**2. Insulin action and downstream molecules**

Insulin is the major regulator of metabolism which is secreted from pancreatic beta cells, and it promotes anabolism and suppresses catabolism in the targeted tissues including the liver [2–5].

In the early 1980s, tyrosine kinase activity of insulin receptor was first reported [6], and the whole cascade of the signaling has been uncovered in the past 40 years. In brief, in the presence of insulin, IR (insulin receptor) phosphorylates IRSs (insulin receptor substrates). Among the isoforms of IRSs, IRS-1 and IRS-2 are the major ones, and they activate two main signaling pathways: the PI3K (phosphatidylinositol 3-kinase)-Akt/ PKB (protein kinase B) pathway and the Ras–MAPK (mitogen-activated protein kinase) pathway. The former is mainly responsible for metabolic actions of insulin, and the latter mainly regulates cell growth and differentiation [5] (**Figure 1**).

In obesity and diabetes, however, the insulin signaling cascade is impaired by various mechanisms despite normal or high concentrations of insulin, which is called insulin resistance. It is generally thought that serine/threonine kinases, such as PKC (protein kinase C), JNK (c-jun N-terminal kinases), IKKβ (inhibitor of nuclear factor kappa-B kinase subunit β), and PP2A (protein phosphatase 2A), are activated in obesity via lipotoxicity, inflammation, hyperglycemia, mitochondrial dysfunction and subsequent oxidative stress, and ER stress, which is reviewed in the following subsection. Serine/threonine kinases thus activated in

**Figure 1.** *Insulin signaling pathways (adapted from [7]).*

turn causes inhibitory phosphorylation of insulin receptor, IRSs, and Akt [8, 9]. Hyperinsulinemia also down-regulates expression of IRS-2 via suppression of a transcription factor, FoxO1 (forkhead box protein O1), in the liver, contributing to the induction of insulin resistance [10, 11].
