Inhibition of hedgehog signaling protects adult mice from diet-induced weight gain.
Inhibition of hedgehog signaling protects adult mice from diet-induced weight gain.
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DOI：
10.1093/jn/134.11.2979
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发表时间：
2004-11-01
影响因子：
4.2
通讯作者：
Davidson, NO
中科院分区：
文献类型：
--
作者：
Buhman, KK;Wang, LC;Davidson, NO
Hedgehog（Hh）信号传导在包括胃肠道在内的许多组织的胚胎发育中起重要作用。Sonic Hh和Indian Hh缺陷小鼠在出生前或出生后不久死亡，排除了对成熟肠道中这种信号通路的进一步研究。母体转移灭活单克隆抗体Hh蛋白（抗Hh单克隆抗体）在胚胎发育的后期阶段或出生后早期小鼠产生肠绒毛异常，进行性侏儒，和严重的膳食脂肪吸收不良。在本研究中，我们试图确定抑制Hh信号传导对成年小鼠体重增加和脂质吸收的影响。抗Hh单克隆抗体给予成年Balb/c小鼠喂食低脂肪，非纯化的饮食或高脂肪，半纯化的饮食，和成年ob/ob小鼠喂食低脂肪，非纯化的饮食。在喂食高脂饮食的Balb/C小鼠中，抗Hh单克隆抗体治疗显著抑制了体重增加，但在ob/ob小鼠中没有。对喂食高脂饲料的成年Balb/c小鼠的进一步分析表明，尽管总脂质吸收正常，但抗Hh单抗处理的小鼠甘油三酯吸收速率显著延迟，并且它们的粪便FFA排泄显著增加。在用对照单克隆抗体处理的高脂肪喂养的Balb/c小鼠中发现的肝脂肪变性通过抗Hh单克隆抗体施用而消除。这些研究结果表明，在饮食诱导的脂质代谢异常的Hh信号通路的潜在作用。
Hedgehog (Hh) signaling plays an important role in embryonic development of many tissues, including the gastrointestinal tract. Sonic Hh-and Indian Hh-deficient mice die before or soon after birth, precluding further study of this signaling pathway in the mature intestine. Maternal transfer of inactivating monoclonal antibodies to Hh proteins (anti-Hh moAb) during late stages of embryogenesis or to early postnatal mice produced intestinal villous abnormalities, progressive runting, and severe malabsorption of dietary fat. In the present study, we sought to determine the effect of inhibiting Hh signaling on weight gain and lipid absorption in adult mice. Anti-Hh moAb was administered to adult Balb/c mice fed either a low-fat, nonpurified diet or a high-fat, semipurified diet, and to adult ob/ob mice fed the low-fat, nonpurified diet. Weight gain was significantly inhibited by anti-Hh moAb treatment in Balb/C mice fed the high-fat, but not the low-fat diet and in ob/ob mice. Further analysis of adult Balb/c mice fed the high-fat diet demonstrated that although total lipid absorption was normal, the rate of triglyceride absorption was significantly delayed in mice treated with anti-Hh moAb and they had significantly increased fecal FFA excretion. Hepatic steatosis, found in high-fat fed Balb/c mice treated with the control moAb, was abrogated by anti-Hh moAb administration. These findings point to a potential role for Hh signaling pathways in diet-induced abnormalities of lipid metabolism.