Downregulation of HIF complex in the hypothalamus exacerbates diet-induced obesity
Downregulation of HIF complex in the hypothalamus exacerbates diet-induced obesity
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DOI：
10.1016/j.bbi.2018.06.020
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发表时间：
2018-10-01
影响因子：
15.1
通讯作者：
Velloso, Lido A.
中科院分区：
文献类型：
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作者：
Gaspar, Joana M.;Mendes, Natalia Ferreira;Velloso, Lido A.
下丘脑缺氧诱导因子-1 （HIF-1）可以调节全身能量稳态以应对血糖的变化，这表明它可以作为全身能量储存的传感器。在这里，我们假设下丘脑HIF-1可能受到饮食诱导的肥胖（DIO）的影响。选用8周龄雄性C57Bl6小鼠，分别饲喂正常鼠粮和高脂鼠粮1、3、7、14和28 d。采用PCR和western blotting检测hif -1 α和hif -1 β的表达，荧光显微镜观察其在下丘脑的分布。采用立体定向注射shRNA慢病毒颗粒对下丘脑弓形核hif -1 β的抑制作用，将动物分为正常鼠粮和高脂鼠粮两组，为期14 d。利用生物信息学，我们发现在人类中，HIF-1转录本的水平与参与炎症、细胞凋亡调节、自噬和泛素/蛋白酶体系统的蛋白质的下丘脑转录本的水平直接相关；此外，在啮齿类动物中，下丘脑HIF-1的表达与能量消耗增加的表型直接相关。在小鼠中，DIO伴有HIF-1表达升高。通过注射shRNA抑制下丘脑HIF-1导致体重进一步增加，基础代谢率降低，下丘脑炎症增加和葡萄糖耐受不良。因此，下丘脑HIF-1在DIO期间增加，其抑制使肥胖相关的代谢表型恶化。因此，下丘脑HIF-1成为肥胖治疗干预的靶点。
Hypothalamic hypoxia-inducible factor-1 (HIF-1) can regulate whole-body energy homeostasis in response to changes in blood glucose, suggesting that it acts as a sensor for systemic energy stores. Here, we hypothesized that hypothalamic HIF-1 could be affected by diet-induced obesity (DIO).We used eight-week old, male C57Bl6 mice, fed normal chow diet or with high fat diet for 1, 3, 7, 14 and 28 days. The expression of HIF-1alpha and HIF-1beta was measured by PCR and western blotting and its hypothalamic distribution was evaluated by fluorescence microscopy. Inhibition of HIF-1beta in arcuate nucleus of hypothalamus was performed using stereotaxic injection of shRNA lentiviral particles and animals were grouped under normal chow diet or high fat diet for 14 days.Using bioinformatics, we show that in humans, the levels of HIF-1 transcripts are directly correlated with those of hypothalamic transcripts for proteins involved in inflammation, regulation of apoptosis, autophagy, and the ubiquitin/proteasome system; furthermore, in rodents, hypothalamic HIF-1 expression is directly correlated with the phenotype of increased energy expenditure. In mice, DIO was accompanied by increased HIF-1 expression. The inhibition of hypothalamic HIF-1 by injection of an shRNA resulted in a further increase in body mass, a decreased basal metabolic rate, increased hypothalamic inflammation, and glucose intolerance.Thus, hypothalamic HIF-1 is increased during DIO, and its inhibition worsens the obesity-associated metabolic phenotype. Thus, hypothalamic HIF-1 emerges as a target for therapeutic intervention against obesity.