Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice.
Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice.
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DOI：
10.1038/s41598-017-18388-6
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发表时间：
2018-01-08
影响因子：
4.6
通讯作者：
Ashford MLJ
中科院分区：
文献类型：
--
作者：
Meakin PJ;Jalicy SM;Montagut G;Allsop DJP;Cavellini DL;Irvine SW;McGinley C;Liddell MK;McNeilly AD;Parmionova K;Liu YR;Bailey CLS;Dale JK;Heisler LK;McCrimmon RJ;Ashford MLJ
肥胖给社会带来巨大的医疗和经济负担。主要的驱动力似乎是中枢瘦素抵抗与高瘦素血症。因此，逆转或预防瘦素抗性的化合物应促进体重正常化并改善葡萄糖稳态。蛋白酶Bace 1驱动β淀粉样蛋白（Aβ）的产生，肥胖会提高下丘脑Bace 1的活性和Aβ1-42的产生。在饮食诱导的肥胖（DIO）小鼠中，Bace 1的药理学抑制降低体重，改善葡萄糖稳态并降低血浆瘦素。这些作用在ob/ob或db/db小鼠中不明显，表明需要功能性瘦素信号传导。降低Bace 1活性使肥胖小鼠下丘脑炎症正常化，降低PTP 1B和SOCS 3，恢复下丘脑瘦素敏感性和pSTAT 3反应，但不影响瘦小鼠的瘦素敏感性。在DIO早期升高中枢Aβ1-42水平可增加下丘脑基底pSTAT 3并降低瘦素pSTAT 3信号的幅度，而不增加炎症。因此，升高的Aβ1-42促进下丘脑瘦素抵抗，这与全身对外源性瘦素的敏感性降低和高脂喂养小鼠体重增加加剧有关。这些结果表明，Bace 1抑制剂，目前在阿尔茨海默病的临床试验，可能是有用的药物用于治疗肥胖症和相关的糖尿病。
Obesity places an enormous medical and economic burden on society. The principal driver appears to be central leptin resistance with hyperleptinemia. Accordingly, a compound that reverses or prevents leptin resistance should promote weight normalisation and improve glucose homeostasis. The protease Bace1 drives beta amyloid (Aβ) production with obesity elevating hypothalamic Bace1 activity and Aβ1–42 production. Pharmacological inhibition of Bace1 reduces body weight, improves glucose homeostasis and lowers plasma leptin in diet-induced obese (DIO) mice. These actions are not apparent in ob/ob or db/db mice, indicating the requirement for functional leptin signalling. Decreasing Bace1 activity normalises hypothalamic inflammation, lowers PTP1B and SOCS3 and restores hypothalamic leptin sensitivity and pSTAT3 response in obese mice, but does not affect leptin sensitivity in lean mice. Raising central Aβ1–42 levels in the early stage of DIO increases hypothalamic basal pSTAT3 and reduces the amplitude of the leptin pSTAT3 signal without increased inflammation. Thus, elevated Aβ1–42 promotes hypothalamic leptin resistance, which is associated with diminished whole-body sensitivity to exogenous leptin and exacerbated body weight gain in high fat fed mice. These results indicate that Bace1 inhibitors, currently in clinical trials for Alzheimer’s disease, may be useful agents for the treatment of obesity and associated diabetes.
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DOI：
10.1042/bj20110512
发表时间：
2012-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Meakin PJ;Harper AJ;Hamilton DL;Gallagher J;McNeilly AD;Burgess LA;Vaanholt LM;Bannon KA;Latcham J;Hussain I;Speakman JR;Howlett DR;Ashford ML
通讯作者：
Ashford ML
影响因子：
15.1
作者：
Chami L;Checler F
通讯作者：
Checler F
DOI：
10.18632/aging.100431
发表时间：
2012-02
期刊：
Aging
影响因子：
--
作者：
Cai D;Liu T
通讯作者：
Liu T
影响因子：
8.2
作者：
Plucińska K;Dekeryte R;Koss D;Shearer K;Mody N;Whitfield PD;Doherty MK;Mingarelli M;Welch A;Riedel G;Delibegovic M;Platt B
通讯作者：
Platt B
影响因子：
3.2
作者：
Briggs, D. I.;Lemus, M. B.;Andrews, Z. B.
通讯作者：
Andrews, Z. B.