Braune Julia, Weyer Ulrike, Matz-Soja Madlen, Hobusch Constance, Kern Matthias, Kunath Anne, Klöting Nora, Kralisch Susann, Blüher Matthias, Gebhardt Rolf, Zavros Yana, Bechmann Ingo, Gericke Martin
Institute of Anatomy, Leipzig University, Oststrasse 25, D-04317, Leipzig, Germany.
Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig, Germany.
Diabetologia. 2017 May;60(5):889-899. doi: 10.1007/s00125-017-4223-5. Epub 2017 Feb 23.
AIMS/HYPOTHESIS: Recently, hedgehog (Hh) was identified as a crucial player in adipose tissue development and energy expenditure. Therefore, we tested whether Hh ligands are regulated in obesity. Further, we aimed at identifying potential target cells of Hh signalling and studied the functional impact of Hh signalling on adipose tissue inflammation and glucose metabolism.
Hh ligands and receptors were analysed in adipose tissue or serum from lean and obese mice as well as in humans. To study the impact on adipose tissue inflammation and glucose metabolism, Hh signalling was specifically blocked in myeloid cells using a conditional knockout approach (Lys-Smo ).
Desert Hh (DHH) and Indian Hh (IHH) are local Hh ligands, whereas Sonic Hh is not expressed in adipose tissue from mice or humans. In mice, obesity leads to a preferential upregulation of Hh ligands (Dhh) and signalling components (Ptch1, Smo and Gli1) in subcutaneous adipose tissue. Further, adipose tissue macrophages are Hh target cells owing to the expression of Hh receptors, such as Patched1 and 2. Conditional knockout of Smo (which encodes Smoothened, a mandatory Hh signalling component) in myeloid cells increases body weight and adipose tissue inflammation and attenuates glucose tolerance, suggesting an anti-inflammatory effect of Hh signalling. In humans, adipose tissue expression of DHH and serum IHH decrease with obesity and type 2 diabetes, which might be explained by the intake of metformin. Interestingly, metformin reduced Dhh and Ihh expression in mouse adipose tissue explants.
CONCLUSIONS/INTERPRETATION: Hh signalling in myeloid cells affects adipose tissue inflammation and glucose metabolism and may be a potential target to treat type 2 diabetes.
目的/假设：最近，刺猬信号通路（Hh）被确定为脂肪组织发育和能量消耗中的关键参与者。因此，我们测试了肥胖状态下Hh配体是否受到调节。此外，我们旨在确定Hh信号的潜在靶细胞，并研究Hh信号对脂肪组织炎症和葡萄糖代谢的功能影响。
分析了瘦小鼠和肥胖小鼠以及人类的脂肪组织或血清中的Hh配体和受体。为了研究对脂肪组织炎症和葡萄糖代谢的影响，采用条件性基因敲除方法（Lys-Smo）特异性阻断髓系细胞中的Hh信号。
沙漠刺猬信号通路配体（DHH）和印度刺猬信号通路配体（IHH）是局部Hh配体，而音猬因子（Shh）在小鼠或人类的脂肪组织中不表达。在小鼠中，肥胖导致皮下脂肪组织中Hh配体（Dhh）和信号成分（Ptch1、Smo和Gli1）优先上调。此外，由于Hh受体（如Patched1和2）的表达，脂肪组织巨噬细胞是Hh靶细胞。髓系细胞中Smo（编码Smo蛋白，一种必需的Hh信号成分）的条件性敲除会增加体重和脂肪组织炎症，并减弱葡萄糖耐量，提示Hh信号具有抗炎作用。在人类中，肥胖和2型糖尿病患者的脂肪组织DHH表达及血清IHH水平降低，这可能与二甲双胍的摄入有关。有趣的是，二甲双胍降低了小鼠脂肪组织外植体中Dhh和Ihh的表达。
结论/解读：髓系细胞中的Hh信号影响脂肪组织炎症和葡萄糖代谢，可能是治疗2型糖尿病的潜在靶点。
