The problem with obesity is not just the weight of the added adipose cells; the metabolism of these cells becomes abnormal, and insulin signaling is reduced. In many individuals, this leads to development of type 2 diabetes. Much of the problem comes from macrophages and other immune-system cells that invade and populate obese adipose tissue, probably attracted by the necrotic adipose cells that accumulate and the greasy lipid droplets they release. These macrophages secrete several so-called inflammatory hormones that profoundly affect the metabolism of the nearby adipose cells. Two of these hormones, TNFα and IL-1, bind to their respective receptors on adipose cells and induce activation of the transcription factor NF-κB (see Figure 16-35a). NF-κB, in turn, induces the expression of several proteins that interfere with insulin signaling, including SOCS proteins; as with cytokine receptors (see Figure 16-14b), SOCS proteins bind to phosphorylated tyrosines in the insulin receptor cytosolic domain, inhibit kinase activity, and lead to degradation of the insulin receptor and associated signaling proteins.
Additionally, NF-κB represses the expression of several essential components of the insulin-signaling pathway, including GLUT4 and PKB. NF-κB also induces the expression of inflammatory cytokines such as TNFα, which in turn act in an autocrine or paracrine manner on adipocytes and exacerbate the development of insulin resistance. Among the biochemical alterations in adipocyte metabolism induced by these “inflammatory” hormones is the hydrolysis of triglycerides into free fatty acids and glycerol; excess fatty acids are released into the blood, whence they can accumulate in and induce insulin resistance in liver and muscle. This in turn leads to an increase in blood glucose, and to overproduction of insulin by the β islet cells in an attempt to overcome the increasing insulin insensitivity in fat, muscle, and liver cells—all leading to what has become a major public health problem in all developed countries in the twenty-first century, the type 2 diabetes epidemic.