Editors' ChoiceObesity

Sweet signals and diabetes: Carbohydrate-binding proteins contribute to insulin resistance

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Science Translational Medicine  23 Nov 2016:
Vol. 8, Issue 366, pp. 366ec188
DOI: 10.1126/scitranslmed.aal2796

Obesity is a significant risk factor for insulin resistance in metabolic syndrome and diabetes. The chronic inflammation found in peripheral tissues with obesity is thought to contribute to insulin resistance, partly through the actions of proinflammatory cytokines. However, recent work from Li et al. suggests that microglia and macrophage-derived galectin-3 (Gal3), a carbohydrate-binding protein that mediates macrophage interactions with the extracellular matrix, may also play a role in obesity-associated insulin resistance.

In previous studies, the authors observed elevated macrophage Gal3 expression in mice fed high-fat chow, which fell when mice returned to a normal diet. Now, the researchers examined the effects of modulating Gal3 levels on insulin resistance. Both heterozygous and homozygous Gal3 knockout (KO) mice were protected from high-fat diet–induced insulin resistance in liver, muscle, and adipose tissue, as well as from age-related insulin resistance seen in a normal diet. Gal3 induced macrophage chemotaxis in vitro and Gal3 KO mice showed reduced adipose tissue macrophage numbers and proinflammatory gene expression. Circulating Gal3 levels were increased in mice on a high-fat diet and in obese humans. Gal3 blocked insulin action in myocytes and adipocytes in vitro, and Gal3 administration to wild-type mice decreased insulin sensitivity leading to glucose intolerance. In clonal adipocytes and myocytes, Gal3 appears to blunt insulin responses at all major points in the signaling pathway through interaction with the insulin receptor but without altering insulin binding to its receptor. Last, the researchers assessed the effects of decreasing Gal3 activity by transplanting bone marrow from Gal3 KO mice into wild-type mice and pharmacological blockade using Gal3 inhibitor. Both decreased Gal3 levels, and Gal3 blockade increased insulin sensitivity and improved glucose tolerance in mice on a high-fat diet.

These studies suggest that macrophage-derived Gal3 may contribute to insulin resistance seen in obesity in mice. Circulating Gal3 levels are elevated in obese individuals and if Gal3, or other lectins, play a similar role in man, inhibiting their actions may provide a therapy to increase insulin sensitivity in diabetes and metabolic syndrome.

P. Li et al., Hematopoietic-derived Galectin-3 causes cellular and systemic insulin resistance. Cell 167, 973–984 (2016). [Abstract]

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