From excess adiposity to insulin resistance: the role of free fatty acids

Vascul Pharmacol. Sep-Oct 2012;57(2-4):91-7. doi: 10.1016/j.vph.2012.05.003. Epub 2012 May 15.

Abstract

With a positive caloric balance, adipocytes undergo excessive hypertrophy, which causes adipocyte dysfunction, as well as adipose tissue endocrine and immune responses. A preferential site of fat accumulation is the abdominal-perivisceral region, due to peculiar factors of the adipose tissue in such sites, namely an excess of glucocorticoid activity, which promotes the accumulation of fat; and the greater metabolic activity and sensitivity to lipolysis, due to increased number and activity of β3-adrenoceptors and, partly, to reduced activity of α2-adrenoceptors. As a consequence, more free fatty acids (FFA) are released into the portal system. Hypertrophic adipocytes begin to secrete low levels of TNF-α, which stimulate preadipocytes and endothelial cells to produce MCP-1, in turn responsible for attracting macrophages to the adipose tissue, thus developing a state of chronic low-grade inflammation which is causally linked to insulin resistance. Excess of circulating FFA, TNF-α and other factors induces insulin resistance. FFA cause insulin resistance by inhibiting insulin signaling through the activation of serin-kinases, i.e. protein kinase C-Θ, and the kinases JNK and IKK, which promote a mechanism of serine phosphorylation of Insulin Receptor Substrates (IRS), leading to interruption of the downstream insulin receptor (IR) signaling. TNF-α, secreted by hypertrophic adipocytes and adipose tissue macrophages, also inhibits IR signaling by a double mechanism of serine-phosphorylation and tyrosine-dephosphorylation of IRS-1, causing inactivation and degradation of IRS-1 and a consequent stop of IR signaling. Such mechanisms explain the transition from excess adiposity to insulin resistance, key to the further development of type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adipocytes / metabolism
  • Adipocytes / pathology
  • Adipose Tissue / metabolism
  • Adiposity*
  • Animals
  • Diabetes Mellitus, Type 2 / physiopathology
  • Fatty Acids, Nonesterified / metabolism*
  • Humans
  • Inflammation / physiopathology
  • Insulin Resistance*
  • Intra-Abdominal Fat / metabolism
  • Lipolysis
  • Obesity / complications
  • Receptor, Insulin / metabolism

Substances

  • Fatty Acids, Nonesterified
  • Receptor, Insulin