Regulation of metabolism by the innate immune system

Abstract

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.

Immunologic impact of the intestine in metabolic disease

“…We propose that in the context of HFD and/or obesity, intestinal barrier leakage may prevent the ability of preabsorptive nutrients to accumulate in the small intestine, leading to an inability to trigger the gut-derived peptide network to regulate postprandial glucose homeostasis (Figure 2). In parallel, a leak of nutrients into the circulation and tissues such as liver, muscle, fat, and brain might also disrupt glucose homeostasis by inducing insulin resistance and/or inflammation in target tissues, resulting in a positive feedback loop to disrupt glucose homeostasis (10,11,110,111).…”

“…Multiple factors contribute to insulin resistance and glucose dysregulation in obesity and diabetes, but chronic low-grade inflammation of metabolic tissues, including visceral adipose tissue (VAT), liver, and brain, are important contributors (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The intestinal immune system has recently emerged as a site that is altered by diet-induced obesity.…”

Insulin resistance causes inflammation in adipose tissue

“…Although the mechanism by which obesity causes insulin resistance is unclear, inflammation has been linked to the development of local and systemic insulin resistance, especially when the inflammation occurs in white adipose tissue (WAT) (4,5).…”

Islet inflammation in type 2 diabetes

“…However, dysregulated or prolonged inflammation states have been associated with many diseases, including type 2 diabetes [1]. Early connections between inflammation, obesity and type 2 diabetes were made in the 1990s, in both rodent models and humans [2,3], and later substantiated by a large body of evidence (see [4][5][6][7] for recent reviews). Then, it was observed that pancreatic islet cells may also show signs of inflammation, including immune cell infiltration [8][9][10] and increased expression of cytokines and chemokines [11][12][13].…”