FAK signalling controls insulin sensitivity through regulation of adipocyte survival.
Focal adhesion kinase (FAK) plays a central role in integrin signalling, which regulates growth and survival of tumours. Here we show that FAK protein levels are increased in adipose tissue of insulin-resistant obese mice and humans. Disruption of adipocyte FAK in mice or in 3T3 L1 cells decreases adipocyte survival. Adipocyte-specific FAK knockout mice display impaired adipose tissue expansion and insulin resistance on prolonged metabolic stress from a high-fat diet or when crossed on an obese db/db or ob/ob genetic background. Treatment of these mice with a PPARγ agonist does not restore adiposity or improve insulin sensitivity. In contrast, inhibition of apoptosis, either genetically or pharmacologically, attenuates adipocyte death, restores normal adiposity and improves insulin sensitivity. Together, these results demonstrate that FAK is required for adipocyte survival and maintenance of insulin sensitivity, particularly in the context of adipose tissue expansion as a result of caloric excess.
Toronto General Hospital Research Institute, University Health Network, MaRS Ctre, TMDT, 101 College Street, 10th Floor, Room 10-363, Toronto, Ontario, Canada M5G 1L7.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Cynthia T
CT
Luk
Toronto General Hospital Research Institute, University Health Network, MaRS Ctre, TMDT, 101 College Street, 10th Floor, Room 10-363, Toronto, Ontario, Canada M5G 1L7.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Sally Yu
SY
Shi
Toronto General Hospital Research Institute, University Health Network, MaRS Ctre, TMDT, 101 College Street, 10th Floor, Room 10-363, Toronto, Ontario, Canada M5G 1L7.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Erica P
EP
Cai
Toronto General Hospital Research Institute, University Health Network, MaRS Ctre, TMDT, 101 College Street, 10th Floor, Room 10-363, Toronto, Ontario, Canada M5G 1L7.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Tharini
T
Sivasubramaniyam
Toronto General Hospital Research Institute, University Health Network, MaRS Ctre, TMDT, 101 College Street, 10th Floor, Room 10-363, Toronto, Ontario, Canada M5G 1L7.
Mansa
M
Krishnamurthy
Toronto General Hospital Research Institute, University Health Network, MaRS Ctre, TMDT, 101 College Street, 10th Floor, Room 10-363, Toronto, Ontario, Canada M5G 1L7.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Jara J
JJ
Brunt
Toronto General Hospital Research Institute, University Health Network, MaRS Ctre, TMDT, 101 College Street, 10th Floor, Room 10-363, Toronto, Ontario, Canada M5G 1L7.
Stephanie A
SA
Schroer
Toronto General Hospital Research Institute, University Health Network, MaRS Ctre, TMDT, 101 College Street, 10th Floor, Room 10-363, Toronto, Ontario, Canada M5G 1L7.|Department of Pathology, University Health Network, Toronto, Ontario, Canada M5G 2C4.
Daniel A
DA
Winer
Toronto General Hospital Research Institute, University Health Network, MaRS Ctre, TMDT, 101 College Street, 10th Floor, Room 10-363, Toronto, Ontario, Canada M5G 1L7.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8.|Division of Endocrinology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 2C4.
Minna
M
Woo
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000502:physiology*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D050154:Adiposity / Q000187:drug effects / Q000235:genetics; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008875:Middle Aged; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D047495:PPAR gamma / Q000819:agonists; D061251:Primary Cell Culture; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology
D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse