Our Research: Faculty/Research Laboratories

Joshua Thaler, MD, PhD

Assistant Professor, Department of Medicine, Division of Metabolism, Endocrinology and Nutrition

Email Address: jpthaler@u.washington.edu

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

Joshua Thaler, MD, PhD

Background:

Dr. Thaler graduated with a major in Biochemistry from Harvard College (Magna Cum Laude with Highest Honors, and on the Dean’s List), then obtained an MD and a PhD in Biomedical Sciences from the University of California, San Diego and the Salk Institute (where he was a Chapman Scholar and a Lucille P. Markey Fellow). He short-tracked through the Internal Medicine residency program at UW and was an endocrinology/metabolism fellow, working in Dr. Michael Schwartz’s laboratory. He is currently an Assistant Professor at the Diabetes and Obesity Center of Excellence at the University of Washington.

Focus:

Dr. Thaler’s focus is the hypothalamic regulation of energy homeostasis and the alterations to this system during obesity pathogenesis. His primary project investigates hypothalamic inflammation and its relationship to high fat diet-induced weight gain with an emphasis on the role of glial cells (astrocytes and microglia) in modulating the neuronal regulation of energy homeostasis. In particular, his research aims to determine whether glial cells provide a repair response to diet-induced damage to critical hypothalamic neurons and whether interventions targeted at glia may therefore influence the course of obesity. A second study examines the role of inflammatory signaling in hypothalamic neurons and microglia in obesity-associated insulin resistance and diabetes. Additionally, Dr. Thaler’s research is examining the metabolic role of POMC neurons through modification of atypical protein kinase C signaling.

Representative Publications:

Thaler JP, Lee SK, Jurata LW, Gill GN, Pfaff SL. LIM factor Lhx3 contributes to the specification of motor neuron and interneuron identity through cell-type-specific protein-protein interactions. Cell 110:237-49, 2002.

Thaler JP, Schwartz MW. Inflammation and obesity pathogenesis: the hypothalamus heats up. Endocrinology. 151(9):4109-15, 2010. (PMID 20573720)

Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR, Nguyen HT, Fischer JD, Matsen ME, Wisse BE, Morton GJ, Horvath TL, Baskin DG, Tschöp MH, and Schwartz MW. Obesity is Associated with Hypothalamic Injury in Rodent Models and Humans. J Clin Invest, 122(1):153–162, 2012. (PMID:22201683)

Guyenet SJ, Nguyen HT, Hwang BH, Schwartz MW, Baskin DG, Thaler JP. High-Fat Diet Feeding Causes Rapid, Non-apoptotic Cleavage of Caspase-3 in Astrocytes. Accepted at Brain Research, Mar 2013.

  • Stewart RJ, Thaler JP, Goldstein LS. Direction of microtubule movement is an intrinsic property of the motor domains of kinesin heavy chain and Drosophila ncd protein. Proc Natl Acad Sci USA 90:5209-13, 1993.

    Thaler J, Harrison K, Sharma K, Lettieri K, Kehrl J, Pfaff SL. Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9. Neuron 23:675-87, 1999.

    Harrison KA, Thaler J, Pfaff SL, Gu H, Kehrl JH. Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice. Nat Genet 23:71-5, 1999.

    Thaler JP, Koo SJ, Kania A, Lettieri K, Andrews S, Cox C, Jessell TM, Pfaff SL. A postmitotic role for Isl-class LIM homeodomain proteins in the assignment of visceral spinal motor neuron identity. Neuron 41:337-50, 2004.

    Mizutani A, Wang L, Rajan H, Vig PJ, Alaynick WA, Thaler JP, Tsai CC. Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1. EMBO J 24:3339-51, 2005.

    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 100:1589-96, 2007.

    Ghosh S, Marquardt T, Thaler JP, Carter N, Andrews SE, Pfaff SL, Hunter T. Instructive role of aPKCzeta subcellular localization in the assembly of adherens junctions in neural progenitors. PNAS 105:335-40, 2008.

    Thaler JP, Cummings DE. Metabolism: Food Alert. Nature 452:941-42, 2008.

    Thaler JP, Cummings DE. Hormonal and Metabolic Mechanisms of Diabetes Remission after Gastrointestinal Surgery. Endocrinology 150: 2518-2525, 2009.

    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. 150:5362-72, 2009. (PMID: 19819945)

    Thaler JP, Choi SJ, Schwartz MW, Wisse BE. Hypothalamic Inflammation and Energy Homeostasis: Resolving the Paradox. Frontiers in Neuroendocrinology. 31:79-84, 2010. (PMID: 19822168)

    Oh-I S*, Thaler JP*, Ogimoto K, Wisse BE, Morton GJ, Schwartz MW. Central administration of interleukin-4 exacerbates hypothalamic inflammation and weight gain during high fat feeding. Am J Physiol Endocrinol Metab 299:E47-53, 2010. (PMID 20371733)

    Sarruf DA, Thaler JP, Morton GJ, German J, Fischer JD, Ogimoto K, Schwartz MW. FGF21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes. 59:1817-1824, 2010. (PMID: 20357365)

    German JP, Wisse BE, Thaler JP, Oh-I S, Sarruf DA, Ogimoto K, Kaiyala KJ, Fischer JD, Matsen ME, Taborsky GJ Jr, Schwartz MW, Morton GJ. Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes 59:1626-1634, 2010. (PMID 2889761)

    German JP, Thaler JP, Wisse BE, Oh-I S, Sarruf DA, Matsen ME, Fischer JD, Taborsky GJ Jr, Schwartz MW, Morton GJ. Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology. 152(2):394-404, 2011. (PMID 21159853)

    Kaiyala KJ, Morton GJ, Thaler JP, Meek TH, Tylee T, Ogimoto K, and Wisse BE. Acutely decreased thermoregulatory energy expenditure or decreased activity energy expenditure both acutely reduce food intake in mice. PLOS One, 7:41473, 2012. (PMID: 22936977)

    Meek TH, Wisse BE, Thaler JP, Guyenet SJ, Matsen ME, Fischer JD, Taborsky GJ Jr, Schwartz MW, Morton GJ. BDNF Action in the Brain Attenuates Diabetic Hyperglycemia via Insulin-Independent Inhibition of Hepatic Glucose Production. Diabetes. 2012 Dec 28. Epub ahead of print (PMID: 23274899)

    Matsen ME, Thaler JP, Wisse BE, Guyenet SJ, Meek TH, Ogimoto K, Cubelo A, Fischer JD, Kaiyala KJ, Schwartz MW, 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. 2013 Feb 5. Epub (PMID: 23384771)

    Lee DH*, Thaler JP*, Berkseth KE, Melhorn SJ, Schwartz MW, and Schur EA. Longer T2 relaxation time is a marker of hypothalamic gliosis in mice with diet-induced obesity. Accepted at Am J Physiol Endocrinol Metab, Mar 2013.

    Thaler JP, Guyenet SJ, Dorfman MD, Wisse BE, Schwartz MW. Hypothalamic Inflammation: Marker or Mechanism of Obesity Pathogenesis? Accepted at Diabetes, Mar 2013.

Current Collaborations:

Within the Diabetes and Obesity Center of Excellence and its Affiliated Members
Michael Schwartz, MD
Brent Wisse, MD
Gregory Morton, PhD

Lab Members:

Mauricio Dorfman, PhD, Senior Fellow