Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle

W He, Y Barak, A Hevener, P Olson… - Proceedings of the …, 2003 - National Acad Sciences
W He, Y Barak, A Hevener, P Olson, D Liao, J Le, M Nelson, E Ong, JM Olefsky, RM Evans
Proceedings of the National Academy of Sciences, 2003National Acad Sciences
Syndrome X, typified by obesity, insulin resistance (IR), dyslipidemia, and other metabolic
abnormalities, is responsive to antidiabetic thiazolidinediones (TZDs). Peroxisome
proliferator-activated receptor (PPAR) γ, a target of TZDs, is expressed abundantly in
adipocytes, suggesting an important role for this tissue in the etiology and treatment of IR.
Targeted deletion of PPARγ in adipose tissue resulted in marked adipocyte hypocellularity
and hypertrophy, elevated levels of plasma free fatty acids and triglyceride, and decreased …
Syndrome X, typified by obesity, insulin resistance (IR), dyslipidemia, and other metabolic abnormalities, is responsive to antidiabetic thiazolidinediones (TZDs). Peroxisome proliferator-activated receptor (PPAR) γ, a target of TZDs, is expressed abundantly in adipocytes, suggesting an important role for this tissue in the etiology and treatment of IR. Targeted deletion of PPARγ in adipose tissue resulted in marked adipocyte hypocellularity and hypertrophy, elevated levels of plasma free fatty acids and triglyceride, and decreased levels of plasma leptin and ACRP30. In addition, increased hepatic glucogenesis and IR were observed. Despite these defects, blood glucose, glucose and insulin tolerance, and insulin-stimulated muscle glucose uptake were all comparable to those of control mice. However, targeted mice were significantly more susceptible to high-fat diet-induced steatosis, hyperinsulinemia, and IR. Surprisingly, TZD treatment effectively reversed liver IR, whereas it failed to lower plasma free fatty acids. These results suggest that syndrome X may be comprised of separable PPARγ-dependent components whose origins and therapeutic sites may reside in distinct tissues.
National Acad Sciences