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BIOLOGICAL SCIENCES / PHYSIOLOGY
Loss of the Par-1b/MARK2 polarity kinase leads to increased metabolic rate, decreased adiposity, and insulin hypersensitivity in vivo

Jonathan B. Hurov^a,b, Mei Huang^c,d, Lynn S. White^a,e, Jochen Lennerz^f, Cheol Soo Choi^g, You-Ree Cho^g,h, Hyo-Jeong Kim^g,h, Julie L. Priorⁱ, David Piwnica-Worms^i,j, Lewis C. Cantley^k,l, Jason K. Kim^g,h, Gerald I. Shulman^e,g, and Helen Piwnica-Worms^a,c,e,l

Departments of ^aCell Biology and Physiology and ^cInternal Medicine, ⁱMolecular Imaging Center, Mallinckrodt Institute of Radiology, and Departments of ^fPathology and Immunology and ^jMolecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110-1093; ^gDepartment of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8020; ^kDivision of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115; and ^eHoward Hughes Medical Institute, Chevy Chase, MD 20815

Contributed by Lewis C. Cantley, February 8, 2007 (received for review January 2, 2007)

Obesity is a major factor central to the development of insulin resistance and type 2 diabetes. The identification and characterization of genes involved in regulation of adiposity, insulin sensitivity, and glucose uptake are key to the design and development of new drug therapies for this disease. In this study, we show that the polarity kinase Par-1b/MARK2 is required for regulating glucose metabolism in vivo. Mice null for Par-1b were lean, insulin hypersensitive, resistant to high-fat diet-induced weight gain, and hypermetabolic. ¹⁸F-FDG microPET and hyperinsulinemic–euglycemic clamp analyses demonstrated increased glucose uptake into white and brown adipose tissue, but not into skeletal muscle of Par-1b null mice relative to wild-type controls. Taken together, these data indicate that Par-1b is a regulator of glucose metabolism and adiposity in the whole animal and may be a valuable drug target for the treatment of both type 2 diabetes and obesity.

glucose | obesity | EMK

Author contributions: J.B.H., M.H., J.L., L.C.C., J.K.K., G.I.S., and H.P.-W. designed research; J.B.H., M.H., L.S.W., J.L., C.S.C., Y.-R.C., H.-J.K., and J.L.P. performed research; J.B.H., D.P.-W., J.K.K., and G.I.S. contributed new reagents/analytic tools; J.B.H., L.S.W., J.L., C.S.C., Y.-R.C., H.-J.K., J.L.P., D.P.-W., L.C.C., J.K.K., G.I.S., and H.P.-W. analyzed data; and J.B.H. wrote the paper.

^bPresent address: Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115.

^dPresent address: Department of Medicine, Southern Illinois University School of Medicine, Springfield, IL 62901.

^hPresent address: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0701179104/DC1.

^lTo whom correspondence may be addressed. E-mail: lewis_cantley{at}hms.harvard.edu or hpiwnica{at}cellbiology.wustl.edu

© 2007 by The National Academy of Sciences of the USA

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