Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha.
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.
Ruan
Hong
H
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Room 601, Cambridge, MA 02142, USA.
Lodish
Harvey F
HF
D052242:Adiponectin; D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D052242:Adiponectin; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha