Our Research: Faculty/Research Laboratories

Michael Schwartz, MD

Robert H. Williams Endowed Chair in Medicine

Director, Diabetes and Obesity Center of Excellence

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/

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 currently holds two R01 grants and has been continuously funded by the NIH and other sources to study body weight regulatory systems, obesity and diabetes for over 20 years with >185 publications in this area. He serves as Director of the UW Medicine Diabetes and 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 the Director of the Nutrition Obesity Research Center (NORC)  at UW, and is Principle Investigator on an NIH T32 Fellowship Training grant and two NIH R01 awards.

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.

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 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.

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.

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.

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.

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. PMC Journal – In Process.

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

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.

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

 

  • Baura, G, Foster, D, Porte, D, Jr., Kahn, SE, Bergman, RN, Cobelli, C, Schwartz, MW. Saturable transport of insulin from plasma into the central nervous system of dogs in vivo:  A mechanism for regulated insulin delivery to the brain. J Clin Invest. 92: 1824-1830, 1993.

    Sipols AJ, Baskin DG, Schwartz MW. Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes. 44:147-151, 1995.

    Schwartz MW, Baskin DG, Bukowski TR, et al. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice.Diabetes. 45:531-535, 1996.

    Porte D Jr, Schwartz MW. Diabetes complications: Why is glucose potentially toxic?Science. 272:699-70, 1996.

    Schwartz MW, Peskind E, Raskind M, Nicolson M, Moore J, Morawiecki A, Boyko EJ, Porte D Jr. Cerebrospinal Fluid leptin levels: Relationship to plasma levels and to adiposity in humans. Nature Medicine. 2:589-93, 1996.

    Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG. Identification of targets of leptin action in rat hypothalamus. J Clin Invest. 98:1101-1106, 1996.

    Schwartz MW, Seeley RJ. Neuroendocrine aspects of Starvation and Weight Loss. New Eng J Med. 336:1802-1811, 1997.

    Seeley RJ, Yagaloff KA, Fisher SL, Burn P, Thiele TE, van Dijk G, Baskin DG, Schwartz MW. Melanocortin receptors in leptin effects. Nature.  390:349, 1997.

    Schwartz MW, Seeley RJ, Weigle DS, Woods SC, Campfield LA, Burn P, Baskin DG. Leptin increases proopimelanocortin (POMC) mRNA expression in the rostral arcuate nucleus.Diabetes. 46:2119-2123, 1997.

    Baskin DG, Seeley RJ, Kuijper JL, Lok S, Weigle DS, Erickson JC, Palmiter RD, Schwartz MW.  Increased expression of mRNA for the long form of the leptin receptor (OB-Rb) in the hypothalamus is associated with leptin hypersensitivity and fasting. Diabetes. 47:535-543, 1998.

    Chavez M, Seeley RJ, Havel PJ, Friedman M, Woods SC, Schwartz MW. Effect of a high-fat diet on hypothalamic neuropeptide gene expression in streptozotocin diabetes. J Clin Invest. 102:340-346, 1998.

    Hahn T, Breininger JF, Baskin DG, Schwartz MW. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nature Neuroscience. 1:271-272, 1998.

    Schwartz MW, Erickson JC, Baskin DG, Palmiter RD. Effect of fasting and leptin deficiency on hypothalamic neuropeptide Y gene transcription in vivo revealed by expression of a lacZ reporter gene. Endocrinology. 139:2629-2635, 1998.

    Sindelar DK, Havel PJ, Seeley RJ, Wilkinson, CW, Woods SC and Schwartz MW. Low plasma leptin levels contribute to diabetic hyperphagia. Diabetes. 48:1275-1280, 1999.

    Woods SC, Seeley RJ, Porte D Jr, Schwartz MW. Signals that regulate food intake and energy homeostasis.  Science. 280:1378-1383, 1998.

    Baskin DG, Breininger JF, Schwartz MW. Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus. Diabetes. 48:828-833, 1999.

    Schwartz MW. Mahogany adds color to the evolving story of body weight regulation.Nature Med. 5:374-375, 1999.

    Schwartz MW, Kahn SE. Insulin resistance and obesity. Nature. 402:860-861, 1999.

    Mystkowski P, Seeley RJ. Hahn TM, Baskin DG, Havel PJ, Matsumoto AM, Wilkinson CW, Peacock-Kinzig K, Blake K, and Schwartz MW. Hypothalamicmelanocortin concentrating hormone and estrogen-induced weight loss.  J Neuroscience. 20:8637-8642, 2000.

    Schwartz MW, Woods SC, Seeley RJ, Porte D Jr., and Baskin DG. Central nervous system control of food intake.  Nature. 404:661-671, 2000.

    Havel PJ, Hahn T, Sindelar DK, Baskin DG, Dallman MF, Weigle, DS, and Schwartz MW. Effects of streptozotocin diabetes and insulin treatment onthe hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats. Diabetes. 49:244-252, 2000.

    Kaiyala KJ, Prigeon RL, Kahn SE, Woods SC, and Schwartz MW. Obesity induced by a high-fat diet is associated with reduced brain transport in dogs. Diabetes. 49:1525-1533, 2000.

    McMinn JE, Sidelar DK, Havel PJ, Schwartz MW. Leptin deficiency induced by fasting impairs the satiety response to cholecystokinin. Endocrinology. 141:4442-4447, 2000.

    Cummings DE and Schwartz MW. Melanocortins and body weight regulation: A tale of two receptors. Nature Genetics. 26:8-9, 2000.

    Schwartz MW. Staying slim with insulin in mind. Science. 2089:266-267, 2000.

    Wisse BE, Frayo RS, Schwartz MW, Cummings DE. Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology. 142:3292-3301, 2001.

    Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG, Schwartz MW. Key enzyme in leptin-induced anorexia. Nature. 413:794-795, 2001.

    Schwartz MW. Progress in the search for neuronal mechanisms coupling type 2 diabetes to obesity. J Clin Invest. 108:963-964, 2001.

    Wisse BE, Schwartz MW. Role of melanocortins in control of obesity. Lancet. 358:857-859, 2001.

    Sindelar DK, Mystkowski P, Marsh DJ, Palmiter RD, and Schwartz MW. Attenuation of diabetic hyperphagia in neuropeptide Y-deficient mice. Diabetes. 51:778-783, 2002.

    Barsh GS, Schwartz MW. Genetic approaches to studying energy balance: Perception and integration. Nature Reviews Genetics. 3:589-600, 2002.

    Schwartz MW, Morton GJ. Keeping hunger at bay. Nature. 418:595-596, 2002.

    Schwartz MW, Gelling R. Rats lighten up with MCH antagonist. Nature Medicine. 8:779-780, 2002.

    Schwartz MW, Woods SC, Seeley RJ, Barsh GS, Baskin DG and Leibel RL. Is the energy homeostasis system inherently biased towards weight gain?  Diabetes. 52:232-238, 2003.

    Cummings DE, Schwartz MW.  Genetics and Pathophysiology of Human Obesity. Annu Rev Med. 54:453-471 2003.

    Niswender, K. D., Morrison C. D, Clegg, D.J., Olson R., Baskin, D.G., Myers, M.G. Jr,. Seeley, R.J., 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.

    Bates SH, Stearns WH, Schubert M, Tso AWK, Wang Y, Banks AS, Dundon T, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW, and Myers MG Jr.Leptin receptor-STAT3 signaling is required for leptin regulation of energy balance but not reproduction. Nature.421:856-859, 2003.

    Morton GJ, Niswender KD, Rhodes CJ, Myers MG, Jr., Blevins JE, Baskin DG, Schwartz MW. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fak/fak) rats. Endocrinology. 144:2016-2024, 2003.

    Wisse BE, Schwartz MW. The skinny on neurotrophins. Nature Neuroscience. 6:655-656, 2003.

    Sindelar DK, St. Marie L, Maura GI, Palmiter RD, McMinn JE and Schwartz MW. Neuropeptide Y is required for hyperphagic feeding in response to neuroglucopenia.Endocrinology. 145(7):3363-8, 2004.

    Gelling RW, Overduin J, Morrison CD, Morton GJ, R. Frayo S, Cummings DE and Schwartz MW. Effect of uncontrolled diabetes on plasma ghrelin concentrations and ghrelin-induced feeding. Endocrinology. 145:4575-4582, 2004.

    Schwartz MW, Niswender K: Adiposity signaling and biological defense against weight gain: Absence of protection or central hormone resistance? J Clin Endocrinol Metab.89:5889-5897, 2004.

    Schwartz MW, 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, 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, Schwartz MW. Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from c. elegans to man. Diabetes.54:1264-1276, 2005.

    Williams D, Schwartz MW. The melanocortin system as a central integrator of direct and indirect controls of food intake. Am J Physiol Regul Integr Comp Physiol. 289:R2-3, 2005.

    Williams D, Schwartz MW. Out of synch: Clock mutation causes obesity in mice. Cell Metab. 1:355-356, 2005.

    Morrison CD, Morton GJ, Niswender KD, Gelling RW and Schwartz MW. Leptin inhibits hypothalamic Npy and Agrp gene expression via a mechanism thatrequires phosphotidylinositol 3-OH kinase signaling. Am J Physiol Endocrinol Metab. 289:E1051-1057, 2005.

    Kim F, Tyselling K, Rice J, Gallis B, Haji L, Giachelli CM, Raines EW, Corson MA, Schwartz MW. Activation of IKKbeta by glucose is necessary and sufficient to impair insulin signaling and nitric oxide production in endothelial cells. J Mol Cell Cardiol. 39:327-334, 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. 2:411-420, 2005.

    Schwartz MW, Porte D Jr. Diabetes, obesity, and the brain. Science. 307:375-379, 2005.

    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. 3:67-73, 2006.

    Schwartz MW. Central Nervous System Regulation of Food Intake. Obesity. 1:1S-8S, 2006.

    Pardini AW, Nguyen HT, Figlewicz DP, Basking DG, Williams DL, Schwartz MW. Distribution of Insulin Receptor Substrate-2 in Brain Areas Involved in Energy Homeostasis.Brain Res. 1112:169-178, 2006.

    Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature. 443:289-295, 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-1a in Huntington’s disease neurodegeneration. Cell Metab. 4:349-362, 2006.

    Williams DL, Baskin DG, Schwartz MW. Leptin regulation of the anorexic response to glucagon-like Peptide-1 receptor stimulation. Diabetes. 55:3387-3393, 2006.

    Kim F, Pham M, Luttrell I, Bannerman DD, Tupper J, Thaler JP, Hawn TR, Raines EW, Schwartz MW. Toll like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circulation Research. 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 thanperipheral, 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. Immunocytochemistry 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. 28:1982-1988, 2008.

    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. 150:707-712, 2009.

    Williams DL, Baskin DG, Schwartz MW. Evidence that intestinal GLP-1 plays a physiological role in satiety. Endocrinology. 150:1680-1687, 2009. PMCID: PMC2659282.

    Posey K, Clegg DJ, Printz RL, Byun J, Morton GJ, Vivekanandan-Giri A, Pennathur S, Baskin DG, Heinecke JW, Woods SC, Schwartz MW, Niswender KD. Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol Endocrinol Metab. 296:E1003-1012, 2009. PMCID: PMC2681305.

    Blevins JE, Morton GJ, Williams DJ, Caldwell DW, Bastian LS, Wisse BE, Schwartz MW, and Baskin DG. Forebrain melanocortin signaling enhances the hindbrain satiety response to CCK-8. Am J Physiol Regul Integr Comp Physiol. 296:R476-484, 2009.

    Sweet IR, Gilbert M, Maloney E, Hockenbery DM, Schwartz MW, and Kim F.  Endothelial inflammation induced by excess glucose is associated with cytosolic glucose-6-phosphate but not increased mitochondrial respiration. Diabetologia. 52:921-931, 2009.  PMCID: PMC2741088.

    Schur E, Kleinhans N, Goldberg J, Buchwald D, Schwartz MW, Maravilla K. Activation in brain energy regulation and reward centers by food cues varies with choice of visual stimulus. Int J Obes (Lond). 33:653-661, 2009. PMCID: PMC2697279.

    Pamir N, McMillen TS, Kaiyala K, Schwartz MW, Leboeuf, R. Receptors for tumor necrosis factor-alpha play a protective role against obesity and alter adipose tissue macrophage status. Endocrinology. 150:4124-4134, 2009. PMCID: PMC2736076.

    Maloney E, Sweet IR, Hockenbery DM, Pham M, Rizzo NO, Tateya, S Handa P, Schwartz MW, and Kim F. Activation of NF-ΚB by Palmitate in Endothelial Cells: A Key Role for NADPH Oxidase-Derived Superoxide in Response to TLR4 Activation. Arterioscler Thromb Vasc Biol. 29:1370-1375, 2009.  PMCID: PMC2775080.

    German J, Kim F, Schwartz GJ, Havel PJ, Rhodes CJ, Schwartz MW, Morton GJ. Hypothalamic Leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve. Endocrinology. 150:4502-4511, 2009. PMCID: PMC2754686.

    Williams DL, Baskin DG, Schwartz MW. Hindbrain leptin receptor stimulation enhances the anorexic response to cholecystokinin. Am J Physiol Regul Integr Comp Physiol.297:R1238-1246, 2009. PMCID: PMC2777775.

    Thaler JP, Choi SJ, Sajan MP, Ogimoto K, Nguyen HT, Matsen M, Benoit SC, Wisse BE, Farese RV, Schwartz MW. Atypical protein kinase C activity in the hypothalamus is required for lipopolysaccharide-mediated sickness responses. Endocrinology. 150:5362-5372, 2009. PMCID: PMC2795721.

    Enns LC, Morton JF, Mangalindan RS, McKnight GS, Schwartz MW, Kaeberlein MR, Kennedy BK, Rabinovitch PS, Ladiges WC. Attenuation of age-related metabolic dysfunction in mice with a targeted disruption of the Cb subunit of protein kinase A.Journal of Gerontology: Biological Sciences. 64:1221-1231, 2009. PMCID: PMC2773816.

    Chiu HK, Qian K, Ogimoto K, Morton GJ, Wisse BE, Agrawal N, MacDonald T, Schwartz, MW, Dichek HL.  Mice lacking hepatic lipase are lean and protected against diet-induced obesity and hepatic steatosis. Endocrinology. 151:993-1001, 2010.  PMCID: PMC2840680.

    Rizzo NO, Maloney E, Pham M, Luttrell I, Wessell H, Tateya S, Daum G, Handa P, Schwartz MW, and Kim F. Reduced Nitric Oxide/cGMP Signaling Contributes to Vascular Inflammation and Insulin Resistance Induced by High Fat Feeding. Atherosclerosis, Thrombosis and Vascular Biology. 30:758-765, 2010. PMCID: PMC2865555.

    Sarruf DA, Thaler JP, Morton GJ, German J, Fischer JD, Ogimoto K, and Schwartz MW. FGF21 Action in the Brain Increases Energy Expenditure and Insulin Sensitivity in Obese Rats. Diabetes. 59:1817-1824, 2010. PMCID: PMC2889784.

    Kaiyala KJ, Morton GJ, Leroux BG, Ogimoto K, Wisse BE and Schwartz MW. Identification of body fat mass as a major determinant of metabolic rate in mice. Diabetes. 59:1657-1666, 2010. PMCID: PMC2889765.

    Oh-I S, Thaler JP, Ogimoto K, Wisse BE, Morton GJ, and Schwartz MW. Central administration of Interleukin-4 exacerbates hypothalamic inflammation and weight gain during hig-fat feeding. Am J Physiology. 299:E47-53, 2010. PMCID: PMC2904047.

    Choi SJ, Kim F, Schwartz MW and Wisse BE. Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids. Am J Physiology. 298:E1122-1130, 2010. PMCID: PMC2886534.

    German J, Wisse BE, Thaler JP, Oh-I S, Sarruf DA, Ogimoto K, Kaiyala K, Fischer JD, Matsen ME, Taborsky GJ, Schwartz MW, and Morton GJ. Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes. 59:1626-1634, 2010. PMCID: PMC2889761.

    Ellacott KL, Morton GJ, Woods SC, Tso P, and Schwartz MW.  Assessment of feeding behavior in laboratory mice.  Cell Metab. 12:10-17, 2010. PMCID: PMC2916675.

    Baskin DG, Kim F, Gelling RW, Russell BJ, Schwartz MW, Morton GJ, Simhan HN, Moralejo DH, and Blevins JE. A new oxytocin-saporin cytotoxin for lesioning oxytocin-receptive neurons in the rat hindbrain. Endocrinology. 151:4207-4213, 2010. PMCID: PMC2940497

    Koch C, Augustine R, Steger J, Ganjam G, Benzler J, Pracht C, Lowe C, Schwartz M, Peter S, Anderson G, Grattan D, Tups A. Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity. J Neurosci. 30:16180-16187, 2010.

    German J, Thaler JP, Wisse BE, Oh-I S, Sarruf DA, Matsen ME, Fischer JD, Taborsky GJ, Schwartz MW, and Morton GJ. Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology. 152:394-404, 2011. PMCID: PMC3037161.

    Morton GJ, Kaiyala K, Fischer JD, Ogimoto K, Schwartz MW, Wisse BE. Identification of a physiological role for leptin in the regulation of ambulatory activity and wheel running in mice. Am J Physiol Endocrinol Metab. 300:E392-401, 2011. PMCID: PMC3043625.

    Lu M, Sarruf D, Talukdar S, Sharma S, Li P, Bandyopadhyay G, Nalbandian S, Fan W, Gayen JR, Mahata SK, Webster N, Schwartz M, Olefsky JM. Brain peroxisome proliferator-activated receptor gamma promotes obesity and is required for the full insulin-sensitizing effect of thiazolidinediones. Nat Med. 17:618-622, 2011. PMCID: PMC3380629.

    Choi SJ, Yablonka-Reuveni Z, Kaiyala KJ, Ogimoto K, Schwartz MW, Wisse BE. Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice. AM J Physiol Endocrinol Metab. 300:E1031-1037, 2011. PMCID: PMC3118591.

    Diano S, Liu Z-W, Jeong JK, Dietrich MO, Ruan H-B, Kim E, Suyama S, Kelly K, Gyengesi E, Arbiser JL, Belsham DD, Sarruf DA, Schwartz MW, Bennett AM, Shanabrough M, Mobbs CV, Yang X, Gao X-B, Horvath TL. Peroxisome proliferation-related control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nat Med. 17:1121-1127, 2011. PMCID: PMC3388795.

    Tateya S, Rizzo NO, Handa P, Cheng AM, Morgan-Stevenson V, Daum G, Clowes AW, Morton GJ, Schwartz MW, Kim F. Endothelial nitric oxide/cGMP/vasodilator-stimulated phosphoprotein signaling attenuates kupffer cell activation and hepatic insulin resistance induced by high-fat feeding. Diabetes. 60:2792-2801, 2011. PMCID: PMC3198085.

    Handa P, Tateya S, Rizzo NO, Cheng AM, Morgan-Stevenson V, Han CY, Clowes AW, Daum G, O’Brien KD, Schwartz MW, Chait A, Kim F. Reduced vascular nitric oxide-cGMP signaling contributes to adipose tissue inflammation during high-fat feeding. Arterioscler Thromb Vasc Biol. 31:2827-2837, 2011. PMCID: PMC3342311.

    Morton GJ, Thatcher BS, Reidelberger RD, Ogimoto K, Wolden-Hanson TW, Baskin DG, Schwartz MW, Blevins JE. Peripheral oxytocin suppresses food intake and causes weight loss in diet-induced obese rats. Am J Physiol Endocrinol Metab. 302:E134-E144, 2012. PMCID: PMC3328087.

    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.

    Buchner DA, Geisinger JM, Glazebrook PA, Morgan MG, Spiezio SH, Kaiyala KJ, Schwartz MW, Sakurai T, Furley AJ, Kunze DL, Croniger CM, Nadeau JH. The juxtaparanodal proteins Cntnap2 and Tag1 regulate diet-induced obesity. Mammalian Genome. 23:431-432, 2012.

    Mehta S, Melhorn SJ, Smeraglio A, Tyagi V, Grabowski T, Schwartz MW, Schur EA. Regional brain response to visual food cues is a marker of satiety that predicts food choice. Am J Clin Nutr. 96:989-999, 2012. PMCID: PMC3471210.

    Benzler J, Ganjam GK, Kruger M, Pinkenburg O, Kutsche M, Stohr S, Steger J, Koch CE, Olkrug R, Schwartz MW, Shepherd PR, Grattan DR, Tups A. Hypothalamic glycogen-synthase-kinase 3β has a central role in the regulation of food intake and glucose metabolism. Biochem J. 447:175-184, 2012. PMCID: PMC3679888.

    Meek T, Wisse B, Thaler J, Guyenet S, Matsen M, Fischer J, Taborsky Jr. G, Schwartz M,  Morton G. BDNF action in the brain attenuates diabetic hyperglycemia via insulin-independent inhibition of hepatic glucose production. Diabetes.62:1512-1518, 2013.  PMCID: PMC3636618.

    Guyenet S, Matsen M, Morton M, Kaiyala K, Schwartz M. Rapid glutamate release in the mediobasal hypothalamus accompanies feeding and is exaggerated by an obesogenic food. Molecular Metabolism. 2:116-122, 2013. PMCID: PMC3817387.

    Matsen ME, Thaler JP, Wisse BE, Guyenet SJ, Meek TH, Ogimoto K, Cubelo A, Fischer JD, Kaiyala KJ, Schwartz MW and Morton GJ.  In uncontrolled diabetes, thyroid hormone and sympathetic activators induce thermogenesis without increasing glucose uptake in brown adipose tissue. Am J Physiol Endocrinol Metab. 304:E734-E746, 2013. PMCID: PMC3625754.

    Lu M, Sarruf DA, Li P, Osborn O, Sanchez-Alavez M, Talukdar S, Chen A, Bandyopadhyay G, Xu J, Morinaga H, Dines K, Watkins S, Kaiyala K, Schwartz MW, Olefsky JM. Neuronal Sirt1 Deficiency Increases Insulin Sensitivity in Both Brain and Peripheral Tissues. J Biol Chem. 288:10722-10735, 2013. PMCID: PMC3624452.

    Guyenet SJ, Nguyen NT, Hwang BH, Schwartz MW, Baskin DG, Thaler JP. High-fat diet feeding causes rapid, non-apoptotic cleavage of caspase-3 in astrocytes. Brain Res. 1512:97-105, 2013. PMCID: PMC3684737.

    Lee D, Thaler JP, Berkseth KE, Melhorn SJ, Schwartz MW, Schur EA. Longer T2 relaxation time is a marker of hypothalamic gliosis in mice with diet-induced obesity. Am J Physiol Endocrinol Metab. 304:E1245-E1250, 2013. PMCID: PMC3680680.

    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.

    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.

    Berkseth K, Schur E, Schwartz M. A Role for Natriuretic Peptides in the Central Control of Energy Balance? Diabetes. 62:1379-1381, 2013. PMCID: PMC3636633.

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

    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.

    Gao Y, Ottaway N, Schriever SC, Legutko B, García-Cáceres C, de la Fuente E, Mergen C, Bour S, Thaler JP, Seeley RJ, Filosa J, Stern JE, Perez-Tilve D, Schwartz MW, Tschöp MH, Yi CX.  Hormones and diet, but not body weight, control hypothalamic microglial activity.  Glia. 62:17-25, 2014.

    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.

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

    Schwartz MW, Tschop M, Zeltser LM. A mother’s influence on metabolic disorders. Nat Med. 20:244-145, 2014.

    Rojas JM, Schwartz MW. Conrol of hepatic glucose metabolism by islet and brain. Diabetes Obes Metab. In press, 2014.

    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. PMC Journal – In Process.

    Ho JM, Anekonda AV, Thompson BW, Zhu M, Curry RW, Hwang BH, Morton GJ, Schwartz MW, Baskin DG, Appleyard SM, Blevins JE. Hindbrain oxytocin receptors contribute to the effects of circulating oxytocin on food intake in male rats. Endocrinology. 155:2845-2857, 2014. PMC Journal – In Process.

    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. In press, 2014. PMC Journal – In Process.

    Spiezio S, Amon L, McMillen T, Vick C, Houston B, Caldwell M, Ogimoto K, Morton G, Kirk E, Schwartz M, Nadeau J, LeBoeuf R. Genetic determinants of atherosclerosis, obesity and energy balance in consomic mice. Mammalian Genome. In press, 2014.

 

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
Joshua Thaler, MD, PhD
Brent Wisse, MD
Vincenzo Cirulli, MD

Lab Members:

Thomas Meek, PhD
Mauricio Dorfman, PhD
Jarrad Scarlett, MD, PhD
Jennifer Rojas, PhD
Hong Nguyen, BS
Kayoko Ogimoto, PhD
Miles Matsen, BS
Alex Cubelo, BS
JD Fischer, BS
Vincent Damian, BS
Jarrell Nelson, BS
Loan Nguyen, BS