Inflammation, stress, and diabetes

Abstract

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. Inflammation, stress, and diabetesSurvival of multicellular organisms depends on the ability to fight infection and heal damage and the ability to store energy for times of low nutrient availability or high energy need.Metabolic and immune systems are therefore among the most basic requirements across the animal kingdom, and many nutrient and pathogen-sensing systems have been highly conserved from organisms such as Caenorhabditis elegans and Drosophila to mammals.Perhaps not surprisingly, metabolic and immune pathways have also evolved to be closely linked and interdependent.Many hormones, cytokines, signaling proteins, transcription factors, and bioactive lipids can function in both metabolic and immune roles.In addition to using some of the same cellular machinery, metabolic and immune systems also regulate each other.The normal inflammatory response relies upon metabolic support, and energy redistribution, particularly the mobilization of stored lipid, plays an important role in fighting infection during the acute-phase response (1).The basic inflammatory response thus favors a catabolic state and suppresses anabolic pathways, such as the highly conserved and powerful insulin signaling pathway.The integration of metabolism and immunity, which under normal conditions is beneficial for the maintenance of good health, can become deleterious under conditions of metabolic challenge, as exemplified by the immunosuppression characteristic of malnourished or starving individuals (1-3).Famine has been a prominent hazard to human health throughout history, and for thousands of years the link between infection and poor nutrition has been well recognized.Today this threat is as widespread as ever, and there are approximately 1 billion undernourished individuals worldwide (3).In the past century, however, the pendulum has also swung in the opposite direction, and now as many if not more people are overweight or obese (4).With the advent of this chronic metabolic overload, a new set of problems and complications at the intersection of metabolism and immunity has emerged, including the obesity-linked inflammatory diseases diabetes, fatty liver disease, airway inflammation, and atherosclerosis (5).There is now a wealth of evidence indicating close ties between metabolic and immune systems.Among the many reasons to maintain a healthy weight is the emerging paradigm that metabolic imbalance leads to immune imbalance, with starvation and immunosuppression on one end of the spectrum and obesity and inflammatory diseases on the other end (Figure 1).In this article, we will discuss the molecular and cellular links between metabolism and inflammation, particularly in the context of obesity and diabetes.Common inflammatory mediators, stress responses, and signaling pathways will be highlighted.Finally, we will consider the origin of and the reasons for the inflammatory response in obesity.