Role of AMP-activated protein kinase gamma 3 genetic variability in glucose and lipid metabolism in non-diabetic whites

Weyrich, Peter; Machicao, Fausto; Staiger, Harald; Simon, Perikles; Thamer, Claus; Machann, Jürgen; Schick, Fritz; Guirguis, Alke; Fritsche, Andreas; Stefan, Norbert; Häring, Hans‐Ulrich

doi:10.1007/s00125-007-0788-8

Cited by 20 publications

(15 citation statements)

References 40 publications

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“…PRKAG3 variants were not associated with insulin sensitivity or secretion in prior studies (15), similar to our current results in PCOS women. Previously, the minor allele of SNP rs692243, which is a non-synonymous variant (proline-to-alanine at codon 71), was shown to be significantly associated with higher serum LDL-cholesterol and apolipoprotein B-100 levels, supporting the functional significance of this SNP (15).…”

Section: Discussionsupporting

confidence: 92%

Association study of AMP-activated protein kinase subunit genes in polycystic ovary syndrome

Sproul

Jones

Azziz³

et al. 2009

European Journal of Endocrinology

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Objective: To examine the genes for AMP-activated protein kinase (AMPK) subunits a2 (PRKAA2) and g3 (PRKAG3) as candidates for polycystic ovary syndrome (PCOS) and its component traits. Design and methods: A total of 287 white PCOS women were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham and 187 white control subjects were recruited from the surrounding community. Seven PRKAA2 single nucleotide polymorphisms (SNPs) and four PRKAG3 SNPs were genotyped in PCOS cases and controls. Genotyping and association analysis were performed at Cedars-Sinai Medical Center. Results: Nominal associations of PRKAA2 variants with insulin-related traits and the PRKAG3 Pro71Ala variant with PCOS were not statistically significant after multiple testing correction. Among PCOS patients, there were no associations between variants in AMPK subunit genes and androgenic or reproductive traits. Conclusions: Variants in genes for AMPKa2 and AMPKg3 were not associated with PCOS or its component traits. Our evidence does not demonstrate that AMPK is a major genetic risk factor for PCOS.

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Section: Discussionsupporting

confidence: 92%

Association study of AMP-activated protein kinase subunit genes in polycystic ovary syndrome

Sproul

Jones

Azziz³

et al. 2009

European Journal of Endocrinology

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“…These studies highlight the role of AMPK in the regulation of mitochondrial content and function in skeletal muscle. Polymorphisms in the AMPK ␥3 subunit in humans do not seem to have an effect on glucose metabolism, but two recently identified single nucleotide polymorphisms (rs692243 and rs6436094) may play an important role in lipoprotein metabolism (43). In humans, a homologous mutation (AMPK ␥3 R225W ) increases AMPK activity and skeletal muscle glycogen content, with a concomitant decrease in intramuscular triglyceride content (44).…”

Section: Discussionmentioning

confidence: 99%

Gain-of-function R225Q Mutation in AMP-activated Protein Kinase γ3 Subunit Increases Mitochondrial Biogenesis in Glycolytic Skeletal Muscle

García-Rovés

Osler

Holmström

et al. 2008

Journal of Biological Chemistry

162

128

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AMP-activated protein kinase (AMPK) is a heterotrimeric complex, composed of a catalytic subunit (␣) and two regulatory subunits (␤ and ␥), that works as a cellular energy sensor. The existence of multiple heterotrimeric complexes provides a molecular basis for the multiple roles of this highly conserved signaling system. The AMPK ␥3 subunit is predominantly expressed in skeletal muscle, mostly in type II glycolytic fiber types. We determined whether the AMPK ␥3 subunit has a role in signaling pathways that mediate mitochondrial biogenesis in skeletal muscle. We provide evidence that overexpression or ablation of the AMPK ␥3 subunit does not appear to play a critical role in defining mitochondrial content in resting skeletal muscle. However, overexpression of a mutant form (R225Q) of the AMPK ␥3 subunit (Tg-AMPK␥3 225Q ) increases mitochondrial biogenesis in glycolytic skeletal muscle. These adaptations are associated with an increase in expression of the co-activator PGC-1␣ and several transcription factors that regulate mitochondrial biogenesis, including NRF-1, NRF-2, and TFAM. Succinate dehydrogenase staining, a marker of the oxidative profile of individual fibers, was also increased in transversal skeletal muscle sections of white gastrocnemius muscle from Tg-AMPK␥3 225Q mice, independent of changes in fiber type composition. In conclusion, a single nucleotide mutation (R225Q) in the AMPK ␥3 subunit is associated with mitochondrial biogenesis in glycolytic skeletal muscle, concomitant with increased expression of the co-activator PGC-1␣ and several transcription factors that regulate mitochondrial proteins, without altering fiber type composition.Skeletal muscle is a heterogeneous tissue that is composed of different fiber types, which are characterized by distinct contractile and metabolic properties. Skeletal muscle adapts to different conditions that require quick or long term alterations in power, force production, or substrate availability and utilization. Regular endurance exercise training promotes mitochondrial biogenesis (1) through an orchestrated change in the expression of genes that encode mitochondrial proteins (2). The AMPK 2 pathway plays a major role in the physiological regulation of mitochondrial function and biogenesis (3-8) and has been suggested to prevent or reverse peripheral insulin resistance associated with Type 2 diabetes (9 -11).AMPK is a cellular energy sensor that is activated in response to an increase in the AMP/ATP ratio. Once activated, AMPK coordinates signaling events to initiate catabolic processes that increase energy production and terminate anabolic processes, such as protein synthesis. AMPK activation modulates transcription of specific genes involved in energy metabolism, thereby exerting long term metabolic control. AMPK exists as a heterotrimeric complex composed of a catalytic (␣) and two regulatory (␤ and ␥) subunits. The ␣-and ␤-subunits are each encoded by two genes (␣1, ␣2, ␤1, and ␤2), and the ␥ subunit is encoded by three genes (␥1, ␥2, and ␥3), yielding 1...

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“…1 H MRS is being used in a large population studies to determine the prevalence of non-alcoholic fatty liver disease in the general adult population [97] and also in an increasing number of longitudinal clinical studies [99][100][101][102][103][104]. In cross-sectional studies it has also been shown, that hepatic lipids strongly depend on hormonal and genetic background of the subjects [26,[105][106][107][108][109][110][111][112][113][114].…”

Section: Proton Magnetic Resonance Spectroscopy ( 1 H Mrs)mentioning

confidence: 98%

Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance

Schwenzer

Springer

Schraml

et al. 2009

Journal of Hepatology

686

562

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Role of AMP-activated protein kinase gamma 3 genetic variability in glucose and lipid metabolism in non-diabetic whites

Cited by 20 publications

References 40 publications

Association study of AMP-activated protein kinase subunit genes in polycystic ovary syndrome

Association study of AMP-activated protein kinase subunit genes in polycystic ovary syndrome

Gain-of-function R225Q Mutation in AMP-activated Protein Kinase γ3 Subunit Increases Mitochondrial Biogenesis in Glycolytic Skeletal Muscle

Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance

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