Dynamic immunological changes in the gut and adipose tissue during obesity

Abstract

The immune system not only defends the host from infection but senses the metabolic state and controls the metabolic homeostasis. Chronic inflammation in metabolic tissues contributes to the systemic insulin resistance, and the excessive infiltration and dysregulation of immune cells in visceral adipose tissue is a hallmark of obesity-associated metabolic disorders. Recent studies have revealed a link between Toll-like receptor (TLR) signaling and the adipose tissue inflammation associated with obesity. Although TLR9 is known to play an important role in inflammation and innate immunity, its role in mediating adipose tissue inflammation has not yet been investigated. In this study, I indicate that TLR9 signaling can regulate immune cells in visceral adipose tissue and maintain the metabolic homeostasis. TLR9-deficient mice gained significantly more weight and body fat under a high-fat diet than wild type mice, and exhibited more severe glucose intolerance and insulin resistance. I also found a dramatic increase of M1 macrophages as well as TH1 cells in the adipose tissue of TLR9-deficient mice compared to wild type mice. Furthermore, the levels of various pro-inflammatory cytokines and chemokines were higher in TLR9- deficient mice. In conclusion, TLR9 signaling plays an important role in regulating adipose tissue inflammation and controlling obesity and the metabolic syndrome. In addition, obesity is caused by excessive nutrient absorption in the gut, the organ with the biggest number of immune cells. Moreover, recent evidences link the development of obesity and metabolic syndromes with the disturbance of gut microbiota. However, the interrelationship between metabolic syndromes and the intestinal immune system has not been systemically addressed yet. Here, I show that obesity greatly influences the small intestinal immune system and the modulation of intestinal immune cells impacts the disease progression. I found the strong reduction of T cell population, especially of TH17 cells, as well as the functional alteration of antigen-presenting cells in the small intestine of obese mice. Enhancement or reduction of small intestinal TH17 cells in obese mice correlates with amelioration or deterioration of metabolic disorders, respectively. Our study demonstrates that intestinal immune system plays a pivotal role in the metabolic homeostasis and can be targeted for a new therapeutic strategy.