PPAR-γ Activation Mediates Adipose Depot−Specific Effects on Gene Expression and Lipoprotein Lipase Activity

Abstract

This study sought to determine whether the adipose depot؊specific (subcutaneous [SF] vs. visceral [VF])action of peroxisome proliferator؊activated receptor-␥ (PPAR-␥) 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-␥ 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 11␤-hydroxysteroid dehydrogenase 1 (11␤-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-␥ 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, 11␤-HSD-1, and UCP-1.

PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

“…The study confirmed the well-established actions of rosiglitazone on morphometric variables, indices of insulin sensitivity and lipidaemia [18][19][20][21]. Several lines of evidence suggest that thiazolidinediones exert their beneficial effects on whole-body insulin sensitivity partly by reducing circulating NEFAs and the consequent exposure of nonadipose tissues to the deleterious effects of NEFA metabolites on insulin signal transduction [2].…”

“…In vitro basal, NA-stimulated, and insulin-inhibited lipolysis Adipose explants (20)(21)(22)(23)(24)(25) In vitro exposure of explants to rosiglitazone Minced pieces (40 mg/well) of each of the four depots described above, obtained from four control, untreated, fasted rats, were incubated in 1 ml of DMEM (Invitrogen, Burlington, ON, Canada) supplemented with pure rosiglitazone (Cayman Chemical Company, Ann Arbor, MI, USA) to a final concentration of 10 μmol/l, or carrier DMSO for 12 h. Treatments were performed in duplicate for each rat. Fat explants were then removed and frozen in liquid nitrogen until RNA isolation and analysis.…”

Metabolic action of peroxisome proliferator-activated receptor γ agonism in rats with exogenous hypercorticosteronemia

“…The orexigenic effect of PPARg agonism confirms earlier rodent studies. 9,25,26 Therefore, PPARg agonism prevents the anorectic effect of hypercorticosteronemia, but not its catabolic action on lean mass. These data further establish the important notion that the combined metabolic effects of HiCORT and PPARg agonism discussed below were independent from altered energy intake, a major potential confounder.…”

“…3 In addition to positive alterations in the adipokine profile that include increased expression of the insulin-sensitizing adiponectin, 4,5 the beneficial effects of PPARg agonists on insulin sensitivity and on the lipid profile appear to be partly attributable to lipid retention in adipose tissue and consequent reduction in lipid exposure of nonadipose tissues. [6][7][8] The lipid retention action of PPARg agonism is linked to its ability to induce the expression of genes involved in lipid accumulation, including lipoprotein lipase (LPL), 9 acyl-CoA synthase 1 (ACS1), 10 diacylglycerol acyltransferase 1 (DGAT1), 11 fatty acid synthase (FAS), 12 and cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C). 13 PPARg agonism also affects local glucocorticoid (GC) metabolism in adipose tissue.…”

“…Because elevated GC production, as seen for instance in Cushing's syndrome, is causally associated with visceral obesity and deterioration of the metabolic profile, 14,15 it has been suggested that some of the effects of PPARg agonism on adipose tissue remodeling and insulin sensitization may be attributable to its inhibitory effect on the expression of the enzyme 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1), 16 particularly in visceral fat. 9 The enzyme generates active GC (cortisol in humans and corticosterone in the rat) from inactive forms (cortisone and 11-dehydrocorticosterone), and it plays a central role in regulating intracellular GC concentration and action in adipose tissue and liver. 17 Overexpression of 11b-HSD1 in adipose tissue results in a phenotype resembling the metabolic syndrome, whereas whole-body specific inhibition of 11b-HSD1 by genetic or pharmacologic means results in overall metabolic improvement.…”