Inflammatory and metabolic role of Kupffer cells in diet-induced obesity and insulin resistance

Obesity is associated with chronic inflammation and insulin resistance that can lead to development of type 2 diabetes. Adipose tissue and adipose tissue-associated macrophages from obese mice are a primary source of the increased circulating pro- inflammatory cytokine interleukin-6 (IL-6), which is linked to development of hepatic insulin resistance. This study addressed the contributions of the hepatic macrophage, or Kupffer cell, and IL-6 to the inflammatory and insulin resistant environment of obesity.;Our hypothesis predicted that Kupffer cells would increase the inflammation and insulin resistance of obesity like their adipose tissue counterparts. In contrast, Kupffer cells actually display characteristics of alternative activation in high-fat diet-induced obese (DIO) mice. To more specifically address their role in obesity, Kupffer cells were acutely ablated in vivo using clodronate-containing liposomes. Loss of Kupffer cells increased hepatic STAT3 signaling and expression of acute phase proteins in lean and DIO mice. This was in association with >84% loss of the anti-inflammatory cytokine interleukin-10 (IL-10). These data support an anti-inflammatory role for Kupffer cells in basal and obese states. Kupffer cells also appear to protect against detrimental metabolic effects of obesity. Ablation in DIO mice increased hepatic steatosis and reduced insulin receptor auto-phosphorylation and Akt activation by 30-40%. Systemic IL-10 loss during obesity (DIO IL-10 knock-out mice) also increased hepatic STAT3 signaling and steatosis, but did not alter insulin signaling. These results suggest that while Kupffer cell-derived IL-10 alone may reduce STAT3 signaling and steatosis, it is not sufficient to mediate Kupffer cell protection against obesity-associated hepatic insulin resistance.;Leptin receptor deficient mice (db/db) mice are obese and insulin resistant. We hypothesized that IL-6 contributes to this dysfunction and that crossing these mice with IL-6 knockout mice would improve hepatic insulin signaling. Loss of IL-6 did not alter systemic glucose or insulin tolerance, but improved pyruvate tolerance in db/db mice. These results suggest that IL-6 regulates hepatic glucose production. While inflammatory markers decreased, hepatic insulin signaling and basal gluconeogenic gene expression remained unaltered. These data indicate that IL-6 is detrimental to hepatic metabolic function in obesity.