Dietary and genetic evidence for enhancing glucose metabolism and reducing obesity by inhibiting klotho functions

Klotho is a multifunctional protein involved in numerous biological functions, ranging from mineral ion metabolism to signaling activities. Recent studies have identified klotho as a target gene for peroxi‐some proliferator‐activated receptor‐γ (PPAR‐γ), a master regulator of adipocyte differentiation, and an adipo‐genesis‐promoting factor. In a similar line of observation, eliminating klotho function from mice resulted in the generation of lean mice with almost no detectable fat tissue. In contrast to the klotho‐ knockout mice (11.7±0.3 g at 9 wk), leptin‐deficient ( ob/ob ) mice are severely obese (49.3±0.6 g at 9 wk), due to excessive fat accumulation. To study the in vivo role of klotho in obesity, we have generated and characterized ob/ob mice lacking klotho activity [ob/ob‐klotho double‐knockout (DKO) mice]. The ob/ob mice started to get bigger from 3 wk onward and gained almost 2 times more weight than their wild‐type (WT) counterparts (WT vs. ob/ob: 34.8±1.3 vs. 65.5±1.2 g at 21 wk). The generated ob/ob‐klotho DKO mice were not only viable throughout their adulthood but also showed markedly reduced fat tissue accumulation compared to their ob/ob littermates. The ob/ob‐klotho DKO mice had significantly ( P <0.01) less retroperitoneal, mesenteric, and epididymal fat accumulation, compared to their ob/ob counterparts. Similarly, the fatty liver that was consistently observed in the ob/ob mice was eliminated in the ob/ob‐klotho DKO mice. Such structural improvement in the liver was also evident from markedly reduced fasting blood glucose levels in ob/ob‐klotho DKO mice, compared to their ob/ob counterparts ( ob/ob vs. ob/ob‐klotho DKO: 266 ± 36 vs. 65 ±2 mg/dl). Finally, to study whether the absence of klotho can induce resistance to high‐fat‐diet‐induced obesity, we provided a high‐fat (60%) diet to klotho ‐knockout mice and compared them with normal‐fat (20%) diet‐fed klotho ‐knockout mice. No significant difference in body weight was detected in klotho ‐knockout mice fed either the normal‐fat diet or high‐fat diet, while WT mice fed the high‐fat diet gradually gained body weight, compared to the normal‐fat‐diet‐fed counterparts. The results of our dietary and genetic manipulation studies provide in vivo evidence for a role of klotho in obesity and offer a novel target to manipulate obesity and associated complications.—Ohnishi, M., Kato, S., Akiyoshi, J., Atfi, A., Razzaque, M. S., Dietary and genetic evidence for enhancing glucose metabolism and reducing obesity by inhibiting klotho functions. FASEB J. 25, 2031–2039 (2011). www.fasebj.org