Metabolic Health Group, Rowett Institute of Nutrition and Health, University of Aberdeen, Greenburn Road, Bucksburn, Aberdeen AB21 9SB, UK.
Proc Nutr Soc. 2012 Nov;71(4):521-33. doi: 10.1017/S002966511200078X. Epub 2012 Sep 6.
A growing number of studies have shown that a diet high in long chain SFA and/or obesity cause profound changes to the energy balance centres of the hypothalamus which results in the loss of central leptin and insulin sensitivity. Insensitivity to these important anorexigenic messengers of nutritional status perpetuates the development of both obesity and peripheral insulin insensitivity. A high-fat diet induces changes in the hypothalamus that include an increase in markers of oxidative stress, inflammation, endoplasmic reticulum (ER) stress, autophagy defect and changes in the rate of apoptosis and neuronal regeneration. In addition, a number of mechanisms have recently come to light that are important in the hypothalamic control of energy balance, which could play a role in perpetuating the effect of a high-fat diet on hypothalamic dysfunction. These include: reactive oxygen species as an important second messenger, lipid metabolism, autophagy and neuronal and synaptic plasticity. The importance of nutritional activation of the Toll-like receptor 4 and the inhibitor of NF-κB kinase subunit β/NK-κB and c-Jun amino-terminal kinase 1 inflammatory pathways in linking a high-fat diet to obesity and insulin insensitivity via the hypothalamus is now widely recognised. All of the hypothalamic changes induced by a high-fat diet appear to be causally linked and inhibitors of inflammation, ER stress and autophagy defect can prevent or reverse the development of obesity pointing to potential drug targets in the prevention of obesity and metabolic dysfunction.
越来越多的研究表明，长链 SFA 含量高的饮食和/或肥胖会导致下丘脑能量平衡中心发生深刻变化，从而导致中枢瘦素和胰岛素敏感性丧失。对这些重要的营养状态厌食性信使的不敏感会促使肥胖和外周胰岛素敏感性丧失的发展。高脂肪饮食会引起下丘脑的变化，包括氧化应激、炎症、内质网 (ER) 应激、自噬缺陷以及细胞凋亡和神经元再生速度的变化的标志物增加。此外，最近发现了一些在能量平衡的下丘脑控制中很重要的机制，这些机制可能在维持高脂肪饮食对下丘脑功能障碍的影响方面发挥作用。这些包括：作为重要第二信使的活性氧、脂质代谢、自噬以及神经元和突触可塑性。营养激活 Toll 样受体 4 和 NF-κB 激酶亚单位β/NK-κB 和 c-Jun 氨基末端激酶 1 炎症途径在将高脂肪饮食与肥胖和胰岛素不敏感通过下丘脑联系起来的重要性现在得到了广泛的认可。高脂肪饮食引起的所有下丘脑变化似乎都有因果关系，炎症、ER 应激和自噬缺陷的抑制剂可以预防或逆转肥胖的发展，这为预防肥胖和代谢功能障碍提供了潜在的药物靶点。
