Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance

• Published in: Cell Vol. 167; no. 4; pp. 973 - 984.e12
• Main Authors: Li, Pingping, Liu, Shuainan, Lu, Min, Bandyopadhyay, Gautum, Oh, Dayoung, Imamura, Takeshi, Johnson, Andrew M.F., Sears, Dorothy, Shen, Zhufang, Cui, Bing, Kong, Lijuan, Hou, Shaocong, Liang, Xiao, Iovino, Salvatore, Watkins, Steven M., Ying, Wei, Osborn, Olivia, Wollam, Joshua, Brenner, Martin, Olefsky, Jerrold M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.11.2016
• Subjects: adipocytes; Adipocytes - metabolism; Adipocytes - pathology; animal disease models; Animals; Chemotaxis; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Galectin 3 - antagonists & inhibitors; Galectin 3 - blood; Galectin 3 - genetics; Galectin 3 - metabolism; galectin-3; glucose; hepatocytes; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; inflammation; insulin; Insulin - blood; insulin receptors; Insulin Resistance; lectins; macrophages; Macrophages - immunology; Macrophages - pathology; Mice; Mice, Knockout; Muscle Cells - metabolism; Muscle Cells - pathology; myocytes; obesity; Obesity - immunology; Obesity - metabolism; Obesity - pathology; tissues; inflammation; galectin-3; insulin resistance
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2016.10.025

In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, 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 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance. [Display omitted] •Galectin-3 blood levels are elevated in human and rodent obesity•Galectin-3 directly impairs insulin action in myocytes, adipocytes, and hepatocytes•Galectin-3 treatment causes systemic insulin resistance in vivo•Galectin-3 loss of function improves insulin sensitivity in obesity A circulating lectin secreted by macrophages in obese individuals drives insulin resistance and glucose intolerance by directly binding the insulin receptor and antagonizing downstream metabolic responses.