ldko - PDF FoxO1 suppresses Fgf21 during hepatic perkaderan insulin resistance to impair Inactivating hepatic follistatin alleviates hyperglycemia LDKO hepatic Irs1Irs2 double knockout mice show a severe diabetic phenotype owing to the impaired communication of the insulin resistant liver throughout the body by the dysregulated production and secretion of hepatokines Excess Fst follistatin secreted by the liver of LDKOmice inhibits insulin action in WAT white adipose tissue and Follistatin knockdown LDKO mice showed increased insulin sensitivity in epigonadal WAT eWAT and improved glucose tolerance compared with LDKO mice with intact follistatin expression This effect FoxO1 suppresses Fgf21 during hepatic insulin resistance to impair Unsuppressed hepatic glucose production HGP contributes substantially to glucose intolerance and diabetes which can be modeled by the genetic inactivation of hepatic insulin receptor substrate 1 Irs1 and Irs2 LDKO mice We previously showed that glucose intolerance in LDKO mice is resolved by Follistatin inactivation improves glucose tolerance Nature Inactivating hepatic follistatin alleviates hyperglycemia 282LB Dysregulated FGF21 Links Hepatic Insulin Resistance to LDKO or pharmacologic inhibition of ACC increased anaplerosis tricarboxylic acid TCA cycle intermediates and gluconeogenesis by activating hepatic CPT1 and pyruvate carboxylase flux in the fed state Fasting should have marginalized the role of ACC but LDKO mice maintained elevated TCA cycle intermediates Email alerts American Diabetes Association Surprisingly Ulk12 LDKO mice display normal autophagic activity in hepatocytes upon overnight fasting but are strongly resistant to acetaminophen APAPinduced liver injury Further studies revealed that Ulk12 are also dispensable for APAPinduced autophagy process but are essential for the maximum activation of cJun Nterminal kinase LDKO mice had similar noroid lotion serum glucose insulin free fatty acid and triglyceride levels to flox controls in both the fed and fasted states but had 22 less p 005 serum cholesterol in the fasted state Table 1 Hepatocytes and liver tissue demonstrated normal insulinstimulation of Akt Supplemental Figure S4 Together these data BAT and skeletal muscle of control CTRL LDKO and LTKO mice Unexpectedly 14C2DOG uptake by eWAT epigonadal WAT and iWAT inguinal WAT in LDKO mice was equivalent to that in CTRL or LTKO mice Figures 1C and 1D By contrast both basal and insulinstimulated 14C2DOG uptake into BAT of LDKO mice were reduced significantly compared Hepatic Irs1Irs2 double knockout mice LDKO developed severe systemic insulin resistance glucose intolerance and dysregulated gluconeogenesis and hyperinsulinemiawhich was largely normalized upon deletion of FoxO1 Although hepatic insulin resistance was established genetically in the LDKO mice altered hepatokine secretion can Knockdown of hepatic Fst in the LDKO mouse liver restored glucose tolerance white adipose tissue insulin signaling and the suppression of HGP by insulin however the expression of Fst in the Liverspecific deficiency of unc51 like kinase 1 and 2 PubMed Hepatic FoxO1 in LDKO mice dysregulates peripheral glucose utilization in a tissuespecific manner As described previously fasted LDKO mice but not LTKO mice LDKOFoxO1 LL Cre Alb displayed glucose intolerance during an intraperitoneal ip GTT glucose tolerance test and relative insulin resistance by ip ITT insulin tolerance test Figures 1A and and1B 1B Dong et al 2008 Genetic inhibition of hepatic acetylCoA carboxylase activity increases PDF Hepatic malonylCoA synthesis merah muda restrains gluconeogenesis by suppressing
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