Disregulated glyceroneogenesis: PCK1 as a candidate diabetes and obesity gene

Beale, Elmus G.; Hammer, Robert E.; Antoine, B; Forest, Claude

doi:10.1016/j.tem.2004.02.006

Cited by 110 publications

(113 citation statements)

References 42 publications

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“…The glycerol-3-phosphate that is required for triglyceride synthesis during re-esterification of FFA can be produced in adipose tissue through two pathways: (a) in the presence of glucose in media or in the postprandial state, glycolysis is a classical source of glycerol-3-phosphate whereas (b) in the absence of glucose in the media or during fasting when glycolysis is suppressed, the glycerol-3-phosphate can be produced by the glyceroneogenesis, 12,13 where phosphoenolpyruvate carboxykinase (PEPCK) is considered to be a key enzyme in the regulation of glyceroneogenesis and subsequent FFA re-esterification. 14,15 In the current study, we found that expression of transgenic resistin in adipocytes induced significant reduction of FFA re-esterification. In addition, the expression of the Pck1 gene encoding the PEPCK enzyme was significantly reduced in epididymal fat tissue of the SHR-Resistin transgenic strain compared to SHR controls.…”

Section: Discussionsupporting

confidence: 57%

Fat-specific transgenic expression of resistin in the spontaneously hypertensive rat impairs fatty acid re-esterification

et al. 2006

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Objective: To investigate the mechanism by which fat-specific transgenic expression of resistin affects fatty acid metabolism in the spontaneously hypertensive rat (SHR). Design: Basal-and adrenaline-stimulated lipolysis, basal-and insulin-stimulated lipogenesis as well as the site (glycerol versus acyl moiety) of glucose incorporated into triglycerides were determined in adipose tissue isolated from SHR-Resistin transgenic and SHR control rats. Results: A moderate expression of transgenic resistin in adipose tissue was associated with significant increase in the FFA/ glycerol ratio during adrenaline-stimulated lipolysis in the SHR-Resistin transgenic rats (3.2770.26) compared to SHR controls (2.1170.10, P ¼ 0.0005). Transgenic SHR also exhibited a significant decrease in FFA re-esterification in adipose tissue (approximately by 23%). Conclusion: These findings raise the possibility that the prodiabetic effects of transgenic resistin may be partly mediated by increased FFA release from adipose tissue due to impaired FFA re-esterification in adipocytes.

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Section: Discussionsupporting

confidence: 57%

Fat-specific transgenic expression of resistin in the spontaneously hypertensive rat impairs fatty acid re-esterification

et al. 2006

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“…As previously described, subjects with established obesity have an increased hepatic lipogenesis, but decreased lipogenic activity in adipose tissue (10). It has been suggested that the dysregulation of glyceroneogenesis (GNG) in WAT is a causal factor for obesity (3) and that a reduction in the expression of PCK1 (a key enzyme for GNG) and G6P, improved insulin sensitivity and glucose metabolism in mice (2). However, our data revealed that PCK1 was dramatically decreased in obese-susceptible subjects.…”

Section: Discussionsupporting

confidence: 50%

Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers

Marrades

González‐Muniesa

Arteta³

et al. 2010

J Physiol Biochem

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There are major variations in the susceptibility to weight gain among individuals under similar external influences (decreased physical activity and excessive calorie intake), depending on the genetic background. In the present study, we performed a microarray analysis and RT-PCR validations in order to find out differential gene expression in subcutaneous abdominal adipose tissue from two groups of subjects that despite living in similar environmental conditions such as a habitual high fat dietary intake (energy as fat >40%) and similar moderate physical activity, some of them were successfully "resistant" (lean) to weight gain, while others were "susceptible" to fat deposition (obese). The classification of up-and down-regulated genes into different categories together with the analysis of the altered biochemical pathways, revealed a coordinated downregulation of catabolic pathways operating in the mitochondria: fatty acid oxidation (P=0.008), TCA cycle (P=0.001) and electron transport chain (P=0.012). At the same time, glucose metabolism (P=0.010) and fatty acid biosynthesis (P=0.011) pathways were also downregulated in obese compared to lean subjects. In conclusion, our data showed an orchestrated downregulation of nuclear-encoded mitochondrial gene expression. These genes are involved in cellular respiration and oxidative metabolism pathways, and could play a role in the susceptibility to weight gain in some individuals.

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“…PCKs are found in the cytosol (encoded by PCK1; MIM 261680) and the mitochondria (encoded by PCK2; MIM 261650) [1,2]. The similar gene structures and the amino acid sequence homology of 68-70% between the cytosolic PCK1 and the mitochondrial PCK2 [3] suggest that they are derived from a common ancestor gene.…”

Section: Introductionmentioning

confidence: 99%

“…It has been proposed that PCK1 is best suited to gluconeogenesis from amino acids and that mitochondrial PCK2 best serves gluconeogenesis from lactate [4]. Recent evidence suggests that PCK may primarily function as an integrator of hepatic energy metabolism rather than as a determinant of gluconeogenesis [1,5,6].…”

Section: Introductionmentioning

confidence: 99%

Association of a polymorphism in the gene encoding phosphoenolpyruvate carboxykinase 1 with high-density lipoprotein and triglyceride levels

et al. 2005

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Aims/hypothesis: Phosphoenolpyruvate carboxykinase (PCK) is the key enzyme involved in the regulation of gluconeogenesis. The aim of this study was to identify genetic polymorphisms in potential candidate genes for type 2 diabetes by sequencing all exons in the PCK genes (PCK1 and PCK2), and examining the association with type 2 diabetes and diabetic phenotypes in a Korean population (775 type 2 diabetic patients and 316 normal control subjects). Materials and methods: Twenty-two polymorphisms in PCK1 and PCK2 were identified in a Korean population (n=24) by direct DNA sequencing. The TaqMan genotyping method was applied for genotyping] the remainder of the study population. Associations of PCK polymorphisms with the risk of type 2 diabetes and diabetic phenotypes were analysed using logistic and multiple regressions, adjusting for age, sex and BMI. Results: Although no significant associations between the genetic polymorphisms in PCK genes and the risk of type 2 diabetes were detected, in further haplotype analysis, one of the common haplotypes, PCK1 ht3, revealed susceptibility to type 2 diabetes (p=0.006). One 3′ untranslated region (UTR) single nucleotide polymorphism (SNP) also showed an association with HDL levels among nondiabetic control subjects: individuals homozygous for the major allele (T/T) had the lowest HDL level (1.11± 0.32 mmol/l), heterozygotes (T/C) had an intermediate level (1.27±0.37 mmol/l), and those homozygous for the minor allele (C/C) had the highest level (1.39±0.28 mmol/l) (p=0.000003). This 3′ UTR SNP was also associated with triglyceride levels, with a lower triglyceride level observed among individuals who were homozygous for the minor allele (C/C) than among those who were not. Conclusions/ interpretation: The strong genetic association of HDL and triglyceride levels with variation/haplotype information identified in this study would be useful for further genetic epidemiological studies of this important gene.

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Disregulated glyceroneogenesis: PCK1 as a candidate diabetes and obesity gene

Cited by 110 publications

References 42 publications

Fat-specific transgenic expression of resistin in the spontaneously hypertensive rat impairs fatty acid re-esterification

Fat-specific transgenic expression of resistin in the spontaneously hypertensive rat impairs fatty acid re-esterification

Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers

Association of a polymorphism in the gene encoding phosphoenolpyruvate carboxykinase 1 with high-density lipoprotein and triglyceride levels

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