Galectin3 Causes Cellular and Systemic Insulin Resistance

Abstract: In obesity， macrophages and other immune cells accumulate in insulin target tissues， promoting a chronic inflammatory state. Chronic tissue inflammation leads to increased levels of proinflammatory cytokines，such as TNFα and IL1β， which impair insulin signaling and induce insulin resistance. However， therapeutic efforts focusing on inhibition of either TNFα or IL1β to ameliorate inflammation-induced insulin resistance have had limited success in clinical studies. Our previous studies found that， after switching the diet in obese mice from a high fat diet (HFD) to normal chow (NC)， adipose tissue CD11c+ macrophages express much lower levels of Galectin3 (Gal3) compared to HFD fed mice. At the same time， there was amelioration of inflammation and insulin resistance in these diet-switched mice， despite retaining the same number of CD11c+ macrophages in adipose tissue. Therefore， we hypothesize that Gal3 can promote insulin resistance， providing a link between inflammation and insuin resistance.Gal3， a lectin mainly secreted by macrophages， is elevated in both obese subjects and mice. Administration of Gal3 to mice causes celluar and systemic insulin resistance. whereas inhibition of Gal3， through either genetic or pharmacologic loss of function， improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis， reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly， we found that Gal3 could bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in insulin target cells， suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance and diabetes.

CSTR: 32200.14.cjcb.2017.05.0001