Liver innate immune cells and insulin resistance: the multiple facets of Kupffer cells

Obesity, which affects 600 million adults worldwide, is a major risk factor for type 2 diabetes (T2D) and insulin resistance. Current therapies for these metabolic disorders include weight management by lifestyle intervention or bariatric surgery and pharmacological treatment with the aim of regulating blood glucose. Probably because of their short-term effectiveness, these therapies have not been able to stop the rapidly rising prevalence of T2D over the past decades, highlighting an urgent need to develop new therapeutic strategies. The role of immune cells, such as macrophages, in insulin resistance has been extensively studied. Major advances have been made to elucidate the role of adipose tissue macrophages in these pathogeneses. Recently, anti-inflammatory drugs have been suggested as an alternative treatment for T2D, and clinical trials of these agents are currently ongoing. In addition, results of previous clinical trials using antibodies against inflammatory cytokines, which showed modest effects, are now being rigorously re-evaluated. However, it is still unclear how liver macrophages [termed Kupffer cells (KCs)], which constitute the major source of macrophages in the body, contribute to the development of insulin resistance. In this review, we will discuss the present understanding of the role of liver immune cells in the development of insulin resistance. We will particularly focus on KCs, which could represent an attractive target for the treatment of metabolic diseases.