title: Role of Janus Kinase 3 in Predisposition to Obesity-associated Metabolic Syndrome.
abstract: Obesity, a worldwide epidemic, is a major risk factor for the development of metabolic syndrome (MetS) including diabetes and associated health complications. Recent studies indicate that chronic low-grade inflammation (CLGI) plays a key role in metabolic deterioration in the obese population. Previously, we reported that Jak3 was essential for mucosal differentiation and enhanced colonic barrier functions and its loss in mice resulted in basal CLGI and predisposition to DSS induced colitis. Since CLGI is associated with diabetes, obesity, and metabolic syndrome, present studies determined the role of Jak3 in development of such conditions. Our data show that loss of Jak3 resulted in increased body weight, basal systemic CLGI, compromised glycemic homeostasis, hyperinsulinemia, and early symptoms of liver steatosis. Lack of Jak3 also resulted in exaggerated symptoms of metabolic syndrome by western high-fat diet. Mechanistically, Jak3 was essential for reduced expression and activation of Toll-like receptors (TLRs) in murine intestinal mucosa and human intestinal epithelial cells where Jak3 interacted with and activated p85, the regulatory subunit of the PI3K, through tyrosine phosphorylation of adapter protein insulin receptor substrate (IRS1). These interactions resulted in activation of PI3K-Akt axis, which was essential for reduced TLR expression and TLR associated NFκB activation. Collectively, these results demonstrate the essential role of Jak3 in promoting mucosal tolerance through suppressed expression and limiting activation of TLRs thereby preventing intestinal and systemic CLGI and associated obesity and MetS.
authors.affiliation: From the Department of Pharmaceutical Sciences, ILR College of Pharmacy, Texas A &M University System Health Science Center, Kingsville, Texas 78363 and mishra@pharmacy.tamhsc.edu.
authors.forename: Jayshree
authors.initials: J
authors.lastname: Mishra
authors.affiliation: From the Department of Pharmaceutical Sciences, ILR College of Pharmacy, Texas A &M University System Health Science Center, Kingsville, Texas 78363 and.
authors.forename: Raj K
authors.initials: RK
authors.lastname: Verma
authors.affiliation: the Central Texas Veterans Health Care System, Scott & White Digestive Disease Research Center, and Texas A&M HSC College of Medicine, Temple, Texas 76504.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.affiliation: the Central Texas Veterans Health Care System, Scott & White Digestive Disease Research Center, and Texas A&M HSC College of Medicine, Temple, Texas 76504.
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.affiliation: From the Department of Pharmaceutical Sciences, ILR College of Pharmacy, Texas A &M University System Health Science Center, Kingsville, Texas 78363 and nkumar@tamhsc.edu.
authors.forename: Narendra
authors.initials: N
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001835:Body Weight; D018938:Caco-2 Cells; D016207:Cytokines / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D007328:Insulin / Q000737:chemistry; D053616:Janus Kinase 3 / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009765:Obesity / Q000235:genetics*; D009929:Organ Size; D010880:Piperidines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D012307:Risk Factors; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D016207:Cytokines; D007328:Insulin; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D051193:Toll-Like Receptors; C479163:tofacitinib; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3
keywords: Janus kinase (JAK); Toll-like receptor 4 (TLR4); diabetes; inflammation; innate immunity; metabolic syndrome