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Sadagurski, Marianna

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Sadagurski

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Marianna

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Sadagurski, Marianna

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2010 - 20132

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Author's Publications: search.filters.isAuthorOfPublication.1f4fc20a-ecb3-43f1-8330-dab51d37a11d

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    Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis★
    (Elsevier, 2013) Sadagurski, Marianna; Dong, X. Charlie; Myers, Martin G.; White, Morris
    Insulin receptor substrates (Irs1, 2, 3 and Irs4) mediate the actions of insulin/IGF1 signaling. They have similar structure, but distinctly regulate development, growth, and metabolic homeostasis. Irs2 contributes to central metabolic sensing, partially by acting in leptin receptor (LepRb)-expressing neurons. Although Irs4 is largely restricted to the hypothalamus, its contribution to metabolic regulation is unclear because Irs4-null mice barely distinguishable from controls. We postulated that Irs2 and Irs4 synergize and complement each other in the brain. To examine this possibility, we investigated the metabolism of whole body Irs4−/y mice that lacked Irs2 in the CNS (bIrs2−/−·Irs4−/y) or only in LepRb-neurons (Lepr∆Irs2·Irs4−/y). bIrs2−/−·Irs4−/y mice developed severe obesity and decreased energy expenditure, along with hyperglycemia and insulin resistance. Unexpectedly, the body weight and fed blood glucose levels of Lepr∆Irs2·Irs4−/y mice were not different from Lepr∆Irs2 mice, suggesting that the functions of Irs2 and Irs4 converge upon neurons that are distinct from those expressing LepRb.
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    Deletion of Irs2 Causes Reduced Kidney Size in Mice: Role for Inhibition of GSK3β?
    (BioMed Central, 2010) Carew, Rosemarie M; Sadagurski, Marianna; Goldschmeding, Roel; Martin, Finian; White, Morris; Brazil, Derek P
    Background: Male \(Irs2^{-/-}\) mice develop fatal type 2 diabetes at 13-14 weeks. Defects in neuronal proliferation, pituitary development and photoreceptor cell survival manifest in \(Irs2^{-/-}\) mice. We identify retarded renal growth in male and female \(Irs2^{-/-}\) mice, independent of diabetes. Results: Kidney size and kidney:body weight ratio were reduced by approximately 20% in \(Irs2^{-/-}\) mice at postnatal day 5 and was maintained in maturity. Reduced glomerular number but similar glomerular density was detected in \(Irs2^{-/-}\) kidney compared to wild-type, suggesting intact global kidney structure. Analysis of insulin signalling revealed renal-specific upregulation of PKBβ/Akt2, hyperphosphorylation of GSK3β and concomitant accumulation of β-catenin in \(Irs2^{-/-}\) kidney. Despite this, no significant upregulation of β-catenin targets was detected. Kidney-specific increases in Yes-associated protein (YAP), a key driver of organ size were also detected in the absence of Irs2. YAP phosphorylation on its inhibitory site Ser127 was also increased, with no change in the levels of YAP-regulated genes, suggesting that overall YAP activity was not increased in \(Irs2^{-/-}\) kidney. Conclusions: In summary, deletion of Irs2 causes reduced kidney size early in mouse development. Compensatory mechanisms such as increased β-catenin and YAP levels failed to overcome this developmental defect. These data point to Irs2 as an important novel mediator of kidney size.