Insulin modulates leptin‐induced STAT3 activation in rat hypothalamus

Carvalheira, José Barreto Campello; Siloto, Rodrigo M.P.; Ignacchitti, Inara; Brenelli, Sigisfredo Luís; Carvalho, Carla Roberta de Oliveira; Leite, Adílson; Velloso, Lı́cio A.; Gontijo, José Antônio Rocha; Saad, Mário José Abdalla

doi:10.1016/s0014-5793(01)02591-1

Cited by 137 publications

(122 citation statements)

References 47 publications

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“…The rats were anesthetized with intraperitoneal injection of a mix of ketamin (10 mg) and diazepam (0.07 mg) (0.2 ml/100 g body wt), after overnight fasting and positioning on a Stoelting stereotaxic apparatus. The implantation of an intracerebroventricular catheter into the third ventricle (27) and the method for liquor sampling (28) have been previously described. Treatments.…”

Section: Methodsmentioning

confidence: 99%

A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet–Induced Weight Loss

et al. 2008

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OBJECTIVE-A high-protein diet (HPD) is known to promote the reduction of body fat, but the mechanisms underlying this change are unclear. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) function as majors regulators of cellular metabolism that respond to changes in energy status, and recent data demonstrated that they also play a critical role in systemic energy balance. Here, we sought to determine whether the response of the AMPK and mTOR pathways could contribute to the molecular effects of an HPD.RESEARCH DESIGN AND METHODS-Western blotting, confocal microscopy, chromatography, light microscopy, and RT-PCR assays were combined to explore the anorexigenic effects of an HPD.RESULTS-An HPD reduced food intake and induced weight loss in both normal rats and ob/ob mice. The intracerebroventricular administration of leucine reduced food intake, and the magnitude of weight loss and reduction of food intake in a leucine-supplemented diet are similar to that achieved by HPD in normal rats and in ob/ob mice, suggesting that leucine is a major component of the effects of an HPD. Leucine and HPD decrease AMPK and increase mTOR activity in the hypothalamus, leading to inhibition of neuropeptide Y and stimulation of pro-opiomelanocortin expression. Consistent with a cross-regulation between AMPK and mTOR to control food intake, our data show that the activation of these enzymes occurs in the same specific neuronal subtypes.CONCLUSIONS-These findings provide support for the hypothesis that AMPK and mTOR interact in the hypothalamus to regulate feeding during HPD in a leucine-dependent manner.

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Section: Methodsmentioning

confidence: 99%

A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet–Induced Weight Loss

et al. 2008

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“…In the CNS, the IR has distinct patterns of expression in the olfactory bulb, the hypothalamus and the pituitary [1,2,3], although its function in these regions is not completely understood. Previous studies have documented a role for insulin signalling in the regulation of food intake [4,5,6,7,8].…”

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confidence: 99%

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

et al. 2003

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Aim/hypothesis. By acting in the brain, insulin suppresses food intake. However, little is known with regard to insulin signalling in the hypothalamus in insulin-resistant states. Methods. Western blotting, immunohistochemistry and polymerase chain reaction assays were combined to compare in vivo hypothalamic insulin signalling through the PI3-kinase and MAP kinase pathways between lean and obese Zucker rats. Results. Intracerebroventricular insulin infusion reduced food intake in lean rats to a greater extent than that observed in obese rats, and pre-treatment with PI3-kinase inhibitors prevented insulin-induced anorexia. The relative abundance of IRS-2 was considerably higher than that of IRS-1 in hypothalamus of both lean and obese rats. Insulin-stimulated phosphorylation of IR, IRS-1/2, the associations of PI 3-kinase to IRS-1/2 and phosphorylation of Akt in hypothalamus were decreased in obese rats compared to lean rats. These effects seem to be mediated by increased phosphoserine content of IR, IRS-1/2 and decreased protein levels of IRS-1/2 in obese rats. In contrast, insulin stimulated the phosphorylation of MAP kinase equally in lean and obese rats. Conclusion/interpretation. This study provides direct measurements of insulin signalling in hypothalamus, and documents selective resistance to insulin signalling in hypothalamus of Zucker rats. These findings provide support for the hypothesis that insulin could have anti-obesity actions mediated by the PI3-kinase pathway, and that impaired insulin signalling in hypothalamus could play a role in the development of obesity in this animal model of insulin-resistance. [Diabetologia (2003[Diabetologia ( ) 46:1629[Diabetologia ( -1640 Keywords Obesity, insulin resistance, hypothalamus, anorexia, signal transduction, phosphatidylinositol 3-kinase/antagonists & inhibitors/*metabolism, mitogen-activated protein kinase. Abbreviations: ERK, extracellular signal-regulated kinase; Grb2, growth factor receptor binding protein 2; IR, insulin receptor; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; PI 3-kinase, phosphatidylinositol 3-kinase; PKC, Protein kinase C; Shc, Src-homology and collagen homology; SHP2, Src-homology phosphatase 2; TNF-α, Tumor-necrosis factor-α.

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“…The maximal tyrosine phosphorylation occurred at 5 min after melatonin infusion and decreased dramatically thereafter. Parallel experiments were performed in which the rats received an infusion of insulin as a positive control for induced tyrosine phosphorylation (Carvalheira et al 2001) (Fig. 1b).…”

Section: Discussionmentioning

confidence: 99%

In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus

Anhê

Caperuto

Pereira-da-Silva

et al. 2004

Journal of Neurochemistry

108

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Melatonin is the pineal hormone that acts via a pertussis toxinsensitive G-protein to inhibit adenylate cyclase. However, the intracellular signalling effects of melatonin are not completely understood. Melatonin receptors are mainly present in the suprachiasmatic nucleus (SCN) and pars tuberalis of both humans and rats. The SCN directly controls, amongst other mechanisms, the circadian rhythm of plasma glucose concentration. In this study, using immunoprecipitation and immunoblotting, we show that melatonin induces rapid tyrosine phosphorylation and activation of the insulin receptor b-subunit tyrosine kinase (IR) in the rat hypothalamic suprachiasmatic region. Upon IR activation, tyrosine phosphorylation of IRS-1 was detected. In addition, melatonin induced IRS-1/PI(3)-kinase and IRS-1/SHP-2 associations and downstream AKT serine phosphorylation and MAPK (mitogen-activated protein kinase) phosphorylation, respectively. These results not only indicate a new signal transduction pathway for melatonin, but also a potential cross-talk between melatonin and insulin.

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Insulin modulates leptin‐induced STAT3 activation in rat hypothalamus

Cited by 137 publications

References 47 publications

A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet–Induced Weight Loss

A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet–Induced Weight Loss

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus

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