Sensitization to insulin induced by beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) in obese Zucker rats in vivo

Mayorek, Nina; Kalderon, B.; Itach, E.; Bar‐Tana, Jacob

doi:10.2337/diabetes.46.12.1958

Cited by 14 publications

(22 citation statements)

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“…This result suggests dissociation in the changes in ACC activity from changes in AMPK activity in JCR:LA-cp rats but supports the concept of a parallel change in ACC and AMPK activity. Although it has been suggested that activation of the AMPK signaling cascade may be effective in correcting insulin resistance (39), our data suggest that hepatic AMPK is activated in insulin resistance. However, if hepatic AMPK activity is increased to reduce hepatic glucose production, the use of AMPK activators may be useful in type 2 diabetes, a situation where hyperglycemia exists.…”

Section: Discussionmentioning

confidence: 39%

“…MEDICA 16 is an ATP-citrate lyase inhibitor, and chronic treatment with MEDICA 16 has previously been shown to reduce plasma TG concentrations by 80% and blunt the development of insulin resistance in the JCR: LA-cp rat (29) as well as in the related Zucker rat (39). Several studies have also shown acute effects of MEDICA 16.…”

Section: Discussionmentioning

confidence: 91%

“…We also demonstrate that changes in AMPK activity do not mediate this increase in ACC activity and TG accumulation. Finally, treatment with MEDICA 16, which decreases TG accumulation (29) and the symptoms of insulin resistance (29,39), results in a decrease in hepatic ACC activity. This supports the concept that increased ACC activity and increased TG accumulation have important roles in the development of insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

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MEDICA 16 Inhibits Hepatic Acetyl-CoA Carboxylase and Reduces Plasma Triacylglycerol Levels in Insulin-Resistant JCR

et al. 2002

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Intracellular triacylglycerol (TG) content of liver and skeletal muscle contributes to insulin resistance, and a significant correlation exists between TG content and the development of insulin resistance. Because acetylCoA carboxylase (ACC) is the rate-limiting enzyme for liver fatty acid biosynthesis and a key regulator of muscle fatty acid oxidation, we examined whether ACC plays a role in the accumulation of intracellular TG. We also determined the potential role of 5-AMP-activated protein kinase (AMPK) in this process, since it can phosphorylate and inhibit ACC activity in both liver and muscle. TG content, ACC, and AMPK were examined in the liver and skeletal muscle of insulin-resistant JCR: LA-cp rats during the time frame when insulin resistance develops. At 12 weeks of age, there was a threefold elevation in liver TG content and a sevenfold elevation in skeletal muscle TG content. Hepatic ACC activity was significantly elevated in 12-week-old JCR: LA-cp rats compared with lean age-matched controls (8.75 ؎ 0.53 vs. 3.30 ؎ 0.18 nmol ⅐ min ؊1 ⅐ mg ؊1 , respectively), even though AMPK activity was also increased. The observed increase in hepatic ACC activity was accompanied by a 300% increase in ACC protein expression. There were no significant differences in ACC activity, ACC protein expression, or AMPK activity in the skeletal muscle of the 12-week JCR:LA-cp rats. Treatment of 12-week JCR:LA-cp rats with MEDICA 16 (an ATP-citrate lyase inhibitor) resulted in a decrease in hepatic ACC and AMPK activities, but had no effect on skeletal muscle ACC and AMPK. Our data suggest that alterations in ACC or AMPK activity in muscle do not contribute to the development of insulin resistance. However, increased liver ACC activity in the JCR:LA-cp rat appears to contribute to the development of lipid abnormalities, although this increase does not appear to occur secondary to a decrease in AMPK activity. Diabetes 51:1548 -1555, 2002

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Section: Discussionmentioning

confidence: 39%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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MEDICA 16 Inhibits Hepatic Acetyl-CoA Carboxylase and Reduces Plasma Triacylglycerol Levels in Insulin-Resistant JCR

et al. 2002

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“…Furthermore, treatment of obese leptin receptor-deficient rats (e.g. Zucker, cp/cp) with MEDICA analogs results in increased oxygen consumption and food consumption together with weight loss, implying increased total body energy expenditure (137,138). Also, the non-protonophoric mitochondrial activity of MEDICA analogs is similar to that of TH (71), in terms of promoting CSAsensitive decrease in phosphate and redox potentials with concomitant increase in oxygen consumption in cultured cells as well as in vivo (11,16,67,139,140), indicating that both MEDICA analogs and TH do converge onto LC/HC-PTP gating (11,71).…”

Section: Thyromimetic Agents and Energy Expenditurementioning

confidence: 99%

Thyroid Hormone and Energy Expenditure

Yehuda‐Shnaidman¹,

Kalderon²,

Bar‐Tana³

2012

Thyroid Hormone

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“…Furthermore, treatment of obese leptin receptor-deficient rats (e.g. Zucker, cp/cp) with MEDICA analogs results in increase in oxygen consumption and food consumption with concomitant decrease in weight gain, implying increased total body energy expenditure (19,20).…”

mentioning

confidence: 99%

Gating of the Mitochondrial Permeability Transition Pore by Long Chain Fatty Acyl Analogs in Vivo

Samovski¹,

Kalderon²,

Yehuda‐Shnaidman

et al. 2010

Journal of Biological Chemistry

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Sensitization to insulin induced by beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) in obese Zucker rats in vivo

Cited by 14 publications

References 0 publications

MEDICA 16 Inhibits Hepatic Acetyl-CoA Carboxylase and Reduces Plasma Triacylglycerol Levels in Insulin-Resistant JCR

MEDICA 16 Inhibits Hepatic Acetyl-CoA Carboxylase and Reduces Plasma Triacylglycerol Levels in Insulin-Resistant JCR

Thyroid Hormone and Energy Expenditure

Gating of the Mitochondrial Permeability Transition Pore by Long Chain Fatty Acyl Analogs in Vivo

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