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Human Kallistatin Promotes Adiposity with Preserved Insulin Sensitivity in mice
Kallistatin (KST), also known as SERPIN A4, is a broadly acting serine proteinase inhibitor with antiinflammatory and antioxidative properties. Moreover, recent studies in humans observed a negative association between plasma KST levels and body fat as well as markers of glucose homeostasis. However, whether or not KST has direct effects on human metabolic control remained unclear. To elucidate the possible effects, transgenic mice overexpressing human KST systemically (hKST-TG) and littermate control wildtype mice were studied on a regular chow diet. Human plasma KST levels were 6.8 ± 3.1 µg/ml in hKST-TG and not detectable in littermate-control mice. Body weights were similar between hKST-TG and littermate-control mice up to an age of 24 weeks. However, body composition analysis, using nuclear magnetic resonance (NMR)-spectroscopy, revealed an increased fat mass and reduced lean mass in hKST-TG mice. Moreover, we observed an enlargement of white adipose tissues (epigonadal, perirenal and subcutaneous) in hKST-TG mice in line with the NMR results. Brown adipose tissue was similar in both genotypes. The TSE PhenoMaster/LabMaster system revealed a reduced respiratory exchange ratio (RER), food intake and punctual physical activity in hKST-TG mice. Interestingly, intraperitoneal glucose tolerance tests yielded similar glucose and insulin excursion curves between groups. In hyperinsulinemic euglycemic clamp studies, glucose infusion rate was similar between genotypes, indicating no difference in insulin sensitivity. In summary, overexpression of human KST predisposed mice fed a regular chow diet to adiposity and had a marked effect on energy homeostasis, while whole body glucose tolerance and insulin sensitivity were preserved. These data suggest that KST may play a role in the regulation of human energy homeostasis. Further studies are needed to determine the molecular mechanisms.