PPAR-γ Activation Mediates Adipose Depot−Specific Effects on Gene Expression and Lipoprotein Lipase Activity
Mechanisms for Modulation of Postprandial Lipemia and Differential Adipose Accretion
- Mathieu Laplante1,
- Henrike Sell1,
- Karen L. MacNaul2,
- Denis Richard1,
- Joel P. Berger2 and
- Yves Deshaies1
- 1Department of Anatomy and Physiology, Laval Hospital Research Center, School of Medicine, Laval University, Québec, Canada
- 2Department of Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey
This study sought to determine whether the adipose depot−specific (subcutaneous [SF] vs. visceral [VF]) action of peroxisome proliferator−activated receptor-γ (PPAR-γ) agonists on fat deposition extends to the expression of lipoprotein lipase (LPL) and other key adipose lipid metabolism genes, and whether changes in LPL impact triglyceridemia. Rats were fed a standard diet or an obesity-promoting diet for 3 weeks, with or without treatment with COOH, a nonthiazolidinedione PPAR-γ agonist. Treatment effects were essentially similar in both dietary cohorts. COOH did not affect weight gain, but increased SF (inguinal) fat mass twofold and reduced VF (retroperitoneal) accretion by half. Corresponding depot-specific alterations were observed in mRNA levels of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD-1) and the thermogenic modulator uncoupling protein 1 (UCP-1). COOH increased brown adipose tissue (BAT) weight and LPL availability by five- to eightfold. In rats refed standard diet after a 24-h fast, COOH reduced the insulin excursion by half. The agonist increased SF LPL activity and mRNA levels, but had no effect on VF LPL. The two- to threefold postprandial increase in plasma triglycerides (TGs) was abrogated in COOH-treated rats, likely in part because of increased LPL in SF and BAT. Thus PPAR-γ agonist treatment had a powerful, site-specific effect on adipose metabolism and lipid deposition, and greatly impacted the postprandial handling of TG-rich lipoproteins. These depot-specific effects may be mediated by differential regulation of key metabolic genes, including LPL, 11β-HSD-1, and UCP-1.
Address correspondence and reprint requests to Dr. Yves Deshaies, Department of Anatomy and Physiology, School of Medicine, Laval University, Québec, QC, Canada G1K 7P4. E-mail:.
Received for publication 12 July 2002 and accepted in revised form 31 October 2002.
BAT, brown adipose tissue; 11β-HSD-1, 11β-hydroxysteroid dehydrogenase 1; HSHF, high sucrose, high fat; LPL, lipoprotein lipase; NEFA, nonesterified fatty acid; PLSD, protected least squares difference; PPAR-γ, peroxisome proliferator−activated receptor-γ; RIA, radioimmunoassay; SF, subcutaneous fat; TG, triglyceride; TZD, thiazolidinedione; UCP-1, uncoupling protein 1; VF, visceral fat; WAT, white adipose tissue.