Introduction Signals from the upper gastrointestinal tract act via vagal afferent neurons to control food intake and autonomic reflexes. Physiological regulators of this system include hormones such as cholecystokinin (CCK), but inflammatory mediators are also known to target this pathway. In obesity, there are elevated plasma concentrations of the adipokine, PAI-1; increased expression of PAI-1 occurs in the stomach with infection and inflammation. In order to study the role of gastric PAI-1 we have generated mice with targeted expression to parietal cells.
Methods Transgenic mice were generated in which mouse PAI-1 was targeted to parietal cells using 1.1 kb of the promoter of the H+/K+ATPase β-subunit (PAI-1-H/Kβ mice). The phenotype was studied using histological and behavioural approaches, qPCR and plasma assays.
Result Male 12-week-old PAI-1-H/Kβ mice fed ad libitum exhibited increased body mass compared to C57Bl/6 mice (30.2+0.9 vs 27.2+0.3 g p<0.05, n=10) and were hyperphagic (5.1+0.4 vs 4.0+0.1 g per 24 h, p<0.01, n=10). Epididymal fat pad weight was increased in PAI-1-H/Kβ mice on both an absolute basis (0.8+0.1 vs 0.4+0.03 g, p<0.01, n=8) and as a proportion of body weight. Pair feeding with wild-type mice reduced body weight significantly. PAI-1-H/Kβ mice had significantly elevated plasma PAI-1 compared to C57Bl/6 mice (3.5+0.2 vs 2.3+0.2 ng/ml, p<0.005, n=13), but there was no difference in plasma ghrelin concentration (2.4+0.3 vs 2.2+0.1 ng/ml, n=7) or in gastric ghrelin mRNA measured by qPCR. There was significant, dose-dependent, inhibition of food intake in C57Bl/6 mice in response to CCK8s over the range 1.25–10 nmol/kg, but in PAI-1-H/Kβ only doses of 5 and 10 nmol/kg produced significant inhibition of food intake.
Conclusion Increased expression of PAI-1 in the stomach is associated with a sustained increase in food intake leading to moderate obesity. This appears to be due to the resistance to the satiety effects of CCK indicating a novel mechanism of gastrointestinal control of food intake.
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