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Diabetes: Macrophage lectin fuels inflammation

Mice deficient in the C-type lectin MGL1 are protected from obesity-associated inflammation. Image courtesy of Mary O'Reilly.

The metabolic and immune systems are closely linked. Cellular stress caused by obesity triggers inflammation that can result in a range of health problems, including diabetes. Inflammation in fat – or adipose – tissue is regulated by two types of adipose tissue macrophages (ATMs). Type 1 ATMs release pro-inflammatory cytokines, whereas type 2 ATMs express anti-inflammatory cytokines and a C-type lectin called MGL1. In The Journal of Experimental Medicine, Carey Lumeng and colleagues report their use of mice lacking MGL1, obtained from the Consortium for Functional Glycomics, to explore the role of the macrophage lectin in obesity-induced inflammation.

MGL1 is highly expressed by anti-inflammatory type 2 ATMs, and the authors hypothesized that loss of the lectin would increase inflammation by tipping the balance toward pro-inflammatory signals from type 1 ATMs. To investigate this possibility, they induced obesity in MGL1 knockout mice by feeding them a high-fat diet. To the authors' surprise, the obese MGL1-deficient mice accumulated fewer type 1 ATMs and had lower inflammatory cytokine levels than obese wildtype mice. Furthermore, lack of MGL1 also protected mice from insulin resistance, an early step in the development of diabetes, despite the fact that they had more abdominal fat.

MGL1 knockout mice fed a diet high in fat gained slightly less weight overall, but the difference was not great enough to account for the considerable reduction in inflammation and insulin resistance. Instead, the improved health of obese MGL1-deficient mice was attributed to reduced numbers of circulating inflammatory macrophage precursors and impaired adhesion of these precursors to fat cells. The expression of carbohydrates containing Lewis X (Le^x) structures, the preferred ligand of MGL1, was also upregulated in the adipose tissue of obese mice on a high-fat diet. Thus, these results suggest that in response to diet-induced obesity, MGL1 recruits or retains pro-inflammatory macrophages in adipose tissue.

This study is the first to describe a regulatory role for MGL1 in the inflammatory response to obesity. Moreover, the unexpected findings that the alteration of fat distribution and inflammatory cell circulation can affect sensitivity to insulin may have important implications for the development of therapies that target diabetes and other obesity-related conditions.

Author: Heather Buschman