Troglitazone inhibits fatty acid oxidation and esterification, and gluconeogenesis in isolated hepatocytes from starved rats

Fulgencio, Jean-Pierre; Kohl, Claude; Girard, Jean; Pégorier, Jean‐Paul

doi:10.2337/diabetes.45.11.1556

Cited by 51 publications

(41 citation statements)

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“…Thiazolidinedione derivatives are also known to act in liver to prevent glucose production [19] or to inhibit fatty acid oxidation [39]. Since PPARg2 only very slightly or not at all exhibits in pancreas and liver, these effects probably depend on another pathway and do not relate to the suppression of TNF-a production.…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone time-dependently reduces tumour necrosis factor-α level in muscle and improves metabolic abnormalities in Wistar fatty rats

et al. 1998

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Metabolic abnormalities in obesity and non-insulindependent diabetes mellitus (NIDDM) are linked to insulin resistance [1±4]. Although the mechanism for the development of insulin resistance has not been fully clarified, recent studies imply a correlation between tumour necrosis factor-a (TNF-a) and insulin resistance. These studies demonstrated that TNF-a mRNA expression is increased in adipose tissue of obese animals [4±6] and humans [7,8], that infusion of TNF-a into rats results in insulin resistance in muscle [9] and that neutralization of TNF-a by infusion of TNF-a receptor-IgG chimeric protein into obese rats increases peripheral glucose uptake in response to insulin [4]. It was also shown that TNF-a mRNA is overexpressed in muscle of diabetic patients [10] and that the RNA transcript encoding the p55 TNF-a receptor is elevated in muscle of genetically obese and diabetic KKA y mice [11]. Since the half-life of TNF-a in blood is very short and muscle plays a principal role in inducing impaired glucose metabolism in insulin resistance [12], it is supposed that TNF-a produced in muscle acts in an autocrine fashion or that produced in adipose tissue works on the adjoining muscle. Diabetologia (1998) Summary In order to evaluate the relationship between tumour necrosis factor-a (TNF-a) level in muscle and metabolic abnormalities in obesity and diabetes mellitus, pioglitazone, a novel insulin-sensitizing agent, was administered to Wistar fatty rats and time-dependent changes in muscle TNF-a content and plasma indicators of diabetes and obesity were measured. Wistar fatty rats were hyperglycaemic, hyperlipidaemic and hyperinsulinaemic, and their plasma and muscle TNF-a levels were two or more times higher than those in normal lean rats at 16 weeks of age. When pioglitazone was administered to fatty rats at a dose of 3 mg × kg ±1 × day ±1 , the plasma triglyceride level and TNF-a levels in plasma and muscle decreased time-dependently, and reached the levels of lean rats within 4 days. Plasma glucose and insulin levels also decreased time-dependently with pioglitazone, but on day 4, these levels were still much higher than the levels in lean rats. Neutral sphingomyelinase (SMase) activity in muscle of fatty rats was two times higher than that in lean rats and was lowered to the level of that in lean rats by 4 days' pioglitazone administration. The plasma leptin level in fatty rats was 8 times higher than that in lean rats, but pioglitazone did not affect the level during the 4-day administration period. These results suggest that an increase in TNF-a production and subsequent activation of SMase in muscle leads to metabolic abnormalities in obesity and diabetes and that antidiabetic activity of pioglitazone is deeply associated with the suppression of TNF-a production. [Diabetologia (1998) 41: 257±264]

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Section: Discussionmentioning

confidence: 99%

Pioglitazone time-dependently reduces tumour necrosis factor-α level in muscle and improves metabolic abnormalities in Wistar fatty rats

et al. 1998

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“…Studies in cultured hepatoma cells show that exogenous fatty acid promotes the amount of VLDL-TAG secreted (17) and that inhibiting the de novo synthesis of TAG with triacsin (48), an inhibitor of acyl-CoA synthetase, longchain (ACSL)1 and ACSL4 (29), or with troglitazone (19), an inhibitor of ACSL4 (29), decreases both TAG synthesis and apoB secretion. Although the initiation of apoB synthesis is constitutive, apoB undergoes both proteasomal and nonproteasomal degradation if TAG is not synthesized concomitantly.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial glycerol-3-phosphate acyltransferase-1 directs the metabolic fate of exogenous fatty acids in hepatocytes

Lewin¹,

Wang²,

Nagle³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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(TAG) in nonadipose tissues is closely associated with the development of insulin resistance, interest has increased in the metabolism of longchain acyl-CoAs toward ␤-oxidation or the synthesis and storage of TAG. To learn whether a mitochondrial isoform of glycerol-3-phosphate acyltransferase (mtGPAT1) competes with carnitine palmitoyltransferase I (CPT I) for acyl-CoAs and whether it contributes to the formation of TAG, we overexpressed rat mtGPAT1 13-fold in primary hepatocytes obtained from fasted rats. When 100, 250, or 750 M oleate was present, both TAG mass and the incorporation of [ 14 C]oleate into TAG increased more than twofold in hepatocytes overexpressing mtGPAT1 compared with vector controls. Although the incorporation of [ 14 C]oleate into CO2 and acid-soluble metabolites increased with increasing amounts of oleate in the media, these metabolites were ϳ40% lower in the Ad-mtGPAT1 infected cells, consistent with competition for acyl-CoAs between CPT I and mtG-PAT1. A 50 -60% decrease was also observed in [14 C]oleate incorporation into cholesteryl ester. With increasing amounts of exogenous oleate, [14 C]TAG secretion increased appropriately in vector controlinfected hepatocytes, suggesting that the machinery for VLDL-TAG biogenesis and secretion was unaffected. Despite the marked increases in TAG synthesis and storage in the Ad-mtGPAT1 cells, however, the Ad-mtGPAT1 cells secreted the same amount of [ 14 C

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“…As discussed above, this prevents the ectopic fat deposition and the development of insulin resistance. Similarly, TZD reduce NEFA oxidation and glucose production in the liver [95]. Perhaps the most impressive model showing this aspect of TZD action is the fat-depleted transgenic mouse model [96,97].…”

Section: Fat Metabolism Targeted Antidiabetic Modalitiesmentioning

confidence: 99%

Diabetes: mellitus or lipidus?

Shafrir

Raz

2003

Diabetologia

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Troglitazone inhibits fatty acid oxidation and esterification, and gluconeogenesis in isolated hepatocytes from starved rats

Cited by 51 publications

References 0 publications

Pioglitazone time-dependently reduces tumour necrosis factor-α level in muscle and improves metabolic abnormalities in Wistar fatty rats

Pioglitazone time-dependently reduces tumour necrosis factor-α level in muscle and improves metabolic abnormalities in Wistar fatty rats

Mitochondrial glycerol-3-phosphate acyltransferase-1 directs the metabolic fate of exogenous fatty acids in hepatocytes

Diabetes: mellitus or lipidus?

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