title: From excess adiposity to insulin resistance: the role of free fatty acids.
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.
authors.affiliation: University of Foggia, Department of Internal Medicine and Geriatrics, Foggia, Italy. a.capurso@alice.it
authors.forename: Cristiano
authors.initials: C
authors.lastname: Capurso
authors.forename: Antonio
authors.initials: A
authors.lastname: Capurso
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism; D008066:Lipolysis; D009765:Obesity / Q000150:complications; D011972:Receptor, Insulin / Q000378:metabolism
chemical_list: D005230:Fatty Acids, Nonesterified; D011972:Receptor, Insulin