Aims/hypothesis The aim of this study was to investigate the effect and mechanisms of action of in vivo peroxisome proliferator-activated receptor γ (PPARγ) activation on white adipose tissue (WAT) lipolysis and NEFA metabolism. Materials and methods Study rats were treated for 7 days with 15 mg/kg of rosiglitazone per day; control rats were not treated. After a 6-h fast, lipolysis and levels of mRNA for lipases were assessed in explants from various adipose depots. Results Rosiglitazone markedly increased basal and noradrenaline (norepinephrine)-stimulated glycerol and NEFA release from WAT explants, and amplified their inhibition by insulin. Primary adipocytes isolated from PPARγ agonist-treated rats were also more responsive to noradrenaline stimulation expressed per cell, ruling out a contribution of an altered number of mature adipocytes in explants. Rosiglitazone concomitantly increased levels of mRNA transcripts for adipose triglyceride lipase (ATGL) and monoglyceride lipase (MGL) in subcutaneous and visceral WAT, and mRNA for hormone-sensitive lipase (HSL) in subcutaneous WAT. Lipase expression increased within 12 h of in vitro exposure of naïve explants to rosiglitazone, suggesting direct transcriptional activation. In parallel, chronic in vivo treatment with rosiglitazone lowered plasma NEFAs and exerted in WAT its expected stimulatory action on glycerol and NEFA recycling, and on the expression of genes involved in NEFA uptake and retention by WAT, such processes counteracting net NEFA export. Conclusions/interpretation These findings demonstrate that, in the face of its plasma NEFA-lowering action, PPARγ agonism stimulates WAT lipolysis, an effect that is compensated by lipid-retaining pathways. The results further suggest that PPARγ agonism stimulates lipolysis by increasing the lipolytic potential, including the expression levels of the genes encoding adipose triglyceride lipase and monoglyceride lipase.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) activation up-regulates thermogenesis-related genes in rodent white and brown adipose tissues (WAT and BAT) without increasing whole-body energy expenditure. We tested here whether such dissociation is the result of a negative modulation of sympathetic activity to WAT and BAT and thyroid axis components by PPARgamma activation. Administration of the PPARgamma agonist rosiglitazone (15 mg/kg.d) for 7 d to male Sprague Dawley rats increased food intake (10%), feed efficiency (31%), weight gain (45%), spontaneous motor activity (60%), and BAT and WAT mass and reduced whole-body oxygen consumption. Consistent with an anabolic setting, rosiglitazone markedly reduced sympathetic activity to BAT and WAT (>50%) and thyroid status as evidenced by reduced levels of plasma thyroid hormones (T(4) and T(3)) and mRNA levels of BAT and liver T(3)-generating enzymes iodothyronine type 2 (-40%) and type 1 (-32%) deiodinases, respectively. Rosiglitazone also decreased mRNA levels of the thyroid hormone receptor (THR) isoforms alpha1 (-34%) and beta (-66%) in BAT and isoforms alpha1 (-20%) and alpha2 (-47%) in retroperitoneal WAT. These metabolic effects were associated with a reduction in mRNA levels of the pro-energy expenditure peptides CRH and CART in specific hypothalamic nuclei. A direct central action of rosiglitazone is, however, unlikely based on its low brain uptake and lack of metabolic effects of intracerebroventricular administration. In conclusion, a reduction in BAT sympathetic activity and thyroid status appears to, at least partly, explain the PPARgamma-induced reduction in energy expenditure and the fact that up-regulation of thermogenic gene expression does not translate into functional stimulation of whole-body thermogenesis in vivo.

Berthiaume M, Laplante M, Festuccia WT, Cianflone K, Turcotte LP, Joanisse DR, Olivecrona G, Thieringer R, Deshaies Y. 11␤-HSD1 inhibition improves triglyceridemia through reduced liver VLDL secretion and partitions lipids toward oxidative tissues. Am J Physiol Endocrinol Metab 293: E1045-E1052, 2007. First published July 31, 2007; doi:10.1152/ajpendo.00276.2007.-Tissue-specific alterations in 11␤-hydroxysteroid dehydrogenase (HSD) type 1 activity, which amplifies glucocorticoid action, are thought to contribute to some of the metabolic complications of obesity. The present study tested whether hypertriglyceridemia is one such complication by investigating the effects of an 11␤-HSD1 inhibitor (compound A, 3 mg⅐ kg Ϫ1 ⅐ day Ϫ1 , 21 days) on triglyceride (TG) metabolism in a rat model of diet-induced obesity. The dose of compound A used did not affect food intake or final body weight. Compound A improved fasting triglyceridemia (Ϫ42%) through a robust reduction (Ϫ41%) in hepatic TG secretion rate, without change in plasma TG clearance rate. Uptake of TG-derived fatty acids was, however, increased in oxidative tissues, including red gastrocnemius (ϩ47%), heart (ϩ39%), and brown adipose tissue (BAT, ϩ46%) at the expense of the liver, with a concomitant increase in plasma membrane fatty acid-binding protein. Lipid oxidation products were increased in red gastrocnemius (ϩ35%) and heart (ϩ33%), as were levels of uncoupling protein 1 mRNA in BAT (ϩ48%), and carnitine palmitoyltransferase 1 activity tended to be increased in some oxidative tissues. These findings demonstrate that pharmacological inhibition of 11␤-HSD1 at a dose that does not affect food intake improves triglyceridemia by reducing hepatic very low density lipoprotein-TG secretion, with a shift in the pattern of TG-derived fatty acid uptake toward oxidative tissues, in which lipid accumulation is prevented by increased lipid oxidation.11␤-hsd1 inhibitor; glucocorticoids; diet-induced obesity; triglycerides; lipid metabolism; lipid partitioning; lipid oxidation EXCESS GLUCOCORTICOIDS (GC) promote visceral obesity, hyperlipidemia, and insulin resistance (62), as seen for instance in human Cushing's syndrome (8,42). Because these abnormalities parallel those of the metabolic syndrome, it has been suggested that increased GC action may be involved in the pathogenesis of the metabolic complications of obesity (4, 31, 50).Beyond systemic GC, which are not particularly elevated in obesity (43,46,59), increasing evidence suggests the importance of 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1)-mediated local amplification in GC action. The enzyme, which converts inactive corticosteroids into bioactive forms such as cortisol in humans and corticosterone in rodents (47, 56), is expressed in many tissues, including the liver (1, 55), adipose tissue (12, 37), heart, and skeletal muscle (10,13,60). These tissues together largely determine the fate of circulating lipids. The involvement of 11␤-HSD1 activity in determining lipemia is emphasized by studies in transgen...

The metabolic consequences of visceral obesity have been associated with amplification of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in adipose tissue. This study aimed to assess in a rat model of diet-induced obesity the effects of pharmacological 11beta-HSD1 inhibition on the morphology and expression of key genes of lipid metabolism in intraabdominal adipose depots. Rats fed a high-sucrose, high-fat diet were treated or not with a specific 11beta-HSD1 inhibitor (compound A, 3 mg/kg.d) for 3 wk. Compound A did not alter food intake or body weight gain but specifically reduced mesenteric adipose weight (-18%) and adipocyte size, without significantly affecting those of epididymal or retroperitoneal depots. In mesenteric fat, the inhibitor decreased (to 25-50% of control) mRNA levels of genes involved in lipid synthesis (FAS, SCD1, DGAT1) and fatty acid cycling (lipolysis/reesterification, ATGL and PEPCK) and increased (30%) the activity of the fatty acid oxidation-promoting enzyme carnitine palmitoyltransferase 1. In striking contrast, in the epididymal depot, 11beta-HSD1 inhibition increased (1.5-5-fold) mRNA levels of those genes related to lipid synthesis/cycling and slightly decreased carnitine palmitoyltransferase 1 activity, whereas gene expression remained unaffected in the retroperitoneal depot. Compound A robustly reduced liver triacylglycerol content and plasma lipids. The study demonstrates that pharmacological inhibition of 11beta-HSD1, at a dose that does not alter food intake, reduces fat accretion specifically in the mesenterical adipose depot, exerts divergent intraabdominal depot-specific effects on genes of lipid metabolism, and reduces steatosis and lipemia.

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists improve insulin sensitivity and lipemia partly through enhancing adipose tissue proliferation and capacity for lipid retention. The agonists also reduce local adipose glucocorticoid production, which may in turn contribute to their metabolic actions. This study assessed the effects of a PPARgamma agonist in the absence of glucocorticoids (adrenalectomy, ADX). Intact, ADX, and intact pair-fed (PF) rats were treated with the PPARgamma agonist rosiglitazone (RSG) for 2 wk. RSG increased inguinal (subcutaneous) white (50%) and brown adipose tissue (6-fold) weight but not that of retroperitoneal (visceral) white adipose tissue. ADX but not PF reduced fat accretion in both inguinal and retroperitoneal adipose depots but did not affect brown adipose mass. RSG no longer increased inguinal weight in ADX and PF rats but increased brown adipose mass, albeit less so than in intact rats. RSG increased cell proliferation in white (3-fold) and brown adipose tissue (6-fold), as assessed microscopically and by total DNA, an effect that was attenuated but not abrogated by ADX. RSG reduced the expression of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) in all adipose depots. RSG improved insulin sensitivity (reduction in fasting insulin and homeostasis model assessment of insulin resistance, both -50%) and triacylglycerolemia (-75%) regardless of the glucocorticoid status, these effects being fully additive to those of ADX and PF. In conclusion, RSG partially retained its ability to induce white and brown adipose cell proliferation and brown adipose fat accretion and further improved insulin sensitivity and lipemia in ADX rats, such effects being therefore independent from the PPARgamma-mediated modulation of glucocorticoids.

Both 11b-hydroxysteroid dehydrogenase (11b-HSD1) inhibition and peroxisome proliferator-activated receptor-g (PPAR-g) agonism reduce liver and plasma lipids in rodents through partly distinct mechanisms. This study aimed to assess their additivity of action on liver and plasma lipids in a model of diet-induced steatosis. Rats were fed an obesogenic diet and were treated either with an 11b-HSD1 inhibitor (Compound A, 3 mg kg À1 day À1 ) or rosiglitazone (RSG, 5 mg kg À1 day À1 ) or both for 6 weeks. Compound A and RSG reduced liver steatosis and triglyceridemia, and did so additively when given in combination. The 11b-HSD1 inhibitor had no effect on serum adiponectin, but increased liver adiponectin receptor type 2 (Adipo-R2) mRNA levels. Conversely, RSG increased serum adiponectin, a likely mediator of its antisteatotic action, but had no effect per se on the Adipo-R2 expression. mRNA levels of representative genes of fatty acid oxidation tended to be increased by both compounds. The study shows that combined 11b-HSD1 inhibition and PPAR-g agonism additively reduce liver steatosis and triglyceridemia, which may eventually prove therapeutically useful.

No abstract

Objective: The beneficial metabolic actions of peroxisome proliferator-activated receptor g (PPARg) agonism are associated with modifications in adipose tissue metabolism that include a reduction in local glucocorticoid (GC) production by 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1). This study aimed to assess the contribution of GC attenuation to PPARg agonism action on gene expression in visceral adipose tissue and global metabolic profile. Design: Rats were treated (2 weeks) with the PPARg agonist rosiglitazone (RSG, 10 mg/kg/day) with concomitant infusion of vehicle (cholesterol implant) or corticosterone (HiCORT, 75 mg/implant/week) to defeat PPARg-mediated GC attenuation. Measurements: mRNA levels of enzymes involved in lipid uptake (and lipoprotein lipase activity), storage, lipolysis, recycling, and oxidation in retroperitoneal white adipose tissue (RWAT). Serum glucose, insulin and lipids, and lipid content of oxidative tissues. Results: Whereas HiCORT did not alter RWAT mass, RSG increased the latter ( þ 33%) independently of the corticosterone status. Both HiCORT and RSG increased lipoprotein lipase activity, the mRNA levels of the de novo lipogenesis enzyme fatty acid synthase, and that of the fatty acid retention-promoting enzyme acyl-CoA synthase 1, albeit in a nonadditive fashion. Expression level of the lipolysis enzyme adipose triglyceride lipase was increased additively by HiCORT and RSG. PPARg agonism increased mRNA of the fatty acid recycling enzymes glycerol kinase and cytosolic phosphoenolpyruvate carboxykinase and those of the fatty acid oxidation enzymes muscle-type carnitine palmitoyltransferase 1 and acyl-CoA oxidase, whereas HiCORT remained without effect. HiCORT resulted in liver steatosis and hyperinsulinemia, which were abrogated by RSG, whereas the HiCORTinduced elevation in serum nonesterified fatty acid levels was only partially prevented. The hypotriglyceridemic action of RSG was maintained in HiCORT rats. Conclusion: The GC and PPARg pathways exert both congruent and opposite actions on specific aspects of adipose tissue metabolism. Both the modulation of adipose gene expression and the beneficial global metabolic actions of PPARg agonism are retained under imposed high ambient GC, and are therefore independent from PPARg effects on 11b-HSD1-mediated GC production.