Effect of PPAR-α and -γ agonist on the expression of visfatin, adiponectin, and TNF-α in visceral fat of OLETF rats

Choi, Ki Choon; Ryu, Ohk Hyun; Lee, K.W.; Kim, H.Y.; Seo, Jae Hyun; Kim, S.G.; Kim, N.H.; Choi, D.S.; Baik, Sei-Hyun; Choi, Ki-Choon

doi:10.1016/j.bbrc.2005.08.203

Cited by 140 publications

(88 citation statements)

References 34 publications

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“…FENO and gemfibrozil) for the treatment of hypertriacylglycerolaemia in type 2 diabetic patients, their effect on insulin sensitivity in humans has not been rigorously examined and conflicting results have been reported [9][10][11][12][13][14]. Studies in rodents conclusively demonstrate that PPAR-α activation with FENO and other more potent PPAR-α agents enhances peripheral (muscle) and hepatic insulin sensitivity [4][5][6][7][8]. Although PPAR-α-null mice do not manifest any obvious alteration in insulin sensitivity [42], PPAR-α activation in nutritional (high-fat diet), genetic (Zucker obese fa/fa rat), and lipoatrophic (A-ZIP/ F-1) models of insulin resistance markedly improves insulin sensitivity [4,7,43] and reduces visceral fat in the two former models.…”

Section: Discussionmentioning

confidence: 99%

“…PPAR-α agonists have been used to treat hypertriacylglycerolaemia and reduce cardiovascular risk [2,3]. Studies in rodents clearly demonstrate that PPAR-α agonists improve hepatic and muscle insulin resistance, decrease hepatic and intramuscular fat content, reduce plasma NEFA and enhance adiponectin (AD) expression [4][5][6][7][8]. Some [9][10][11], but not all [12][13][14], studies in humans with hypertriacylglycerolaemia and/or type 2 diabetes suggest that PPAR-α agonists, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Increased NEFA transport/oxidation in muscle and a reduction in plasma NEFA and muscle triacylglycerol concentration have also been reported following AD administration to rodents [26]. Although studies in rodents demonstrate that PPAR-α stimulation enhances AD expression [8], the effect of PPAR-α treatment on hepatic fat content, plasma AD concentration and muscle AMPK activity in humans with type 2 diabetes has been less well studied.…”

Section: Introductionmentioning

confidence: 99%

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Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

et al. 2007

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Aims/hypothesis The aim of the study was to examine the effects of pioglitazone (PIO), a peroxisome proliferatoractivated receptor (PPAR)-γ agonist, and fenofibrate (FENO), a PPAR-α agonist, as monotherapy and in combination on glucose and lipid metabolism. Subjects and methods Fifteen type 2 diabetic patients received FENO (n=8) or PIO (n=7) for 3 months, followed by the addition of the other agent for 3 months in an openlabel study. Subjects received a 4 h hyperinsulinaemiceuglycaemic clamp and a hepatic fat content measurement at 0, 3 and 6 months. Results Following PIO, fasting plasma glucose (FPG) (p<0.05) and HbA 1c (p<0.01) decreased, while plasma adiponectin (AD) (5.5±0.9 to 13.8±3.5 μg/ml [SEM], p<0.03) and the rate of insulin-stimulated total-body glucose disposal (R d ) (23.8 ± 3.8 to 40.5 ± 4.4 μmol kg −1 min −1 , p < 0.005) increased. After FENO, FPG, HbA 1c , AD and R d did not change. PIO reduced fasting NEFA (784±53 to 546± 43 μmol/l, p<0.05), triacylglycerol (2.12±0.28 to 1.61± 0.22 mmol/l, p<0.05) and hepatic fat content (20.4±4.8 to 10.2±2.5%, p<0.02). Following FENO, fasting NEFA and hepatic fat content did not change, while triacylglycerol decreased (2.20± 0.14 to 1.59± 0.13 mmol/l, p<0.01).Addition of FENO to PIO had no effect on R d , FPG, HbA 1c , NEFA, hepatic fat content or AD, but triacylglycerol decreased (1.61±0.22 to 1.00±0.15 mmol/l, p<0.05). Addition of PIO to FENO increased R d (24.9±4.4 to 36.1± 2.2 μmol kg −1 min −1 , p<0.005) and AD (4.1±0.8 to 13.1± 2.5 μg/ml, p<0.005) and reduced FPG (p<0.05), HbA 1c (p<0.05), NEFA (p<0.01), hepatic fat content (18.3±3.1 to 13.5±2.1%, p<0.03) and triacylglycerol (1.59±0.13 to 0.96±0.9 mmol/l, p<0.01). Muscle adenosine 5′-monophosphate-activated protein kinase (AMPK) activity did not change following FENO; following the addition of PIO, muscle AMPK activity increased significantly (phosphorylated AMPK:total AMPK ratio 1.2±0.2 to 2.2±0.3, p<0.01). Conclusions/interpretation We conclude that PPAR-α therapy has no effect on NEFA or glucose metabolism and that addition of a PPAR-α agonist to a PPAR-γ agent causes a further decrease in plasma triacylglycerol, but has no effect on NEFA or glucose metabolism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

et al. 2007

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“…Taken together, a possible mechanistic link between PPAR␣ activation and leptin regulation remains obscure. There were a couple of studies (6,19) showing that fenofibrate decreased body weight, as well as adipose tissue weight, in OLETF rats. In the present study, both bezafibrate and fenofibrate treatments tended to increase body weight and mesenteric fat weight (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Bezafibrate regulates the expression and enzyme activity of 11β-hydroxysteroid dehydrogenase type 1 in murine adipose tissue and 3T3-L1 adipocytes

Nakano¹,

Inada²,

Masuzaki³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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regulates the expression and enzyme activity of 11␤-hydroxysteroid dehydrogenase type 1 in murine adipose tissue and 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab 292: E1213-E1222, 2007. First published December 26, 2006; doi:10.1152/ajpendo.00340.2006.-A clinically employed antihyperlipidemic drug, bezafibrate, has been characterized as a PPAR(␣, -␥, and -␦) pan-agonist in vitro. Recent extended trials have highlighted its antidiabetic properties in humans. However, the underlying molecular mechanism is not fully elucidated. The present study was designed to explore potential regulatory mechanisms of intracellular glucocorticoid reactivating enzyme, 11␤-HSD1 and anti-diabetic hormone, adiponectin by bezafibrate in murine adipose tissue, and cultured adipocytes. Treatment of db/db mice with bezafibrate significantly ameliorated hyperglycemia and insulin resistance, accompanied by a marked reduction of triglyceride and nonesterified fatty acids. Despite equipotent in lipid-lowering effects, another fibrate, fenofibrate, did not show such beneficial effects on glycemic control. Treatment of bezafibrate caused a marked decrease in the mRNA level of 11␤-HSD1 preferentially in adipose tissue of db/db mice (Ϫ47%, P Ͻ 0.05), concomitant with a significant increase in plasma adiponectin level (ϩ37%, P Ͻ 0.01). Notably, treatment of bezafibrate caused a marked decrease in the mRNA level (Ϫ34%, P Ͻ 0.01) and enzyme activity (Ϫ32%, P Ͻ 0.01) of 11␤-HSD1, whereas the treatment substantially augmented the expression (ϩ71%, P Ͻ 0.01) and secretion (ϩ27%, P Ͻ 0.01) of adiponectin in 3T3-L1 adipocytes. Knockdown of 11␤-HSD1 by siRNA confirmed that 11␤-HSD1 acts as a distinct oxoreductase in adipocytes and validated the enzyme activity assays in the present study. Effects of bezafibrate on regulation of 11␤-HSD1 and adiponectin in murine adipocytes were comparable with those in thiazolidinediones. This is the first demonstration that bezafibrate directly regulates 11␤-HSD1 and adiponectin in murine adipocytes, both of which may contribute to metabolicallybeneficial effects by bezafibrate. metabolic syndrome; adiponectin FAMILY GENES of peroxisome proliferator-activated receptors (PPARs) are profoundly relevant to fuel homeostasis (14, 41). Agonists for PPAR␣ and PPAR␥ have been widely used for the treatment of dyslipidemia and type 2 diabetes (46). Recent research progress (3) has highlighted the potential usefulness of PPAR␣/␥ dual agonists or PPAR(␣, -␥, and -␦) pan-agonists for metabolic diseases. However, some of these compounds are reported to cause adverse effects, including carcinogenesis, edema, hepatotoxicity, and increase in body weight in rodent experiments (45). Bezafibrate has been widely used for the treatment of dyslipidemia in human clinics (11). Recent in vitro experiments have shown that bezafibrate serves as a pan-agonist for PPAR␣, -␥, and -␦ (9, 48). Furthermore, recent extended clinical trials (15, 43) have highlighted its antidiabetic properties. However, the underlying mechanism is not fully clarified...

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“…However, the details of adiponectin production and release have varied among studies, especially in animal models (10,28,29,32,33). This is probably due to the apparently different etiology of the three types of obese animal models: genetic, diet-induced, and hypothalamic obesity (20,34).…”

Section: Discussionmentioning

confidence: 99%

Vagal Hyperactivity Due to Ventromedial Hypothalamic Lesions Increases Adiponectin Production and Release

et al. 2014

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In obese humans and animals, adiponectin production and release in adipose tissue are downregulated by feedback inhibition, resulting in decreased serum adiponectin. We investigated adiponectin production and release in ventromedial hypothalamic (VMH)-lesioned animals. VMH-lesioned mice showed significant increases in food intake and body weight gain, with hyperinsulinemia and hyperleptinemia at 1 and 4 weeks after VMH-lesioning. Serum adiponectin was elevated in VMH-lesioned mice at 1 and 4 weeks, despite adipocyte hypertrophy in subcutaneous and visceral adipose tissues and increased body fat. Adiponectin production and mRNA were also increased in both adipose tissues in VMH-lesioned mice at 1 week. These results were replicated in VMH-lesioned rats at 1 week. Daily atropine administration for 5 days or subdiaphragmatic vagotomy completely reversed the body weight gain and eliminated the increased adiponectin production and release in these rats, with reversal to a normal serum adiponectin level. Parasympathetic nerve activation by carbachol infusion for 5 days in rats increased serum adiponectin, with increased adiponectin production in visceral and subcutaneous adipose tissues without changes of body weight. These results demonstrate that activation of the parasympathetic nerve by VMH lesions stimulates production of adiponectin in visceral and subcutaneous adipose tissues and adiponectin release, resulting in elevated serum adiponectin.

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Effect of PPAR-α and -γ agonist on the expression of visfatin, adiponectin, and TNF-α in visceral fat of OLETF rats

Cited by 140 publications

References 34 publications

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

Bezafibrate regulates the expression and enzyme activity of 11β-hydroxysteroid dehydrogenase type 1 in murine adipose tissue and 3T3-L1 adipocytes

Vagal Hyperactivity Due to Ventromedial Hypothalamic Lesions Increases Adiponectin Production and Release

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