Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways

Kellerer, Monika; Koch, Matthias; Metzinger, E.; Mushack, Joanne; Capp, Edison; Häring, Hans‐Ulrich

doi:10.1007/s001250050832

Cited by 190 publications

(133 citation statements)

References 10 publications

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“…After addition of 150 μl of 1 mol/l HCl, lipids were extracted twice with 450 μl chloroform/methanol (1:1 by volume). Products were separated by thin layer chromatography as described [19]. 32 Plabelled phospholipids were detected by autoradiography.…”

Section: Methodsmentioning

confidence: 99%

Insulin-mediated cortical activity in the slow frequency range is diminished in obese mice and promotes physical inactivity

et al. 2009

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Aims/hypothesis There is evidence from mouse models and humans that alterations in insulin action in the brain are accompanied by an obese phenotype; however, the impact of insulin with regard to behavioural aspects such as locomotion is unknown. Methods To address insulin action in the brain with regard to cortical activity in distinct frequency bands and the behavioural consequences, the insulin signalling pathway was followed from the receptor to electrical activity and locomotion. Western blot analysis, electrocorticograms with intracerebroventricular (i.c.v.) application of insulin, and measurements of locomotor activity were performed in lean and obese, as well as Toll-like receptor (TLR) 2/4-deficient, mice.Results We show that insulin application i.c.v. into lean mice was accompanied by a profound increase in cortical activity in the slow frequency range, while diet-induced obese mice displayed insulin resistance. In parallel, insulin administered i.c.v. increased locomotor activity in lean mice, whereas a phosphatidylinositol-3 (PI3) kinase inhibitor or obesity abolished insulin-mediated locomotion. A potential candidate that links insulin signalling to locomotion is the Kv1.3 channel that is activated by PI3-kinase. Pharmacological inhibition of Kv1.3 channels that bypassed insulin receptor activation promoted activity. Moreover, mice deficient in TLR2/4-dependent signalling displayed an increase in cortical activity in the slow frequency range that was correlated with improved spontaneous and insulin-mediated locomotor activity. Conclusions/interpretation Our data provide functional evidence for a direct effect of insulin on brain activation patterns in the slow frequency bands and locomotor activity in lean mice, while in obese mice, insulin-mediated locomotion is blunted and further aggravates physical inactivity.

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Section: Methodsmentioning

confidence: 99%

Insulin-mediated cortical activity in the slow frequency range is diminished in obese mice and promotes physical inactivity

et al. 2009

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“…After addition of 150 μl 1 mol/l HCl, lipids were extracted twice with 450 μl chloroform/methanol (1:1 by volume). Products were separated by thin layer chromatography as described [20]. 32 P-labelled phospholipids were detected by autoradiography.…”

Section: Methodsmentioning

confidence: 99%

Tissue selectivity of insulin detemir action in vivo

et al. 2006

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Aims/hypothesis: Recombinant DNA technology is a useful tool that can be used to create insulin analogues with modified absorption kinetics to improve glycaemic control in patients with type 1 and type 2 diabetes. Among conventional insulin analogues, which are usually created by amino acid exchange, insulin detemir is the first analogue to be acylated with a fatty acid to enable reversible albumin binding. In this study we determined activation of the insulin receptor (IR)-signalling cascade by insulin detemir at the level of IR and IR substrate (Irs) phosphorylation, as well as downstream signalling elements such as phosphatidylinositol 3-kinase and Akt, and performed epidural EEG in vivo. Methods: C57Bl/6 mice were injected i.v. with either insulin detemir or human insulin and Western blot analysis was performed on liver, muscle, hypothalamic and cerebrocortical tissues. Moreover, cerebrocortical activity was detected by EEG in awake mice and cerebral insulin concentrations were measured following human insulin and insulin detemir injection. Results: The time course and extent of IR phosphorylation in peripheral tissues were similar following insulin detemir treatment compared with human insulin, but insulin signalling in hypothalamic and cerebrocortical tissue determined by tyrosine-phosphorylation of the IR and Irs2 proteins occurred faster and was enhanced due to a higher insulin detemir concentration in the brain. Moreover, epidural EEG in mice displayed increased cortical activity using insulin detemir. Conclusions/interpretation: Taken together, these data suggest that insulin detemir has a tissue-selective action, with a relative preference for brain compared with peripheral tissues.

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“…It binds the long form of leptin receptor (LRb) and triggers the tyrosine kinase JAK, eventually controlling STAT transcription factors and gene expression (Munzberg & Myers 2005). The way by which leptin also stimulates PI3K is not yet precisely defined, although different studies suggest JAK2-dependent and -independent mechanisms that trigger p85 binding to tyrosine-phosphorylated insulin receptor substrate (IRS, see below for description) adaptor proteins (Kellerer et al 1997, Munzberg & Myers 2005, Mansour et al 2006Fig. 6).…”

Section: Pi3k-mediated Effects Of Leptinmentioning

confidence: 99%

Phosphoinositide 3-kinases as a common platform for multi-hormone signaling

Hirsch

Costa²,

Ciraolo³

2007

Journal of Endocrinology

121

128

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In multicellular organisms, concerted actions of different tissues are regulated inside single cells by signal transduction mechanisms that, subsequently to hormones sensing, trigger intracellular responses. In recent years, increasing evidence indicates phosphoinositide 3-kinases (PI3K) as crucial signal transducing elements that regulate communication across the plasma membrane. PI3K generate lipid secondary messengers that trigger a plethora of intracellular responses ranging from metabolic regulation to cell proliferation, survival, and migration. The growing number of hormones that relay signals by activating PI3K suggests not only multiple roles of these enzymes in the regulation of different physiological responses but also a way by which common reactions can be stimulated by different inputs. This review will thus focus on the different pathways that converge on PI3K activation, with particular attention to the paradigmatic PI3K involvement in insulin signaling.

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Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways

Cited by 190 publications

References 10 publications

Insulin-mediated cortical activity in the slow frequency range is diminished in obese mice and promotes physical inactivity

Insulin-mediated cortical activity in the slow frequency range is diminished in obese mice and promotes physical inactivity

Tissue selectivity of insulin detemir action in vivo

Phosphoinositide 3-kinases as a common platform for multi-hormone signaling

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