Editors' ChoiceMetabolism

Inhibiting the insulin receptor with galectin3

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Science Signaling  15 Nov 2016:
Vol. 9, Issue 454, pp. ec270
DOI: 10.1126/scisignal.aal3896

Obesity is associated with adipose tissue accumulation of macrophages, which release proinflammatory cytokines, and the development of insulin resistance. However, clinical studies have found that inhibition of these proinflammatory cytokines does not ameliorate insulin resistance. Li et al. (see also Siwicki et al.) found that insulin resistance in obesity was mediated by galectin-3 (Gal3), a lectin that is released from macrophages and that has been implicated in inflammatory diseases. Compared with lean humans, obese humans had more circulating Gal3. Circulating Gal3 was also increased in mice by high-fat diet, an effect that was attenuated in the mice when the mice were depleted of macrophages. Compared with wild-type mice fed a high-fat diet, various metabolic parameters were better in Gal3 knockout mice, such as glucose tolerance and insulin sensitivity. Furthermore, the adipose tissue of Gal3 knockout mice accumulated fewer proinflammatory macrophages in response to a high-fat diet than did that of wild-type mice. Administration of exogenous Gal3 or adenoviral overexpression of Gal3 induced insulin resistance in lean mice on a normal chow diet. Through its receptor, insulin inhibits hepatic glucose output and facilitates glucose uptake in various tissues, in particular skeletal muscle, by promoting the trafficking of the glucose transporter GLUT4 to the cell surface. Application of Gal3 impaired insulin-stimulated glucose uptake in L6 myocytes, 3T3-L1 adipocytes, and primary hepatocytes. Gal3 also stimulated glucose output and prevented insulin from inhibiting glucose output in primary hepatocytes and blocked insulin receptor-mediated signaling and the cell surface trafficking of GLUT4 in L6 myocytes and 3T3-L1 adipocytes. Chimeric wild-type mice that received bone marrow from Gal3 knockout mice had better metabolic parameters than those that received bone marrow from wild-type mice. Gal3 bound directly to the insulin receptor to a site that was distinct from the insulin-binding site. Administration of compound 47, which prevents Gal3 from binding to carbohydrate structures like those found on the insulin receptor, improved glucose tolerance in mice that were obese from a high-fat diet. These results suggest that macrophages provoke insulin resistance in obesity through the release of Gal3, which blocks signaling through the insulin receptor.

P. Li, S. Liu, M. Lu, G. Bandyopadhyay, D. Oh, T. Imamura, A. M. F. Johnson, D. Sears, Z. Shen, B. Cui, L. Kong, S. Hou, X. Liang, S. Iovino, S. M. Watkins, W. Ying, O. Osborn, J. Wollam, M. Brenner, J. M. Olefsky, Hematopoietic-derived galectin-3 causes cellular and systemic insulin resistance. Cell 167, 973–984 (2016). [PubMed]

M. Siwicki, C. Engblom, M. J. Pittet, Gal3 links inflammation and insulin resistance. Cell Metab. 24, 655–656 (2016). [PubMed]

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