Effects of pioglitazone on promoting energy storage, not expenditure, in brown adipose tissue of obese fa/fa zucker rats: comparison to cl 316,243

Burkey, Bryan F.; Dong, Mei; Gagen, Karen; Eckhardt, Michele; Dragonas, Nancy; Chen, Wei; Grosenstein, Paul; Argentieri, Greg; Souza, C. J. De

doi:10.1053/meta.2000.9524

Cited by 33 publications

(27 citation statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…In fa/fa Zucker rats, pioglitazone has no impact on whole-body energy expenditure (22), but these measures may not have been properly adjusted for the expected increase of thermogenesis associated with excess energy intake. Thus, it is likely that adjustment for food intake yield lowers measures of energy expenditure per consumed calorie.…”

Section: Discussionmentioning

confidence: 99%

Differential Influences of Peroxisome Proliferator–Activated Receptorsγ and -α on Food Intake and Energy Homeostasis

Larsen

Jensen²,

Sørensen³

et al. 2003

Diabetes

110

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Chronic treatment with compounds activating peroxisome proliferator-activated receptor (PPAR)␥ and -␣ influences body energy stores, but the underlying mechanisms are only partially known. In a chronic-dosing study, equiefficacious antihyperglycemic doses of the PPAR␥ agonist pioglitazone and PPAR␣/␥ dual activator ragaglitazar were administered to obesity-prone male rats. The PPAR␣ agonist fenofibrate had no effect on insulin sensitivity. Pioglitazone transiently increased and fenofibrate transiently decreased food intake, whereas ragaglitazar had no impact on feeding. As a result, body adiposity increased in pioglitazone-treated rats and decreased in fenofibrate-treated rats. PPAR␥ compounds markedly increased feed efficiency, whereas PPAR␣ agonist treatment decreased feed efficiency. In fenofibrate-treated rats, plasma acetoacetate was significantly elevated. Plasma levels of this potentially anorectic ketone body were unaffected in pioglitazoneand ragaglitazar-treated rats. High-fat feeding markedly increased visceral fat pads, and this was prevented by pioglitazone and ragaglitazar treatment. Pioglitazone treatment enlarged subcutaneous adiposity in high-fatfed rats. In conclusion, PPAR␥ activation increases both food intake and feed efficiency, resulting in net accumulation of subcutaneous body fat. The impact of PPAR␥ activation on feeding and feed efficiency appears to be partially independent because the PPAR␣ component of ragaglitazar completely counteracts the orexigenic actions of PPAR␥ activation without marked impact on feed efficiency. Diabetes 52:2249 -2259, 2003 T he nuclear receptors, peroxisome proliferatoractivated receptors (PPARs), constitute a family of three genes, PPAR␣, -␥, and -␤(␦), all of which are involved in control of energy homeostasis (1,2). Unequivocal evidence of endogenous ligands for PPAR␣ and -␥ is lacking, but a number of synthetic PPAR activating ligands exist, of which hypolipidemic fibric acids are typical examples of PPAR␣ activators while hypoglycemic thiazolidinediones are typical examples of PPAR␥ activators.The antidiabetic effects of PPAR␥ agonists are partly mediated via increased insulin sensitivity of adipose tissue and skeletal muscle. From clinical experience, PPAR␥ agonists are associated with weight gain, whereas PPAR␣ agonists appear body weight neutral (3). Part of the body weight increase may be caused by their oedema-inducing class effect, but activators of PPAR␥ also induce adipogenesis (4,5). They act preferentially on subcutaneous adipocytes, which in comparison to intrabdominal adipocytes express higher levels of PPAR␥ (6). The long-term metabolic consequences of the increased fat accumulation accompanying treatment with PPAR␥ agonists are not fully elucidated. Intrabdominal body fat accumulation is one of several hallmarks typifying the metabolic syndrome and, as such, an independent risk factor of type 2 diabetes (7-9). Many clinical trials of oral antidiabetic agents (including PPAR␥ agonists) are conspicuous by their absence of obese test subjec...

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“…This reduction in adiposity is thought to be primarily caused by an increase in energy expenditure, i.e., a sustained stimulation of BAT-mediated thermogenesis, since average energy intake remains unaltered [Yoshida et al, 1994a;Ghorbani et al, 1998;Burkey et al, 2000]. In both obese and lean rodents, chronic stimulation of β 3 -AR induces marked morphological and biochemical changes in BAT that are similar to those following cold exposure or hibernation [Himms-Hagen and Ricquier, 1998] (Fig.…”

Section: Chronic Effectsmentioning

confidence: 99%

“…Although the mechanisms underlying the antidiabetic effects of β 3 -AR agonists remain to be fully clarified, in the absence of sustained effects on insulin secretion it is widely believed that improved peripheral insulin sensitivity is the major mechanism of action. Like PPAR-γ agonists, another class of antidiabetic agents with insulin-sensitizing properties [Saltiel and Olefsky, 1996], β 3 -AR agonists are effective in reducing, or even correcting, the hyperinsulinemia, hyperglycemia, and hyperlipidemia associated with insulin resistance [Burkey et al, 2000]. Unlike PPAR-γ agonists, however, which are known to cause an increase in body weight and adiposity [Schoonjansm et al, 1996;Hallakou et al, 1997], the alleviation in insulin resistance following treatment with β 3 -AR agonists is accompanied by a decrease in body weight and adiposity.…”

Section: Chronic Effectsmentioning

confidence: 99%

Development of ?3-adrenoceptor agonists as antiobesity and antidiabetes drugs in humans: Current status and future prospects

Weyer

Souza

2000

Drug Dev. Res.

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Effects of pioglitazone on promoting energy storage, not expenditure, in brown adipose tissue of obese fa/fa zucker rats: comparison to cl 316,243

Cited by 33 publications

References 0 publications

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

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

Differential Influences of Peroxisome Proliferator–Activated Receptorsγ and -α on Food Intake and Energy Homeostasis

Development of ?3-adrenoceptor agonists as antiobesity and antidiabetes drugs in humans: Current status and future prospects

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