title: Gastric expression of plasminogen activator inhibitor (PAI)-1 is associated with hyperphagia and obesity in mice.
abstract: The adipokine plasminogen activator inhibitor (PAI)-1 is increased in plasma of obese individuals and exhibits increased expression in the stomachs of individuals infected with Helicobacter. To investigate the relevance of gastric PAI-1, we used 1.1 kb of the H(+)/K(+)β subunit promoter to overexpress PAI-1 specifically in mouse gastric parietal cells (PAI-1-H/Kβ mice). We studied the physiological, biochemical, and behavioral characteristics of these and mice null for PAI-1 or a putative receptor, urokinase plasminogen activator receptor (uPAR). PAI-1-H/Kβ mice had increased plasma concentrations of PAI-1 and increased body mass, adiposity, and hyperphagia compared with wild-type mice. In the latter, food intake was inhibited by cholecystokinin (CCK)8s, but PAI-1-H/Kβ mice were insensitive to the satiating effects of CCK8s. PAI-1-H/Kβ mice also had significantly reduced expression of c-fos in the nucleus tractus solitarius in response to CCK8s and refeeding compared with wild-type mice. Exogenous PAI-1 reversed the effects of CCK8s on food intake and c-fos levels in the nucleus tractus solitarius of wild-type mice, but not uPAR-null mice. Infection of C57BL/6 mice with Helicobacter felis increased gastric abundance of PAI-1 and reduced the satiating effects of CCK8s, whereas the response to CCK8s was maintained in infected PAI-1-null mice. In cultured vagal afferent neurons, PAI-1 inhibited stimulation of neuropeptide Y type 2 receptor (Y2R) expression by CCK8s. Thus, gastric expression of PAI-1 is associated with hyperphagia, moderate obesity, and resistance to the satiating effects of CCK indicating a new role in suppressing signals from the upper gut that inhibit food intake.
authors.affiliation: Departments of Cell and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Kenny
authors.forename: Joanne
authors.initials: J
authors.lastname: Gamble
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lyons
authors.forename: Nikolina
authors.initials: N
authors.lastname: Vlatkovic
authors.forename: Rod
authors.initials: R
authors.lastname: Dimaline
authors.forename: Andrea
authors.initials: A
authors.lastname: Varro
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Dockray
mesh_terms: D000818:Animals; D002766:Cholecystokinin / Q000494:pharmacology; D005753:Gastric Mucosa / Q000378:metabolism*; D016481:Helicobacter Infections / Q000503:physiopathology; D044922:Helicobacter felis; D006963:Hyperphagia / Q000378:metabolism*; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000502:physiology; D012527:Satiation / Q000187:drug effects
chemical_list: D017395:Plasminogen Activator Inhibitor 1; C524899:Plaur protein, mouse; D055293:Receptors, Urokinase Plasminogen Activator; D002766:Cholecystokinin