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

TLDR

Syndrome X, characterized by obesity, insulin resistance, dyslipidemia, and other metabolic abnormalities, responds to thiazolidinediones, and PPARγ is highly expressed in adipocytes, implicating this tissue in the disease’s etiology and treatment. Deletion of PPARγ specifically in adipose tissue produced adipocyte hypocellularity and hypertrophy, elevated plasma free fatty acids and triglycerides, and reduced leptin and ACRP30 levels. These mice exhibited increased hepatic gluconeogenesis and insulin resistance, heightened susceptibility to high‑fat diet‑induced steatosis, hyperinsulinemia, and insulin resistance, yet maintained normal blood glucose and muscle glucose uptake, and TZD treatment reversed liver insulin resistance but not plasma free fatty acids, indicating tissue‑specific PPARγ‑dependent components of syndrome X.

Abstract

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.