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There are currently over 1.9 billion people who are obese or overweight, leading to a rise in related health complications, including insulin resistance, type 2 diabetes, cardiovascular disease, liver disease, cancer, and neurodegeneration. The finding that obesity and metabolic disorder are accompanied by chronic low-grade inflammation has fundamentally changed our view of the underlying causes and progression of obesity and metabolic syndrome. We now know that an inflammatory program is activated early in adipose expansion and during chronic obesity, permanently skewing the immune system to a proinflammatory phenotype, and we are beginning to delineate the reciprocal influence of obesity and inflammation. Reviews in this series examine the activation of the innate and adaptive immune system in obesity; inflammation within diabetic islets, brain, liver, gut, and muscle; the role of inflammation in fibrosis and angiogenesis; the factors that contribute to the initiation of inflammation; and therapeutic approaches to modulate inflammation in the context of obesity and metabolic syndrome.

It is now recognized that obesity is driving the type 2 diabetes epidemic in Western countries. Obesity-associated chronic tissue inflammation is a key contributing factor to type 2 diabetes and cardiovascular disease, and a number of studies have clearly demonstrated that the immune system and metabolism are highly integrated. Recent advances in deciphering the various cellular and signaling networks that participate in linking the immune and metabolic systems together have contributed to understanding of the pathogenesis of metabolic diseases and may also inform new therapeutic strategies based on immunomodulation. Here we discuss how these various networks underlie the etiology of the inflammatory component of insulin resistance, with a particular focus on the central roles of macrophages in adipose tissue and liver. This review highlights the importance of immunometabolism to obesity and metabolic diseases such as diabetes. The authors describe recent advances in dissecting the cellular and signaling networks that link the immune and metabolic systems together, and how these insights could be translated to develop new therapeutic strategies to combat metabolic disease.

Key Points Obesity increases production of proinflammatory cytokines that interfere with the insulin signalling pathway In the obese state, chemotactic signals originating from inflamed adipose tissue, liver and muscle lead to monocyte infiltration, polarization of proinflammatory macrophages, tissue inflammation and insulin resistance In adipose tissue in the lean state, group 2 innate lymphoid cells and eosinophils maintain a type 2 cytokine environment by promoting polarization of alternatively activated macrophages Liver Kupffer cells become activated in obesity and secrete chemokines that induce the accumulation of proinflammatory liver macrophages, which contribute to insulin resistance and hepatic steatosis Macrophage infiltration participates in muscle and pancreas inflammation; however, further research is necessary to determine whether such inflammation is causally related to either muscle insulin resistance or β-cell dysfunction Anti-inflammatory treatments have proven less effective at promoting insulin sensitization in humans than in rodents; consequently, demonstrating clear-cut treatment effects for patients remains a future translational challenge Here, Denise Lackey and Jerrold Olefsky discuss the innate immune cells involved in secreting inflammatory factors during obesity. The role of innate immune cells in maintaining an anti-inflammatory and insulin-sensitive environment in the lean state is also reviewed. This Review also provides an overview of the mechanisms for regulating proinflammatory immune responses that could lead to future therapeutic opportunities to improve insulin sensitivity. Low-grade tissue inflammation induced by obesity can result in insulin resistance, which in turn is a key cause of type 2 diabetes mellitus. Cells of the innate immune system produce cytokines and other factors that impair insulin signalling, which contributes to the connection between obesity and the onset of type 2 diabetes mellitus. Here, we review the innate immune cells involved in secreting inflammatory factors in the obese state. In the adipose tissue, these cells include proinflammatory adipose tissue macrophages and natural killer cells. We also discuss the role of innate immune cells, such as anti-inflammatory adipose tissue macrophages, eosinophils, group 2 innate lymphoid cells and invariant natural killer T cells, in maintaining an anti-inflammatory and insulin-sensitive environment in the lean state. In the liver, both Kupffer cells and recruited hepatic macrophages can contribute to decreased hepatic insulin sensitivity. Proinflammatory macrophages might also adversely affect insulin sensitivity in the skeletal muscle and pancreatic β-cell function. Finally, this Review provides an overview of the mechanisms for regulating proinflammatory immune responses that could lead to future therapeutic opportunities to improve insulin sensitivity.

Key Points G protein-coupled receptors (GPCRs) can affect insulin action, insulin secretion and β-cell expansion, and certain GPCRs have emerged as potential drug targets for the development of anti-diabetic therapeutics. Decreased insulin sensitivity is a major metabolic defect in the great majority of individualswith type 2 diabetes (T2D), and one of the key mechanisms underlying insulin resistance is chronic tissue inflammation. Leukotriene B4 (LTB4) receptor 1 (LTB4R1) inhibitors may be anti-diabetic insulin sensitizers, as they inhibit inflammation and directly block the capacity of LTB4 to impair cellular insulin signalling in hepatocytes and myocytes. The long-chain fatty acid receptors, free fatty acid receptor 1 (FFAR1, also known as GPR40) and FFAR4 (also known as GPR120), mediate beneficial effects by promoting glucose-induced insulin secretion or by inhibiting inflammatory signalling in immune cells, respectively. The stimulation of β-cell glucose-dependent insulinotropic receptor (GPR119) leads directly to an increase in insulin secretion, and agonism of GPR119 on enteroendocrine cells promotes both glucagon-like peptide 1 (GLP1) and gastric inhibitory polypeptide (GIP) release. Therefore, GPR119 could be an important anti-diabetic drug target to promote insulin secretion. Administration of exogenous CX3C-chemokine ligand 1 (CX3CL1, also known as fractalkine) to mice strikingly improves glucose tolerance and enhances β-cell insulin secretion. CX3CL1 and its receptor, CX3CR1, could be new targets used to positively influence β-cell function, and CX3CL1-based reagents might be future therapeutic approaches to anti-diabetes therapy. Modulators of glucagon-like peptide 1 (GLP1) and the resulting G protein-coupled receptor (GPCR) signalling have recently come to the fore of the treatment of type 2 diabetes. In this Opinion article, Oh and Olefsky discuss the potential for intervention with other GPCRs for the treatment of this disease, highlighting GPCR-mediated effects on insulin secretion, insulin sensitivity and inflammation. The prevalence of obesity and type 2 diabetes (T2D) is increasing worldwide, and these two metabolic disorders are closely linked. Lifestyle modification, including weight loss and exercise, are effective treatments for T2D, but, unfortunately, most patients are unsuccessful at maintaining durable weight reduction and recidivism is all too common. Therefore, safe and efficacious drugs are required for the successful treatment of T2D in a large proportion of patients. Targeting G protein-coupled receptors (GPCRs) in metabolic tissues — such as adipose tissue, liver, muscle, pancreatic islets, immune cells and the central nervous system — has emerged as a key target for current and future anti-diabetic compounds. This Opinion focuses on the potential of GPCRs as targets for the discovery of new drugs to successfully treat T2D.

Infiltration of various immune cell types into the fat tissue and liver has been implicated in obesity-induced insulin resistance. Jerry Olefsky and his colleagues now show that neutrophils are one of the earliest immune cells to arrive in these tissues, that they release the protease neutrophil elastase and that this enzyme degrades IRS-1, a key member of the insulin signaling pathway. These results show that neutrophils contribute to insulin resistance and how they may do so. Chronic low-grade adipose tissue and liver inflammation is a major cause of systemic insulin resistance and is a key component of the low degree of insulin sensitivity that exists in obesity and type 2 diabetes 1 , 2 . Immune cells, such as macrophages, T cells, B cells, mast cells and eosinophils, have all been implicated as having a role in this process 3 , 4 , 5 , 6 , 7 , 8 . Neutrophils are typically the first immune cells to respond to inflammation and can exacerbate the chronic inflammatory state by helping to recruit macrophages and by interacting with antigen-presenting cells 9 , 10 , 11 . Neutrophils secrete several proteases, one of which is neutrophil elastase, which can promote inflammatory responses in several disease models 12 . Here we show that treatment of hepatocytes with neutrophil elastase causes cellular insulin resistance and that deletion of neutrophil elastase in high-fat-diet–induced obese (DIO) mice leads to less tissue inflammation that is associated with lower adipose tissue neutrophil and macrophage content. These changes are accompanied by improved glucose tolerance and increased insulin sensitivity. Taken together, we show that neutrophils can be added to the extensive repertoire of immune cells that participate in inflammation-induced metabolic disease.

Genetic and pharmacological inhibition of the high-affinity LTB4 receptor promotes improved metabolism in obese mice. Insulin resistance results from several pathophysiologic mechanisms, including chronic tissue inflammation and defective insulin signaling. We found that liver, muscle and adipose tissue exhibit higher levels of the chemotactic eicosanoid LTB4 in obese high-fat diet (HFD)–fed mice. Inhibition of the LTB4 receptor Ltb4r1, through either genetic or pharmacologic loss of function, led to an anti-inflammatory phenotype with protection from insulin resistance and hepatic steatosis. In vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways, reduced insulin-stimulated glucose uptake in L6 myocytes, and impaired insulin-mediated suppression of hepatic glucose output in primary mouse hepatocytes. This was accompanied by lower insulin-stimulated Akt phosphorylation and higher Irs-1/2 serine phosphorylation, and all of these events were dependent on Gαi and Jnk1, two downstream mediators of Ltb4r1 signaling. These observations elucidate a novel role of the LTB4–Ltb4r1 signaling pathway in hepatocyte and myocyte insulin resistance, and they show that in vivo inhibition of Ltb4r1 leads to robust insulin-sensitizing effects.

Many mechanisms contribute to type 2 diabetes, but few connections have established a pathway from diet to disease. Jamey Marth and his colleagues now provide a pathway to diet-induced obesity–associated diabetes that identifies defects in protein glycosylation in pancreatic beta cells as an early pathogenic step. This change results in reduced glucose transport and induces systemic disease signs, including impaired glucose tolerance and insulin resistance. A connection between diet, obesity and diabetes exists in multiple species and is the basis of an escalating human health problem. The factors responsible provoke both insulin resistance and pancreatic beta cell dysfunction but remain to be fully identified. We report a combination of molecular events in human and mouse pancreatic beta cells, induced by elevated levels of free fatty acids or by administration of a high-fat diet with associated obesity, that comprise a pathogenic pathway to diabetes. Elevated concentrations of free fatty acids caused nuclear exclusion and reduced expression of the transcription factors FOXA2 and HNF1A in beta cells. This resulted in a deficit of GnT-4a glycosyltransferase expression in beta cells that produced signs of metabolic disease, including hyperglycemia, impaired glucose tolerance, hyperinsulinemia, hepatic steatosis and diminished insulin action in muscle and adipose tissues. Protection from disease was conferred by enforced beta cell–specific GnT-4a protein glycosylation and involved the maintenance of glucose transporter expression and the preservation of glucose transport. We observed that this pathogenic process was active in human islet cells obtained from donors with type 2 diabetes; thus, illuminating a pathway to disease implicated in the diet- and obesity-associated component of type 2 diabetes mellitus.

The development of intestinal permeability and the penetration of microbial products are key factors associated with the onset of metabolic disease. However, the mechanisms underlying this remain unclear. Here we show that, unlike liver or adipose tissue, high fat diet (HFD)/obesity in mice does not cause monocyte/macrophage infiltration into the intestine or pro-inflammatory changes in gene expression. Rather HFD causes depletion of intestinal eosinophils associated with the onset of intestinal permeability. Intestinal eosinophil numbers were restored by returning HFD fed mice to normal chow and were unchanged in leptin-deficient (Ob/Ob) mice, indicating that eosinophil depletion is caused specifically by a high fat diet and not obesity per se. Analysis of different aspects of intestinal permeability in HFD fed and Ob/Ob mice shows an association between eosinophil depletion and ileal paracelullar permeability, as well as leakage of albumin into the feces, but not overall permeability to FITC dextran. These findings provide the first evidence that a high fat diet causes intestinal eosinophil depletion, rather than inflammation, which may contribute to defective barrier integrity and the onset of metabolic disease.

Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD) exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old) and aged (15 months old) mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions.

Pharmacological fibroblast growth factor 1 (FGF1) normalizes blood glucose in diabetic mice by means of an FGF receptor signalling pathway that is independent of its mitogenic activity. Glucose-lowering activity of 'endocrine' FGF1 As a non-endocrine member of the fibroblast growth factor (FGF) family, FGF1 is known as a classic growth factor with mitogenic and angiogenic activity. This study identifies FGF1 as a powerful metabolic regulator. Injection of recombinant FGF1 (rFGF1) results in potent, insulin-dependent glucose lowering in diabetic mice, but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses hepatic glucose production to achieve whole-body insulin sensitization. This work raises the possibility that FGF1 could have therapeutic potential for the treatment of insulin resistance and type 2 diabetes. Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation 1 , 2 . Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a potential role in nutrient homeostasis 3 , 4 . Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin-sensitizing therapies. We also show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 signalling. Thus we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes.