Michael W. Schwartz, M.D.
Metabolism, Endocrinology and Nutrition
Professor of Medicine
Director, Diabetes and Obesity Center of Excellence
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, Neuron Injury and Energy Homeostasis.
This research 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) and astrocytes contribute to the link between nutrient excess and injury to hypothalamic neurons that control body weight. Major goals of this project are to identify the cellular mechanisms that drive hypothalamic injury and inflammation during high fat feeding, and to determine the consequences of this response for the control of energy homeostasis and peripheral glucose metabolism.
Schwartz MW, Woods SC, Seeley RJ, Porte D Jr, and Baskin DG: Central nervous system control of food intake. Nature 404:661-671, 2000.
Schwartz MW: Staying slim with insulin in mind. Science 2089:266-267, 2000.
Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG, and Schwartz MW: Key enzyme in leptin-induced anorexia. Nature 413:794-795, 2001.
Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers MG Jr, Seeley RJ, Schwartz MW: Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: A key mediator of insulin-induced anorexia. Diabetes 52:227-231, 2003.
Schwartz MW and Porte D Jr: Diabetes, obesity, and the brain. Science 307:375-379, 2005.
Morton GJ, Blevins JE, Williams DL, Niswender KD, Gelling RW, Rhodes CJ, Baskin DG, and Schwartz MW: Leptin action in the forebrain regulates the hindbrain response to satiety signals. J Clin Invest 115:703-710, 2005.
Porte D Jr, Baskin DG, and Schwartz MW: Insulin signaling in the central nervous system: A critical role in metabolic homeostasis and disease from C. elegans to humans. Diabetes 54:1264-1276, 2005.
Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW: Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab 2:411-20, 2005.
Xu AW, Kaelin CB, Takeda K, Akira S, Schwartz MW, Barsh GS: PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest 115:951-8, 2005.
Williams DL, Baskin DG, Schwartz MW: Leptin regulation of the anorexic response to glucagon-like peptide-1 receptor stimulation. Diabetes 55:3387-93, 2006.
Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW: Central nervous system control of food intake and body weight. Nature 443:289-95, 2006.
Gelling RW, Morton GJ, Morrison CD, Niswender KD, Myers MG Jr, Rhodes CJ, Schwartz MW: Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes. Cell Metab 3:67-73, 2006.
Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF, Lazarowski ER, Gilbert ML, Morton GJ, Bammler TK, Strand AD, Cui L, Beyer RP, Easley CN, Smith AC, Krainc D, Luquet S, Sweet IR, Schwartz MW, La Spada AR: Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1alpha in Huntington’s disease neurodegeneration. Cell Metab 4:349-362, 2006.
Kim F, Pham M, Luttrell I, Bannerman DD, Tupper J, Thaler J, Hawn TR, Raines EW, Schwartz MW: Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 100:1589-1596, 2007.
Wisse BE, Ogimoto K, Tang J, Harris MK Jr, Raines EW, Schwartz MW: Evidence that LPS-induced anorexia depends upon central, rather than peripheral, inflammatory signals. Endocrinology 148:5230-5237, 2007.
Wisse BE, Kim F, Schwartz MW: Physiology. An integrative view of obesity. Science 318:928-929, 2007.
Williams DL, Schwartz MW, Bastian LS, Blevins JE, Baskin DG: Immunoctyochemistry and laser capture microdissection for real-time quantitative PCR identify hindbrain neurons activated by interaction between leptin and cholecystokinin. J Histochem Cytochem 56:285-293, 2008.
Gelling RW, Yan W, Fitzgerald SM, Lim PO, Al-Noori S, Pardini A, Morton GJ, Ogimoto K, Schwartz MW, Dempsey PJ: Deficiency of TNF-alpha converting enzyme (TACE/ADAM17) causes a lean, hyper metabolic phenotype in mice. Endocrinology 149:6053-6064, 2008.
Kim F, Pham M, Maloney E, Rizzo N, Morton GJ, Wisse BE, Kirk EA, Chait A, Schwartz MW: Vascular inflammation, insulin resistance and reduced nitric oxide production precede the onset of peripheral insulin resistance. Atheroscler Thromb Vasc Biol, Sept 4 2008 [Epub ahead of print].
Sarruf DA, Yu F, Nguyen H, Williams DL, Printz RL, Niswender KD, Schwartz MW: Expression of PPARg in key neuronal subsets regulating glucose metabolism and energy homeostasis. Endocrinology, Oct 9 2008 [Epub ahead of print].
Williams DL, Baskin DG, Schwartz MW: Evidence that intestinal GLP-1 plays a physiological role in satiety. Endocrinology, Dec 12 2008 [Epub ahead of print].