Studies on the STAT6 Knockout Mouse : A Novel Animal Mode for Diabetes Mellitus Associated with Visceral Obesity Syndrome

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The STAT6 knockout (-/-) genotype, upon introduction into the C57BL/6 background, results in the development of late-onset obesity. At 30 weeks of age, body weights of male STAT6 (-/-) mice, were increased, by 39% compared with male wild-type mice, with approximately five-fold elevation of circulating leptin. Plasma levels of total cholesterol and triglyceride were also increased. Thirty to 45-week-old male STAT6 (-/-) mice showed fasting and post-glucose load hyperglycemia. Female STAT6 (-/-) mice were also heavier than female wild-type mice, although the difference was smaller than that for male mice. Histological studies of diabetic mice showed hepatosteatosis and β-cell hyperplasia with deregulation. Food intake was significantly increased in male STAT6 (-/-) mice at the prediabetic stage when compared with wild-type mice. These observations indicate that STAT6 signaling is involved not only in the 'regulation of immune responses but also in the control of energy balance and metabolism.Screening of the human STAT6 gene for mutations showed two dinucleotide (GT) repeat polymorphic sites. (-790 and -866) in the putative promoter region, while no polymorphisms were detected in the coding region. Genotyping of 105 lean (BMI <25) and 77 obese (BMI>30) subjects demonstrated a significant association between the proximal polymorphism at-790 from the translation initiation site and obesity (p=0.007), with a significantly higher ratio of GT18 allele in obese subjects (p=0.0095). The polymorphic site was significantly associated with obesity in men but not in women. No significant difference was observed in the relative luciferase activity among the haplotypes. However, the STAT6 gene is a novel candidate gene for the development of obesity in Japanese men.