Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, United States.
Department of Medicine, Washington University School of Medicine, St. Louis, United States.
Elife. 2017 Dec 5;6:e31649. doi: 10.7554/eLife.31649.
Obesity poses a significant risk of developing type II diabetes and other diseases. Hedgehog (Hh) signaling has been shown to inhibit adipose tissue development, but its effect on diet-induced obesity during postnatal life is not known. Here by inducing expression of constitutively active Smoothened (SmoM2) or Gli2 (ΔNGli2) in the adipocyte lineage of postnatal mice, we show that targeted activation of Hh signaling suppresses high-fat-diet-induced obesity and improves whole-body glucose tolerance and insulin sensitivity. Both SmoM2 and ΔNGli2 induce the expression of Wnt6, a known anti-adipogenic factor, in fat depots of the mouse. Hh-Gli2 signaling inhibits not only adipocyte differentiation but also lipogenesis in adipocytes in vitro. Finally, pharmacological inhibition of Porcupine, an acyltransferase essential for Wnt secretion, alleviates both anti-adipogenic and anti-lipogenic effects of Hh in cell culture models. Overall, targeted activation of Hh signaling ameliorates diet-induced obesity and may be explored for pharmaceutical development.
肥胖会增加患 II 型糖尿病和其他疾病的风险。 hedgehog (Hh) 信号已被证明可以抑制脂肪组织的发育，但它在出生后生活中对饮食诱导肥胖的影响尚不清楚。在这里，通过在出生后小鼠的脂肪细胞谱系中诱导组成型激活 Smoothened (SmoM2) 或 Gli2 (ΔNGli2) 的表达，我们表明靶向激活 Hh 信号可抑制高脂肪饮食诱导的肥胖，并改善全身葡萄糖耐量和胰岛素敏感性。SmoM2 和 ΔNGli2 均诱导脂肪组织中已知的抗脂肪生成因子 Wnt6 的表达。Hh-Gli2 信号不仅抑制脂肪细胞分化，还抑制体外脂肪细胞中的脂肪生成。最后，Porcupine 的药理学抑制，一种 Wnt 分泌所必需的酰基转移酶，可减轻细胞培养模型中 Hh 的抗脂肪生成和抗脂肪生成作用。总的来说，靶向激活 Hh 信号可改善饮食诱导的肥胖，并且可能被探索用于药物开发。
