Gal3 links inflammation and insulin resistance

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Gal3 links inflammation and insulin resistance

SIWICKI, Marie, ENGBLOM, Camilla, PITTET, Mikaël

Abstract

The connection between obesity-induced insulin resistance and inflammation is established, but targeting inflammatory mediators like TNF-α and IL-1β have had limited success improving insulin sensitivity in patients. Now, Li et al. (2016) indicate that galectin-3 could be a targetable link between inflammation and insulin sensitivity.

SIWICKI, Marie, ENGBLOM, Camilla, PITTET, Mikaël. Gal3 links inflammation and insulin resistance. Cell Metabolism , 2016, vol. 24, no. 5, p. 655-656

DOI : 10.1016/j.cmet.2016.10.014 PMID : 27829136

Available at:

http://archive-ouverte.unige.ch/unige:154061

Disclaimer: layout of this document may differ from the published version.

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Gal3 Links Inflammation and Insulin Resistance

Marie Siwicki,^1,2Camilla Engblom,^1,2and Mikael J. Pittet^1,*

1Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA

2Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA

*Correspondence:mpittet@mgh.harvard.edu http://dx.doi.org/10.1016/j.cmet.2016.10.014

The connection between obesity-induced insulin resistance and inflammation is established, but targeting inflammatory mediators like TNF-a and IL-1b have had limited success improving insulin sensitivity in pa- tients. Now,

Li et al. (2016)

indicate that galectin-3 could be a targetable link between inflammation and insulin sensitivity.

Obesity induces inflammatory reactions that can have multiple pathologic con- sequences, one of the most debilitating being insulin resistance. A canonically important aspect of inflammation in obese metabolic tissues, including adipose tissue, liver, and muscle, is the expansion of macrophages with polarized pro-inflammatory phenotypes. This macrophage accumulation can be fueled by local cell proliferation and an influx of circulating monocytes that subsequently polarize to pathological macrophage phenotypes (Lackey and Olefsky, 2016).

While obesity-induced inflammation is complex and involves many different cell types (Mathis, 2013), macrophages are considered to be key promoters of insulin resistance through various mechanisms.

Pro-inflammatory mediators produced by macrophages in obese metabolic tissue include chemokine (C-C motif) ligand 2 (CCL2) and leukotriene B4 (LTB4), which are chemoattractants and drive a feedforward loop of monocyte recruitment and inflammatory macrophage enrichment.

The cytokines tumor necrosis factor- alpha (TNF-a) and interleukin-1 beta (IL- 1b) are additional macrophage-derived pro-inflammatory mediators, which have direct effects on insulin sensitivity (Lackey and Olefsky, 2016). Previous preclinical work inhibiting these macrophage-ex- pressed factors has established their critical roles in insulin resistance in mice;

however, to date, none of these approaches have been broadly successful in a clinical setting. Thus, there is a need to define new druggable targets to control insulin resistance. Li et al. (2016) now report in Cell that the lectin Galectin-3 (Gal3) is a macrophage-derived instigator of insulin resistance and impaired glucose tolerance, which are two phenotypes

associated with obesity-induced type 2 diabetes. Their findings highlight Gal3 as a candidate new therapeutic target to restore insulin sensitivity (Figure 1).

Gal3 has previously been defined as a secreted chemotactic factor for monocytes and as a modulator of intracellular processes like cell survival and proliferation (Rabinovich et al., 2002; Sano et al., 2000). The lectin is also implicated in dis- eases such as autoimmunity and heart failure (Sharma et al., 2004), and while it has received attention in obesity-related metabolic dysfunction, previous studies have been without consensus. For example, different approaches in Gal3 knockout mice have indicated contradic- tory phenotypes regarding weight gain and metabolic function, and mechanisms by which Gal3 may be acting remain undefined.

In this study, Li et al. (2016)address major gaps in understanding Gal3 biology during obesity-related disease, clearly defining a metabolic phenotype and deciphering multiple mechanisms by which Gal3 drives pathology. The authors demonstrate that Gal3 impairs glucose tolerance and increases insulin resistance through Gal3 loss- and gain- of-function experiments. Gal3 knockout mice exposed to high fat diet exhibited reduced insulin resistance, and accord- ingly, supplementing healthy mice with Gal3 recapitulated metabolic defects typical of mice on a high fat diet.

Importantly, a Gal3 inhibitor compound (Cpd47) limited metabolic dysfunction in obese mice.Li et al. (2016) further provide new mechanistic insight into these processes. First, they show that Gal3 op- erates in a canonical fashion as a recruitment factor for monocytes homing to the adipose and liver tissue. Second, they

provide evidence that Gal3 binds directly to the insulin receptor in metabolic tissues, and while not competing with insulin for binding, it impedes down- stream signaling. These findings are both biologically and therapeutically important—they add to the picture of aberrant processes at play in insulin resistance and specifically endow Gal3 with a novel function directly promoting insulin insensitivity.

Li et al. (2016)report several supporting lines of evidence that macrophages are the major drivers of Gal3-mediated insulin resistance. For example, clodronate treatment, which depletes macrophages and monocytes, lowered circulating Gal3 levels in obese mice. Additionally, recon- stitution of wild-type mice with Gal3-defi- cient bone marrow significantly limited obesity-triggered insulin resistance. While these experiments, in conjunction with previous work by the same authors (Li et al., 2010), certainly support the monocyte/macrophage lineage as a mediator of Gal3 biology, they do not yet establish whether adipose tissue macrophages are the major players. Future studies involving conditional deletion of Gal3 in macrophages (and other cell types) would serve to mechanistically pinpoint the cellular source(s) of Gal3-mediated insulin resistance.

By showing that Gal3 mediates monocyte recruitment to adipose and liver tissue, Li et al. (2016) identify Gal3 as central to macrophage seeding of the metabolic tissue—a critical step in the etiology of obesity-associated inflammation and insulin resistance (Lackey and Olefsky, 2016). These findings thus sug- gest that macrophage-produced Gal3 acts as a lynchpin in a feedforward loop fostering pathological inflammation in Cell Metabolism24, November 8, 2016ª2016 Elsevier Inc. 655

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the metabolic tissue. This makes Gal3 a compelling target for therapy, since inter- fering at this juncture could potentially halt runaway inflammation and directly restore insulin signaling.

Current treatment options for insulin- resistance and type 2 diabetes are imper- fect. Many focus on management of blood glucose levels or lifestyle changes, and few target causal factors that render important metabolic tissues insensitive to insulin (Inzucchi et al., 2015). There is thus a critical need for new therapies to stem obesity-induced processes leading to insulin dysfunction. Informing whether Gal3 is indeed a viable therapeutic target

for insulin resistance will require broad- scale, comprehensive clinical studies.

Interestingly, there is clinical evidence for Gal3 upregulation in obese patients (Weigert et al., 2010), supporting the idea that the Gal3 pathway is at play in hu- man disease. While Gal3’s therapeutic potential is enticing, caution must be exercised due to its broad activity as a cell cycle and survival factor and chemo- attractant, especially if used as a long- term treatment option for a chronic condi- tion. Another approach may be to target macrophage biology, potentially side- lining Gal3 along with multiple other inflammatory mechanisms of insulin resis-

tance—although macrophage targeting comes with its unique set of challenges and side effects. Successful approaches may also involve targeting upstream mechanisms by which pathological levels of Gal3 are induced during obesity, but these processes remain to be elucidated.

Despite caveats inherent in clinical imple- mentation, the present study possesses great value, not only in identifying a promising clinical target, but also in teasing out the complex relationship between obesity-related inflammation and insulin resistance.

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Figure 1. Galectin-3 Produced by Inflammatory Cells Perpetuates Obesity-Induced Insulin- Resistance

Li et al. (2016)present a model wherein inflammatory cells—likely macrophages—in obese tissue express Gal3, which (1) perpetuates inflammatory cell seeding of the adipose tissue from circulation, and (2) directly inhibits signaling via the insulin receptor.

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