ABSTRACT
Physiology, 725 North Wolfe Street Baltimore, MD 21205, USA 2Center for Metabolism and Obesity Research, Johns Hopkins University School
of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA
Tumor necrosis factor alpha (TNF-α), a multifunctional cytokine and adipokine, exerts pleiotropic eff ects on many cell types and tissues. As an adipokine, this protein negatively regulates many aspects of glucose and lipid metabolism. Downstream targets of TNF-α down-regulate genes involved in the uptake and storage of free fatty acids and glucose in adipocytes. Additionally, TNF-α promotes insulin resistance by inducing serine phosphorylation of insulin receptor substrate 1 (IRS-1) and reducing the expression of IRS-1 mRNA, attenuating downstream insulin signaling. Reduction in insulin signaling results in decreased insulinstimulated GLUT4 translocation to the plasma membrane, reducing glucose uptake into muscle and adipocytes. TNF-α also decreases the uptake of fatty acids into adipocytes while promoting lipolysis, thus contributing to dyslipidemia and exacerbating tissue insulin resistance. Th e increased levels of TNF-α found in obesity promote infl ammation within the adipose compartment, which dysregulates the expression of adipokines (e.g., adiponectin) that promote insulin sensitivity. Collectively, TNF-α exerts a negative impact on whole-body insulin sensitivity and metabolism. Despite its importance, the therapeutic effi cacy of blocking TNF-α is currently disputed. Understanding the many mechanisms of action of TNF-α will likely provide new avenues in treating metabolic disorders associated with diabetes and obesity.
