Abstract 18872: Krúppel-like Factor 6 Promotes Obesity and Glucose Intolerance Through Adipocyte Differentiation

Abstract

Introduction: Obesity and diabetes mellitus are regarded as major risk factors for cardiovascular disease. Recent studies suggest a potential role for some Krüppel-like zinc-finger transcription factors (KLFs) in adipogenesis. KLF6 is ubiquitously expressed and is also suggested to promote adipocyte differentiation in vitro. However, the metabolic roles of KLF6 in vivo have yet to be addressed.

Hypothesis: We assessed the hypothesis that KLF6 promotes obesity and pathogenesis of glucose intolerance through adipocyte differentiation.

Methods: In the present study, we used heterozygote KLF6 knockout (KLF6 ^+/-) mice and investigated whether KLF6 is involved in obesity in vivo.

Results: On a normal diet, the body weight of KLF6 ^+/- mice was similar to that of wild-type mice (28.5 ± 2.8 g versus 30.9 ± 2.9 g, n=5 in each group. p=ns), however KLF6 ^+/- mice were resistant to high fat-induced obesity (39.8 ± 4.0 g versus 50.1 ± 3.7 g, n=7 in each group. p<0.0002). As for food intake, there was no significant difference between two genotypes (2.9 ± 0.3 versus 3.2 ± 0.3 g/day, n=5 in each group. p=ns). Adipocytes from KLF6 ^+/- mice were smaller and showed a reduced hypertrophic response to this dietary manipulation, and adipocyte markers were less expressed in white adipose tissue of KLF6 ^+/- mice. Brown adipose tissue of KLF6 ^+/- mice also showed less steatotic change, which indicated enhanced heat production. On a high fat diet, KLF6 ^+/- mice and wild-type littermates were similar in fasting blood glucose levels, however KLF6 ^+/- mice showed significantly lower glucose concentrations after glucose challenge (27.5 ± 4.0 versus 13.1 ± 1.9 mmol / L, n=5 in each group . p=0.006). Serum adiponectin levels were markedly higher in KLF6 ^+/- mice (3.4 ± 0.7 versus 2.4 ± 0.3, n=8 in each group. p=0.03). Embryonic fibroblasts from KLF6 ^+/- mice were significantly impaired in adipogenic differentiation.

Conclusions: KLF6 ^+/- mice showed no metabolic phenotype under a normal intake, whereas they were resistant to excessive nutrition, compared with wild-type littermate. KLF6 promotes adipocyte hypertrophy, which leads to the pathogenesis of obesity, glucose intolerance and diabetes mellitus.