FP15-2 Adipocyte-specific FAK deletion in mice leads to insulin resistance but divergent adipose tissue remodelling under lean and obese conditions

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: 10:50 AM
Room 303 (Moscone Center)

Poster Board SUN-651
Cynthia Theresa Luk*1, Sally Yu Shi1, Erica P. Cai1, Tharini Sivasubramaniyam1, Stephanie A. Schroer2 and Minna Woo3
1University of Toronto, Toronto, ON, Canada, 2Toronto General Research Institute, Toronto, ON, Canada, 3University Health Network/University of Toronto, Toronto, ON, Canada
Emerging evidence suggests adipose tissue extracellular matrix plays an important role in adiposity and glucose homeostasis, but the mechanisms by which extracellular signals are translated into adipocytes remain unclear.  A likely candidate is focal adhesion kinase (FAK), a ubiquitously expressed tyrosine kinase central to integrin signalling and essential for development and proliferation. The aim of this study was to assess the role of adipocyte FAK in metabolism.

First, we found that FAK was upregulated in adipoctyes with diabetes and obesity in both mice and humans, suggesting that FAK could play a role in glucose and energy homeostasis. To study adipocyte FAK in vivo, we generated a novel adipose tissue-specific FAK knockout mouse (aP2Cre+FAKfl/fl), by crossbreeding mice with adipocyte protein 2 (aP2) promotor-driven CRE recombinase expression with FAKfl/fl mice. By 12 weeks of age, FAK disruption resulted in increased adiposity despite no difference in total body weight. To further investigate the role of FAK in adipose tissue accumulation, aP2Cre+FAKfl/fl mice were placed on high-fat diet (HFD) for 16 weeks. Surprisingly, with HFD, aP2Cre+FAKfl/fl mice did not gain as much weight as controls and had significantly decreased adipose tissue fat pad weights. Differences in body composition could not be accounted for by differences in energy homeostasis, as measured by food intake, ambulatory activity, respiratory exchange ratio or oxygen consumption. Interestingly with both chow and HFD, despite the differences in adiposity, aP2Cre+FAKfl/fl mice were insulin resistant as evidenced by elevated fasting blood glucose, elevated fasting insulin levels and  impaired response to insulin tolerance testing (ITT) compared to wild-type littermate controls. Analysis of adipogenic genes by qRT-PCR showed that disruption of FAK in adipocytes was associated with increased sterol regulatory element binding protein-1c (SREBP-1c).  Moreover, particularly with HFD, increased adipocyte apoptosis as assessed by TUNEL and disrupted actin architecture were seen with immunofluorescence, suggesting that FAK regulates adipocyte turnover.

Overall, knockdown of adipocyte FAK resulted in divergent adipose tissue remodelling, with increased adiposity under basal conditions but impaired adipose tissue expansion with energy excess, contributing to insulin resistance. These results demonstrate a new and important role for FAK in adipose tissue regulation and whole body insulin sensitivity.

Nothing to Disclose: CTL, SYS, EPC, TS, SAS, 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: Canadian Institute of Health Research (CIHR) operating grants MOP-201188, MOP-191501 and Canadian Diabetes Association (CDA) Grant-in-Aid awarded to MW; Eliot Phillipson Clinician Scientist Training Program and Banting and Best Diabetes Centre (BBDC) Postdoctoral Fellowship awarded to CTL; Canadian Liver Foundation (CLF) Graduate Studentship and CDA Doctoral Student Research Award awarded to SYS; BBDC-Novo Nordisk Studentship awarded to TS