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

Li, Pingping; Liu, Shuainan; Lü, Min; Bandyopadhyay, Gautum K.; Oh, Dayoung; Imamura, Teruhiko; Johnson, Andrew M.; Sears, Dorothy D.; 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.

doi:10.1016/j.cell.2016.10.025

Cited by 232 publications

(267 citation statements)

References 55 publications

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“…Likewise, galectin-3 is a lectin largely secreted by macrophages that promotes inflammation and may also directly cause insulin resistance in muscle, liver, and fat cells by interfering with insulin receptor signaling (35). Cytokines such as TNF-α that are locally secreted from M1 proinflammatory adipose tissue macrophages initiate NF-κB and JNK pathways.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory mechanisms linking obesity and metabolic disease

Saltiel¹,

Olefsky²

2017

Journal of Clinical Investigation

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1,398

1,032

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We are in the midst of a worldwide obesity epidemic. Over 1.9 billion people are now obese or overweight, including more than 50 million children under age 5, and the worldwide prevalence of obesity has doubled since 1980 (1). The complications of obesity are taking a major public health toll, which will only worsen in future years. Among the most devastating of these complications is type 2 diabetes (T2D). Most patients with T2D are obese or overweight, and there are numerous longitudinal studies linking obesity with insulin resistance, a frequent forerunner of diabetes.Over the past two decades, the search for a mechanism linking the pathogenesis of obesity with insulin resistance and diabetes has revealed a close relationship between nutrient excess and activation of the innate immune system in most organs pertinent to energy homeostasis (2-4). Numerous studies indicate that inflammation occurs as a consequence of obesity, and recent insights suggest that it may play a causative role in generating insulin resistance, defective insulin secretion, and disruption of other aspects of energy homeostasis. The nature of obesityinduced inflammation differs from other inflammatory paradigms in that it involves tonic activation of the innate immune system that impacts metabolic homeostasis, in some cases over a lifetime. Inflammation also leads to maladaptive responses such as fibrosis and necrosis that can cause significant tissue damage. Moreover, obesity-induced inflammation is unique in that it involves multiple organs, including adipose, pancreas, liver, skeletal muscle, heart, and brain. These features of obesity-induced inflammation present a challenge to understanding the underlying mechanisms and the manner by which they impact metabolic systems. In this issue of the JCI, a group of experts have provided reviews that dive deeply into the mechanisms by which obesity-induced inflammation influences metabolic homeostasis, surveying the modes and mechanisms of inflammation in different tissues and how they might contribute to disease. These Reviews also discuss how inflammation can lead to other aspects of metabolic syndrome, including hyperphagia, reduced energy expenditure, β cell dysfunction, and liver disease, and summarize the status of therapeutic interventions that target inflammation in the context of metabolic syndrome. Activation of the innate immune system in obesityMuch of what has been learned about the immune response to obesity has come from studies in adipose tissue, although it is clear that inflammation occurs in other organs as well. Adipose depots normally contain multiple immune cells that together surveil and maintain the integrity and hormonal sensitivity of adipocytes. In lean animals, these immune cells operate in an overall Th2 or type 2 state that coordinately controls tissue integrity and metabolism by controlling the activity of subsets of T lymphocytes. These cells release a cascade of cytokines that coordinately regulate other immune cells, including eosinophils, mast cells, and othe...

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Section: Discussionmentioning

confidence: 99%

Inflammatory mechanisms linking obesity and metabolic disease

Saltiel¹,

Olefsky²

2017

Journal of Clinical Investigation

Self Cite

1,398

1,032

View full text Add to dashboard Cite

show abstract

“…Recently, Galectin-3, a lectin produced by macrophages, was also demonstrated to promote adipose tissue inflammation and glucose intolerance. Furthermore, both genetic deletion and pharmacological inhibition of this molecule resulted in resolution of adipose tissue inflammation and marked improvements in insulin sensitivity and glucose tolerance (Li et al, 2016). These studies, along with related findings from many other groups, indicate the potential that specific metaflammatory pathways may exist that will offer novel therapeutic strategies for metabolic disease.…”

Section: Innate Immune Cellular Mediators Of Inflammationmentioning

confidence: 99%

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

2017

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Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health.

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“…TNF-α induces insulin resistance through several mechanisms including inhibition of insulin receptor signaling and increases in FFA 129 . M1 macrophages secrete a chemotactic proinflammatory lectin Galectin-3 that directly decreases insulin signaling and promotes adipose tissue inflammation 130 . Selective ablation of M1 macrophages (CD11c+) by administration of diphtheria toxin in transgenic obese mice with expression of diphtheria toxin receptor under control of the CD11c promoter improved insulin sensitivity and lowered inflammatory markers 131 .…”

Section: Macrophage and Adipocyte Dysfunction In Obese Adipose Tissuementioning

confidence: 99%

Macrophage functions in lean and obese adipose tissue

2017

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Summary Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes.

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

Cited by 232 publications

References 55 publications

Inflammatory mechanisms linking obesity and metabolic disease

Inflammatory mechanisms linking obesity and metabolic disease

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

Macrophage functions in lean and obese adipose tissue

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