title: Hepatic Expression of Adenovirus 36 E4ORF1 Improves Glycemic Control and Promotes Glucose Metabolism Through AKT Activation.
abstract: Considering that impaired proximal insulin signaling is linked with diabetes, approaches that enhance glucose disposal independent of insulin signaling are attractive. In vitro data indicate that the E4ORF1 peptide derived from human adenovirus 36 (Ad36) interacts with cells from adipose tissue, skeletal muscle, and liver to enhance glucose disposal, independent of proximal insulin signaling. Adipocyte-specific expression of Ad36E4ORF1 improves hyperglycemia in mice. To determine the hepatic interaction of Ad36E4ORF1 in enhancing glycemic control, we expressed E4ORF1 of Ad36 or Ad5 or fluorescent tag alone by using recombinant adeno-associated viral vector in the liver of three mouse models. In db/db or diet-induced obesity (DIO) mice, hepatic expression of Ad36E4ORF1 but not Ad5E4ORF1 robustly improved glycemic control. In normoglycemic wild-type mice, hepatic expression of Ad36E4ORF1 lowered nonfasting blood glucose at a high dose of expression. Of note, Ad36E4ORF1 significantly reduced insulin levels in db/db and DIO mice. The improvement in glycemic control was observed without stimulation of the proximal insulin signaling pathway. Collectively, these data indicate that Ad36E4ORF1 is not a typical sensitizer, mimetic, or secretagogue of insulin. Instead, it may have insulin-sparing action, which seems to reduce the need for insulin and, hence, to reduce insulin levels.
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH.|The Comprehensive Cancer Center, Ohio State University, Columbus, OH.
authors.forename: Travis B
authors.initials: TB
authors.lastname: McMurphy
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH.|The Comprehensive Cancer Center, Ohio State University, Columbus, OH.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH.|The Comprehensive Cancer Center, Ohio State University, Columbus, OH.
authors.forename: Run
authors.initials: R
authors.lastname: Xiao
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH.|The Comprehensive Cancer Center, Ohio State University, Columbus, OH.
authors.forename: Xianglan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Nutritional Sciences, Texas Tech University, Lubbock, TX.
authors.forename: Nikhil V
authors.initials: NV
authors.lastname: Dhurandhar
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH lei.cao@osumc.edu.|The Comprehensive Cancer Center, Ohio State University, Columbus, OH.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
mesh_terms: D017504:Adenovirus E4 Proteins / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D003920:Diabetes Mellitus / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017504:Adenovirus E4 Proteins; D001786:Blood Glucose; D007328:Insulin; D005947:Glucose