effect of CCK to activate neurons in key hindbrain areas for processing satiety-related inputs, and also reduced meal size and strongly enhanced CCK-induced satiety in fak/fak rats. These data support the hypothesis that forebrain signaling by leptin limits food intake on a meal-to-meal basis by regulating the hindbrain response to short-acting satiety signals.
Mechanism of diabetic hyperphagia
Uncontrolled diabetes lowers the circulating levels of both leptin and insulin, raises plasma levels of ghrelin, and is associated with progressive weight loss and insulin resistance, as well as pronounced hyperphagia. We therefore seek to determine the independent contributions made by reduced insulin, reduced leptin, and increased ghrelin signaling in the brain as mediators of these responses. In addition, we propose to investigate the specific contribution to diabetic hyperphagia made by various neuropeptides involved in feeding (e.g., neuropeptide Y, agouti-related peptide, and melanocortins) and signal transduction molecules as mediators of these responses. To accomplish this, studies are performed in genetically normal rodents and in mice with targeted mutations that affect specific signaling pathways.
Representative Publications:
Morton GJ, Blevins JE, Williams DL, Niswender KD, Gelling RW, Rhodes CJ, Baskin DG, Schwartz MW. Leptin action in the forebrain regulates the hindbrain response to satiety signals. J Clin Invest 115:703-10, 2005.
Morton, GJ, Gelling, RN, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW. Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab 2(6):411-20, 2005.
Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature. 2006 Sep 21;443(7109):289-95.
Gelling RW, Morton GJ, Niswender KD, Morrison CD, Myers M, Rhodes CJ, Schwartz MW. Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes. Cell Metab 3(1):67-73, 2006.
Wisse BE, Kim F, Schwartz MW. Physiology. An integrative view of obesity. Science. 2007 Nov 9;318(5852):928-9.
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Current Collaborations:
Within the Diabetes and Obesity Center of Excellence and its Affiliated Members
Denis Baskin, PhD
Ernie Blevins, PhD
Renee LeBoeuf, PhD
Jay Heinecke, MD
Steven Kahn, MB, ChB
Francis Kim, MD
Greg Morton, PhD
Brent Wisse, MD
Lab Members:
Josh Thaler, MD, PhD
David Sarruf, PhD
Shinsuke Oi, PhD
Hong Nguyen, BS
Kayoko Ogimoto, PhD
Miles Matsen, BS
Jonathan German, BS
Loan Nguyen, BS
Iaela David, BS
Alex Cubelo, BS
JD Fischer, BS