Metabolic syndrome compromises a constellation of conditions including central obesity, glucose intolerance, and dyslipidemia. These conditions enhance the risk of type 2 diabetes, cardiovascular disease, fatty liver/cirrhosis, hypertension, and cancer. The finding over 20 years ago that the inflammatory mediator TNF is overexpressed in adipose fundamentally changed our understanding of obesity and metabolic syndrome. We now know that metabolic syndrome in humans is characterized by chronic low-grade inflammation in multiple organs and we are now beginning to delineate the mechanisms by which inflammation and metabolism influence each other. 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. We now know that an inflammatory program is activated early in adipose expansion and during chronic obesity, permanently skewing the immune system to a pro-inflammatory phenotype.
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.
Alan R. Saltiel, Jerrold M. Olefsky
The finding of islet inflammation in type 2 diabetes (T2D) and its involvement in β cell dysfunction has further highlighted the significance of inflammation in metabolic diseases. The number of intra-islet macrophages is increased in T2D, and these cells are the main source of proinflammatory cytokines within islets. Multiple human studies of T2D have shown that targeting islet inflammation has the potential to be an effective therapeutic strategy. In this Review we provide an overview of the cellular and molecular mechanisms by which islet inflammation develops and causes β cell dysfunction. We also emphasize the regulation and roles of macrophage polarity shift within islets in the context of T2D pathology and β cell health, which may have broad translational implications for therapeutics aimed at improving islet function.
Kosei Eguchi, Ryozo Nagai
Over the last years, hypothalamic inflammation has been linked to the development and progression of obesity and its sequelae. There is accumulating evidence that this inflammation not only impairs energy balance but also contributes to obesity-associated insulin resistance. Elevated activation of key inflammatory mediators such as JNK and IκB kinase (IKK) occurs rapidly upon consumption of a high-fat diet, even prior to significant weight gain. This activation of hypothalamic inflammatory pathways results in the uncoupling of caloric intake and energy expenditure, fostering overeating and further weight gain. In addition, these inflammatory processes contribute to obesity-associated insulin resistance and deterioration of glucose metabolism via altered neurocircuit functions. An understanding of the contributions of different neuronal and non-neuronal cell types to hypothalamic inflammatory processes, and delineation of the differences and similarities between acute and chronic activation of these inflammatory pathways, will be critical for the development of novel therapeutic strategies for the treatment of obesity and metabolic syndrome.
Alexander Jais, Jens C. Brüning
Obesity and diabetes are associated with increased chronic low-grade inflammation and elevated plasma glucose levels. Although inflammation in the fat and liver are established features of obesity-associated insulin resistance, the intestine is emerging as a new site for immunologic changes that affect whole-body metabolism. Specifically, microbial and dietary factors incurred by diet-induced obesity influence underlying innate and adaptive responses of the intestinal immune system. These responses affect the maintenance of the intestinal barrier, systemic inflammation, and glucose metabolism. In this Review we propose that an understanding of the changes to the intestinal immune system, and how these changes influence systemic immunity and glucose metabolism in a whole-body integrative and a neuronal-dependent network, will unveil novel intestinal pathologic and therapeutic targets for diabetes and obesity.
Daniel A. Winer, Shawn Winer, Helen J. Dranse, Tony K.T. Lam
Obesity is associated with chronic inflammation, which contributes to insulin resistance and type 2 diabetes mellitus. Under normal conditions, skeletal muscle is responsible for the majority of insulin-stimulated whole-body glucose disposal; thus, dysregulation of skeletal muscle metabolism can strongly influence whole-body glucose homeostasis and insulin sensitivity. Increasing evidence suggests that inflammation occurs in skeletal muscle in obesity and is mainly manifested by increased immune cell infiltration and proinflammatory activation in intermyocellular and perimuscular adipose tissue. By secreting proinflammatory molecules, immune cells may induce myocyte inflammation, adversely regulate myocyte metabolism, and contribute to insulin resistance via paracrine effects. Increased influx of fatty acids and inflammatory molecules from other tissues, particularly visceral adipose tissue, can also induce muscle inflammation and negatively regulate myocyte metabolism, leading to insulin resistance.
Huaizhu Wu, Christie M. Ballantyne
Chronic inflammation in adipose tissue, possibly related to adipose cell hypertrophy, hypoxia, and/or intestinal leakage of bacteria and their metabolic products, likely plays a critical role in the development of obesity-associated insulin resistance (IR). Cells of both the innate and adaptive immune system residing in adipose tissues, as well as in the intestine, participate in this process. Thus, M1 macrophages, IFN-γ–secreting Th1 cells, CD8+ T cells, and B cells promote IR, in part through secretion of proinflammatory cytokines. Conversely, eosinophils, Th2 T cells, type 2 innate lymphoid cells, and possibly Foxp3+ Tregs protect against IR through local control of inflammation.
Tracey McLaughlin, Shelley E. Ackerman, Lei Shen, Edgar Engleman
Chronic liver inflammation leads to fibrosis and cirrhosis, which is the 12th leading cause of death in the United States. Hepatocyte steatosis is a component of metabolic syndrome and insulin resistance. Hepatic steatosis may be benign or progress to hepatocyte injury and the initiation of inflammation, which activates immune cells. While Kupffer cells are the resident macrophage in the liver, inflammatory cells such as infiltrating macrophages, T lymphocytes, neutrophils, and DCs all contribute to liver inflammation. The inflammatory cells activate hepatic stellate cells, which are the major source of myofibroblasts in the liver. Here we review the initiation of inflammation in the liver, the liver inflammatory cells, and their crosstalk with myofibroblasts.
Yukinori Koyama, David A. Brenner
An understanding of the events that initiate metabolic inflammation (metainflammation) can support the identification of targets for preventing metabolic disease and its negative effects on health. There is ample evidence demonstrating that the initiating events in obesity-induced inflammation start early in childhood. This has significant implications on our understanding of how early life events in childhood influence adult disease. In this Review we frame the initiating events of metainflammation in the context of child development and discuss what this reveals about the mechanisms by which this unique form of chronic inflammation is initiated and sustained into adulthood.
Kanakadurga Singer, Carey N. Lumeng
There are three dominant contributors to the pathogenesis of dysfunctional adipose tissue (AT) in obesity: unresolved inflammation, inappropriate extracellular matrix (ECM) remodeling and insufficient angiogenic potential. The interactions of these processes during AT expansion reflect both a linear progression as well as feed-forward mechanisms. For example, both inflammation and inadequate angiogenic remodeling can drive fibrosis, which can in turn promote migration of immune cells into adipose depots and impede further angiogenesis. Therefore, the relationship between the members of this triad is complex but important for our understanding of the pathogenesis of obesity. Here we untangle some of these intricacies to highlight the contributions of inflammation, angiogenesis, and the ECM to both “healthy” and “unhealthy” AT expansion.
Clair Crewe, Yu Aaron An, Philipp E. Scherer
Obesity-related sub-acute chronic inflammation has been associated with incident type 2 diabetes and atherosclerotic cardiovascular disease. Inflammation is increasingly considered to be a pathologic mediator of these commonly co-occurring diseases. A growing number of preclinical and clinical studies support the inflammatory hypothesis, but clinical trials to confirm the therapeutic potential to target inflammation to treat or prevent cardiometabolic conditions are still ongoing. There are multiple inflammatory signaling pathways. Regulation is complex, with substantial crosstalk across these multiple pathways. The activity of select pathways may be differentially regulated in different tissues. Pharmacologic approaches to diabetes management may have direct or indirect antiinflammatory effects, the latter potentially attributable to an improved metabolic state. Conversely, some antiinflammatory approaches may affect glucose metabolism and cardiovascular health. To date, clinical trials suggest that targeting one portion of the inflammatory cascade may differentially affect dysglycemia and atherothrombosis. Understanding the underlying biological processes may contribute to the development of safe and effective therapies, although a single approach may not be sufficient for optimal management of both metabolic and athrothrombotic disease states.
Allison B. Goldfine, Steven E. Shoelson