title: Erythropoietin alleviates hepatic insulin resistance via PPARγ-dependent AKT activation.
abstract: Erythropoietin (EPO) has beneficial effects on glucose metabolism and insulin resistance. However, the mechanism underlying these effects has not yet been elucidated. This study aimed to investigate how EPO affects hepatic glucose metabolism. Here, we report that EPO administration promoted phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation in palmitic acid (PA)-treated HepG2 cells and in the liver of high-fat diet (HFD)-fed mice, whereas adenovirus-mediated silencing of the erythropoietin receptor (EPOR) blocked EPO-induced AKT signalling in HepG2 cells. Importantly, a peroxisome proliferator-activated receptor γ (PPARγ) antagonist and PPARγ small interfering RNA (siRNA) abrogated the EPO-induced increase in p-AKT in HepG2 cells. Lentiviral vector-mediated hepatic PPARγ silencing in HFD-fed C57BL/6 mice impaired EPO-mediated increases in glucose tolerance, insulin sensitivity and hepatic AKT activation. Furthermore, EPO activated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) signalling pathway, and AMPKα and SIRT1 knockdown each attenuated the EPO-induced PPARγ expression and deacetylation and PPARγ-dependent AKT activation in HepG2 cells. In summary, these findings suggest that PPARγ is involved in EPO/EPOR-induced AKT activation, and targeting the PPARγ/AKT pathway via EPO may have therapeutic implications for hepatic insulin resistance and type 2 diabetes.
authors.affiliation: Department of Endocrinology, DrumTower hospital affiliated to Nanjing University Medical School, No321 Zhongshan Road, Nanjing, 210008, China.
authors.forename: Zhijuan
authors.initials: Z
authors.lastname: Ge
authors.affiliation: Department of Endocrinology, DrumTower hospital affiliated to Nanjing University Medical School, No321 Zhongshan Road, Nanjing, 210008, China.
authors.forename: Pengzi
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, 210008, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Hong
authors.affiliation: Department of Endocrinology, DrumTower hospital affiliated to Nanjing University Medical School, No321 Zhongshan Road, Nanjing, 210008, China.
authors.forename: Sunyinyan
authors.initials: S
authors.lastname: Tang
authors.affiliation: Department of Endocrinology, DrumTower hospital affiliated to Nanjing University Medical School, No321 Zhongshan Road, Nanjing, 210008, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Meng
authors.affiliation: Department of Endocrinology, DrumTower hospital affiliated to Nanjing University Medical School, No321 Zhongshan Road, Nanjing, 210008, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Department of Endocrinology, DrumTower hospital affiliated to Nanjing University Medical School, No321 Zhongshan Road, Nanjing, 210008, China.
authors.forename: Dalong
authors.initials: D
authors.lastname: Zhu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D047495:PPAR gamma; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D051057:Proto-Oncogene Proteins c-akt; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1; D005947:Glucose