The metabolic syndrome

Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients. This should have been an important clue to link inflammation to the pathogenesis of type 2 diabetes (T2D), but the antihyperglycemic and antiinflammatory effects of salicylates were not connected to the pathogenesis of insulin resistance until recently. Together with the discovery of an important role for tissue macrophages, these new findings are helping to reshape thinking about how obesity increases the risk for developing T2D and the metabolic syndrome. The evolving concept of insulin resistance and T2D as having immunological components and an improving picture of how inflammation modulates metabolism provide new opportunities for using antiinflammatory strategies to correct the metabolic consequences of excess adiposity.

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Inflammation and insulin resistance

Over the last decade, an abundance of evidence has emerged demonstrating a close link between metabolism and immunity. It is now clear that obesity is associated with a state of chronic low-level inflammation. In this article, we discuss the molecular and cellular underpinnings of obesity-induced inflammation and the signaling pathways at the intersection of metabolism and inflammation that contribute to diabetes. We also consider mechanisms through which the inflammatory response may be initiated and discuss the reasons for the inflammatory response in obesity. We put forth for consideration some hypotheses regarding important unanswered questions in the field and suggest a model for the integration of inflammatory and metabolic pathways in metabolic disease.

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Inflammation, stress, and diabetes

The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function.

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Adipokines in inflammation and metabolic disease

There has been much effort recently to define the role of adipocytokines, which are soluble mediators derived mainly from adipocytes (fat cells), in the interaction between adipose tissue, inflammation and immunity. The adipocytokines adiponectin and leptin have emerged as the most abundant adipocyte products, thereby redefining adipose tissue as a key component not only of the endocrine system, but also of the immune system. Indeed, as we discuss here, several adipocytokines have a central role in the regulation of insulin resistance, as well as many aspects of inflammation and immunity. Other adipocytokines, such as visfatin, have only recently been identified. Understanding this rapidly growing family of mainly adipocyte-derived mediators might be of importance in the development of new therapies for obesity-associated diseases.

Adipocytokines: mediators linking adipose tissue, inflammation and immunity.

Fat tissue produces a variety of secreted proteins (adipocytokines) with important roles in metabolism. We isolated a newly identified adipocytokine, visfatin, that is highly enriched in the visceral fat of both humans and mice and whose expression level in plasma increases during the development of obesity. Visfatin corresponds to a protein identified previously as pre-B cell colony-enhancing factor (PBEF), a 52-kilodalton cytokine expressed in lymphocytes. Visfatin exerted insulin-mimetic effects in cultured cells and lowered plasma glucose levels in mice. Mice heterozygous for a targeted mutation in the visfatin gene had modestly higher levels of plasma glucose relative to wild-type littermates. Surprisingly, visfatin binds to and activates the insulin receptor. Further study of visfatin's physiological role may lead to new insights into glucose homeostasis and/or new therapies for metabolic disorders such as diabetes.

https://science.sciencemag.org/content/sci/307/5708/426.full.pdf

Visfatin: a protein secreted by visceral fat that mimics the effects of insulin.

Recent studies of obesity show that fat tissue fulfills an endocrine function by producing a variety of secreted proteins, called adipocytokines, that may play key metabolic roles. The present investigators have isolateda newly identified adipocytokine, visfatin, from visceral fat of both mice and humans. Expression of visfatin in the plasma increases as obesity develops. This substance corresponds to a protein identified as preB cell colony-enhancing factor (PBEF), a cytokine expressed in lymphocytes. In a study of 101 human males and females, plasma levels of PBEF correlated closely with the amount of visceral fat as estimated by computed tomography. Correlation with the amount of subcutaneous fat was weak. Significant elevations of PBEF mRNA were also found in KKAy mice, which serve as a model for obesity-related type 2 diabetes. These mice become obese at age 6 to 12 weeks and, at the same time, plasma PBEF levels increase significantly, as do levels of PBEF mRNA in visceral fat. Levels in subcutaneous fat change very little. Mice fed a high-fat diet had higher plasma PBEF concentrations than those fed normal chow. When recombinant visfatin was administered intravenously to c57BL/6J mice, plasma glucose decreased within 30 minutes in a dose-dependent manner. The same effect was noted in insulin-resistant obese KKAy mice, mimicking the effect of insulin injection. Visfatin also had insulin-like effects on cultured cells. In both strains of mice, chronic exposure to visfatin, using adenovirus, significantly lowered plasma levels of both glucose and insulin. Visfatin was found to bind to-and activate-the insulin receptor but in a way different from insulin. These studies indicate that visfatin shares properties of insulin both in vitro and in vivo. In addition to helping to understand glucose and lipid homeostasis and adipocyte proliferation, visfatin may prove to be a useful target when developing drug treatments for diabetes.

Kae Kishimoto

Papers

Visfatin: a protein secreted by visceral fat that mimics the effects of insulin.

Visfatin : A protein secreted by visceral fat that mimics the effects of insulin