Tumor necrosis factor-α (TNF-α) is a contributing cause of the insulin resistance seen in obesity and obesity-linked type 2 diabetes, but the mechanism(s) by which TNF-α induces insulin resistance is not understood. By using 3T3-L1 adipocytes and oligonucleotide microarrays, we identified 142 known genes reproducibly upregulated by at least threefold after 4 h and/or 24 h of TNF-α treatment, and 78 known genes downregulated by at least twofold after 24 h of TNF-α incubation. TNF-α-induced genes include transcription factors implicated in preadipocyte gene expression or NF-κB activation, cytokines and cytokine-induced proteins, growth factors, enzymes, and signaling molecules. Importantly, a number of adipocyte-abundant genes, including GLUT4, hormone sensitive lipase, long-chain fatty acyl-CoA synthase, adipocyte complement-related protein of 30 kDa, and transcription factors CCAAT/enhancer binding protein-α, receptor retinoid X receptor-α, and peroxisome profilerator-activated receptor γ were significantly downregulated by TNF-α treatment. Correspondingly, 24-h exposure of 3T3-L1 adipocytes to TNF-α resulted in reduced protein levels of GLUT4 and several insulin signaling proteins, including the insulin receptor, insulin receptor substrate 1 (IRS-1), and protein kinase B (AKT). Nuclear factor-κB (NF-κB) was activated within 15 min of TNF-α addition. 3T3-L1 adipocytes expressing IκBα-DN, a nondegradable NF-κB inhibitor, exhibited normal morphology, global gene expression, and insulin responses. However, absence of NF-κB activation abolished suppression of >98% of the genes normally suppressed by TNF-α and induction of 60–70% of the genes normally induced by TNF-α. Moreover, extensive cell death occurred in IκBα-DN-expressing adipocytes after 2 h of TNF-α treatment. Thus the changes in adipocyte gene expression induced by TNF-α could lead to insulin resistance. Further, NF-κB is an obligatory mediator of most of these TNF-α responses.

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Obesity-linked type 2 diabetes is one of the paramount causes of morbidity and mortality worldwide, posing a major threat on human health, productivity, and quality of life. Despite great progress made towards a better understanding of the molecular basis of diabetes, the available clinical counter-measures against insulin resistance, a defect that is central to obesity-linked type 2 diabetes, remain inadequate. Adiponectin, an abundant adipocyte-secreted factor with a wide-range of biological activities, improves insulin sensitivity in major insulin target tissues, modulates inflammatory responses, and plays a crucial role in the regulation of energy metabolism. However, adiponectin as a promising therapeutic approach has not been thoroughly explored in the context of pharmacological intervention, and extensive efforts are being devoted to gain mechanistic understanding of adiponectin signaling and its regulation, and reveal therapeutic targets. Here, we discuss tissue- and cell-specific functions of adiponectin, with an emphasis on the regulation of adiponectin signaling pathways, and the potential crosstalk between the adiponectin and other signaling pathways involved in metabolic regulation. Understanding better just why and how adiponectin and its downstream effector molecules work will be essential, together with empirical trials, to guide us to therapies that target the root cause(s) of type 2 diabetes and insulin resistance.

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