Regulation of PPAR g Gene Expression by Nutrition and Obesity in Rodents

The orphan nuclear receptor, peroxisome proliferator-activated receptor (PPAR) g , is implicated in mediating expression of fat-specific genes and in activating the program of adipocyte differentiation. The potential for regulation of PPAR g gene expression in vivo is unknown. We cloned a partial mouse PPAR g cDNA and developed an RNase protection assay that permits simultaneous quantitation of mRNAs for both g 1 and g 2 isoforms encoded by the PPAR g gene. Probes for detection of adipocyte P2, the obese gene product, leptin, and 18S mRNAs were also employed. Both g 1 and g 2 mRNAs were abundantly expressed in adipose tissue. PPAR g 1 expression was also detected at lower levels in liver, spleen, and heart; whereas, g 1 and g 2 mRNA were expressed at low levels in skeletal muscle. Adipose tissue levels of g 1 and g 2 were not altered in two murine models of obesity (gold thioglucose and ob/ob), but were modestly increased in mice with toxigene-induced brown fat ablation uncoupling protein diphtheria toxin A mice. Fasting (12–48 h) was associated with an 80% fall in PPAR g 2 and a 50% fall in PPAR g 1 mRNA levels in adipose tissue. Western blot analysis demonstrated a marked effect of fasting to reduce PPAR g protein levels in adipose tissue. Similar effects of fasting on PPAR g mRNAs were noted in all three models of obesity. Insulin-deficient (streptozotocin) diabetes suppressed adipose tissue g 1 and g 2 expression by 75% in normal mice with partial restoration during insulin treatment. Levels of adipose tissue PPAR g 2 mRNA were increased by 50% in normal mice exposed to a high fat diet. In obese uncoupling protein diphtheria toxin A mice, high fat feeding resulted in de novo induction of PPAR g 2 expression in liver. We conclude ( a ) PPAR g 2 mRNA expression is most abundant in adipocytes in normal mice, but lower level expression is seen in skeletal muscle; ( b ) expression of adipose tissue g 1 or g 2 mRNAs is increased in only one of the three models of obesity; ( c ) PPAR g 1 and g 2 expression is downregulated by fasting and insulin-deficient diabetes; and ( d ) exposure of mice to a high fat diet increases adipose tissue expression of PPAR g (in normal mice) and induces PPAR g 2 mRNA expression in liver (in obese mice). These findings demonstrate in vivo modulation of PPAR g mRNA levels over a fourfold range and provide an additional level of regulation for the control of adipocyte development and function. ( J. Clin. Invest. 1996. 97:2553–2561.)