Globular and full-length forms of adiponectin mediate specific changes in glucose and fatty acid uptake and metabolism in cardiomyocytes

Palanivel, Rengasamy; Fang, Xia; Park, Min; Eguchi, Megumi; Pallan, Shelley; Girolamo, Sabrina De; Liu, Ying; Wang, Yudong; Xu, Aimin; Sweeney, Gary

doi:10.1016/j.cardiores.2007.04.011

Cited by 97 publications

(97 citation statements)

References 39 publications

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“…5B). These data resemble those reported by Palanivel et al (2007) who found recombinant adiponectin produced with a mammalian expression system likewise preferentially formed high and medium size oligomers. By contrast, globular adiponectin predominantly formed dimers, with only small amounts of trimers and possibly tetramers visible.…”

Section: Discussionsupporting

confidence: 89%

Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form

Fuerst¹,

Taylor²,

Wright³

et al. 2012

Journal of Endocrinology

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Accelerated atherosclerosis is the primary cardiovascular manifestation of diabetes and correlates inversely with levels of circulating adiponectin, an anti-atherosclerotic adipokine that declines in diabetes. We therefore initiated a study to examine the mechanisms by which adiponectin, a hormone released from adipose tissue, influences the proliferation of vascular smooth muscle cells (SMCs). Addition of adiponectin to quiescent porcine coronary artery SMCs increased both protein and DNA synthesis and concurrently activated ERK1/2 and Akt. By contrast, globular adiponectin, a truncated form of this protein, exhibited anti-mitogenic properties as indicated by the inhibition of protein and DNA synthesis in SMCs stimulated with platelet-derived growth factor (PDGF). Whereas globular adiponectin did not stimulate growth-related signal transduction pathways, it was able to block the PDGF-dependent phosphorylation of eukaryotic elongation factor 2 kinase, a regulator of protein synthesis. Proteolysis of adiponectin with trypsin, which produces globular adiponectin, reversed the growth-stimulating actions of the undigested protein. As the existence of globular adiponectin remains controversial, western blotting was used to establish its presence in rat serum. We found that globular adiponectin was detectable in rat serum, but this result was not obtained with all antibodies. The contrasting properties of adiponectin and its globular form with respect to SMC proliferation suggest that protection against atherosclerosis may therefore be mediated, in part, by the level of globular adiponectin.

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Section: Discussionsupporting

confidence: 89%

Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form

Fuerst¹,

Taylor²,

Wright³

et al. 2012

Journal of Endocrinology

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“…After 4 h of transfection, the medium was replaced with ␣-minimum essential medium containing 10% FBS, and the cells were harvested for 48 h. Isolation of RNA, cDNA synthesis, primers, and qRT-PCR condition for AdipoR1 and AdipoR2 were conducted as described (16).…”

Section: Methodsmentioning

confidence: 99%

C1q Tumor Necrosis Factor α-related Protein Isoform 5 Is Increased in Mitochondrial DNA-depleted Myocytes and Activates AMP-activated Protein Kinase

Park¹,

Choi²,

Ryu³

et al. 2009

Journal of Biological Chemistry

102

108

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Depletion of mtDNA in myocytes causes insulin resistance and alters nuclear gene expression that may be involved in rescuing processes against cellular stress. Here we show that the expression of C1q tumor necrosis factor ␣-related protein isoform 5 (C1QTNF5) is drastically increased following depletion of mtDNA in myocytes. C1QTNF5 is homologous to adiponectin in respect to domain structure, and its expression and secretion from myocytes correlated negatively with the cellular mtDNA content. Similar to adiponectin, C1QTNF5 induced the phosphorylation of AMP-activated protein kinase (AMPK), leading to increased cell surface recruitment of GLUT4 and increased glucose uptake. Treatment of cells with purified recombinant C1QTNF5 increased the phosphorylation of acetyl-CoA carboxylase and stimulated fatty acid oxidation. C1QTNF5-mediated phosphorylation of AMPK or acetyl-CoA carboxylase was unaffected by depletion of adiponectin receptors such as AdipoR1 or AdipoR2, which indicated that adiponectin receptors do not participate in C1QTNF5-induced activation of AMPK. Serum C1QTNF5 levels were significantly higher in obese/diabetic animals (OLETF rats, ob/ob mice, and db/db mice). These results highlight C1QTNF5 as a putative biomarker for mitochondrial dysfunction and a potent activator of AMPK.

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“…Small interfering RNA to knockdown expression of AMPKα L6 cells were cultured in 24-well tissue culture plates and transfected for 24 h with 50 nmol/l AMPKα1 (also known as PRKAA1) and 50 nmol/l AMPKα2 (also known as PRKAA2), or with scrambled small interfering RNA (siRNA) (Silencer Negative Control 1 siRNA; Ambion, Austin, TX, USA) as previously described [29]. siRNA sequences for AMPKα1 and AMPKα2 were: AMPKα1 GCAUAUGCUGCAGGUAGAU; AMPKα2, CGUCAUU GAUGAUGAGGCU (Ambion).…”

Section: Methodsmentioning

confidence: 99%

Leptin prevents the metabolic effects of adiponectin in L6 myotubes

et al. 2009

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Aims/hypothesis Adiponectin and leptin are negatively and positively correlated with human obesity respectively, and have both been shown to regulate energy metabolism in skeletal muscle. However, little is known about their signalling and functional crosstalk. Here we investigated the effects of leptin on metabolic actions of (1) globular adiponectin (gAd) and (2) full-length adiponectin (fAd) in L6 cells. Methods Glucose uptake was measured upon gAd and fAd treatment after incubation with different doses (0.3, 0.6, 3, 6, 60 nmol/l) of leptin for 6, 12 and 24 h. We also measured adiponectin receptor (ADIPOR) expression and stimulation of downstream signalling by gAd and fAd using coimmunoprecipitation and western blotting following leptin pretreatment, as well as analysis of fatty acid uptake and oxidation using radiolabelled tracers. Results Leptin attenuated the stimulation of glucose uptake by gAd and fAd in a dose-and time-dependent manner, a finding correlated with decreased levels of ADIPOR1 and ADIPOR2. gAd and fAd increased palmitate uptake via activation of AMP protein kinase (T172), enhanced expression of the fatty acid transporter CD36, phosphorylated acetyl-CoA carboxylase (S79) and enhanced palmitate oxidation, all of which were attenuated by leptin pretreatment. Adiponectin can also enhance insulin sensitivity via direct signalling crosstalk; here we show that enhanced insulin-stimulated IRS-1 (Y612) and Akt (T308) phosphorylation in response to fAd was attenuated by leptin. APPL1 was recently identified as a critical mediator of adiponectin action in skeletal muscle. We demonstrated that leptin attenuated binding of APPL1 to LKB1, a downstream target leading to AMPK phosphorylation. Conclusions/interpretation The direct metabolic and insulin-sensitising effects of adiponectin were attenuated in the presence of leptin.

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Globular and full-length forms of adiponectin mediate specific changes in glucose and fatty acid uptake and metabolism in cardiomyocytes

Abstract: These results clearly demonstrate that gAd and fAd mediate distinct and time-dependent effects on cardiomyocyte energy metabolism via AdipoR1 and AdipoR2.

Cited by 97 publications

References 39 publications

Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form

Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form

C1q Tumor Necrosis Factor α-related Protein Isoform 5 Is Increased in Mitochondrial DNA-depleted Myocytes and Activates AMP-activated Protein Kinase

Leptin prevents the metabolic effects of adiponectin in L6 myotubes

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