Insulin resistance is a fundamental defect that precedes the development of the full insulin resistance syndrome as well as beta cell failure and type 2 diabetes. Tumor necrosis factor-alpha (TNF-alpha), a paracrine/autocrine factor highly expressed in adipose tissues of obese animals and human subjects, is implicated in the induction of insulin resistance seen in obesity and type 2 diabetes. Here, we review several molecular aspects of adipose tissue physiology, and highlight the direct effects of TNF-alpha on the functions of adipose tissue including induction of lipolysis, inhibition of insulin signaling, and alterations in expression of adipocyte important genes through activation of NF-kappaB, as well as their pertinence to insulin sensitivity of adipocytes. We also review the ability of TNF-alpha to inhibit synthesis of several adipocyte-specific proteins including Acrp30 (adiponectin) and enhance release of free fatty acids (FFAs) from adipose tissue, and discuss how these factors may act as systemic mediators of TNF-alpha and affect whole body energy homeostasis and overall insulin sensitivity. On the basis of these mechanisms, we examine the therapeutic potential of blocking specific autocrine/paracrine signaling pathways in adipocytes, particularly those involving NF-kappaB, in the treatment of type 2 diabetes.

中文翻译：

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脂肪组织中的胰岛素抵抗：肿瘤坏死因子-α的直接和间接作用。

胰岛素抵抗是在完全胰岛素抵抗综合征以及β细胞衰竭和2型糖尿病发生之前的根本缺陷。肿瘤坏死因子-α（TNF-alpha）是一种在肥胖动物和人类受试者的脂肪组织中高度表达的旁分泌/自分泌因子，与肥胖症和2型糖尿病中胰岛素抵抗的诱导有关。在这里，我们回顾了脂肪组织生理学的几个分子方面，并重点介绍了TNF-α对脂肪组织功能的直接影响，包括诱导脂解作用，抑制胰岛素信号传导以及通过激活NF-κB改变脂肪细胞重要基因的表达。 kappaB以及它们与脂肪细胞胰岛素敏感性的相关性。我们还综述了TNF-α抑制包括Acrp30（脂联素）在内的几种脂肪细胞特异性蛋白质的合成并增强脂肪组织中游离脂肪酸（FFA）释放的能力，并讨论了这些因素如何充当TNF-α的系统性介质。并影响全身能量稳态和整体胰岛素敏感性。基于这些机制，我们研究了在2型糖尿病的治疗中，阻断脂肪细胞中特定自分泌/旁分泌信号通路的治疗潜力，特别是涉及NF-κB的那些。