FP15-3 Adipocyte-specific Deletion of Janus kinase 2 (JAK2) Leads to Increased Adiposity and Age-related Glucose Intolerance

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP15-Adipocyte Biology
Bench to Bedside
Sunday, June 16, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 10:55 AM
Room 303 (Moscone Center)

Poster Board SUN-649
Sally Yu Shi*1, Cynthia Theresa Luk1, Jara J. Brunt1, Stephanie A. Schroer2, Kay-Uwe Wagner3 and Minna Woo4
1University of Toronto, Toronto, ON, Canada, 2Toronto General Research Institute, Toronto, ON, Canada, 3University of Nebraska Medical Center, Omaha, NE, 4University Health Network/University of Toronto, Toronto, ON, Canada
Adipocytes were once thought to be inert energy storage depots, but are now recognized as active endocrine cells with indispensible physiological functions. Alterations in adipocyte development and/or function have been implicated in the pathophysiology of type 2 diabetes. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway mediates the signal transduction of numerous cytokines and hormones that regulate adipocyte development and function. Several adipokines secreted by adipocytes also utilize this pathway, illustrating the physiological importance of JAK-STATs in adipocyte biology. The aim of this study was to investigate potential metabolic roles of JAK2, an essential player of the JAK-STAT pathway, in adipocytes. We utilized an in vivo genetic approach and generated mice with deletion of JAK2 specifically in fat cells (F-JAK2 KO) using the Cre-loxP recombination system. Starting at 2-3 months of age, F-JAK2 KO mice gradually gained more body weight compared to control littermates on a chow diet. Body composition analysis revealed significantly higher weight of the inguinal, perigonadal and brown fat pads from 5-6-month-old F-JAK2 KO mice, consistent with increased adiposity. This was associated with an increased size of the perigonadal adipocytes, increased circulating leptin levels and decreased adiponectin levels. To determine the underlying basis for the increased adiposity, energy balance was assessed using indirect calorimetry. No difference in absolute daily food intake was observed between F-JAK2 KO mice and littermate controls. On the other hand, energy expenditure, measured by O2 consumption rate, was significantly reduced in F-JAK2 KO mice, which was associated with reduced physical activity. This was not a primary effect of adipose JAK2 deficiency as F-JAK2 KO mice had normal energy balance and physical activity at 1 month of age when there was no change in body weight. Gene expression analysis of perigonadal adipose tissue from 5-6-month-old mice indicated a 2-fold increase in mRNA levels of hormone sensitive lipase (Hsl) and a 50% reduction in expression of adipose triglyceride lipase (Atgl), suggesting dysregulated lipolysis. At two months of age, despite being significantly obese, F-JAK2 KO mice had normal fasting blood glucose, glucose tolerance and insulin sensitivity. Even at 5-6 months of age, F-JAK2 KO mice maintained normal blood glucose levels. However, when given an intraperitoneal glucose challenge, they were more glucose intolerant than littermate controls and there was also a trend towards reduced insulin sensitivity. Taken together, our results implicate a critical role of adipocyte JAK2 in regulation of adipocyte biology and whole-body glucose metabolism. Targeting the JAK-STAT pathway may therefore provide a novel therapeutic strategy for the treatment of obesity and type 2 diabetes.

Nothing to Disclose: SYS, CTL, JJB, SAS, KUW, MW

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: CIHR operating grants MOP-201188 and MOP-191501; Canadian Diabetes Association (CDA) Grant-in-Aid; Canadian Liver Foundation Graduate Studentship; CDA Doctoral Student Research Award; Banting and Best Diabetes Centre