Kupffer cell activation is a causal factor for hepatic insulin resistance

Abstract

Recruited adipose tissue macrophages contribute to chronic and low-grade inflammation causing insulin resistance in obesity. Similarly, we hypothesized here that Kupffer cells, the hepatic resident macrophages, play a pathogenic role in hepatic insulin resistance induced by a high-fat diet. Mice were fed a normal diet or high-fat diet for 3 days. Kupffer cell activation was evaluated by immunohistochemistry and quantitative RT-PCR. Insulin sensitivity was assessed in vivo by hyperinsulinemic-euglycemic clamp and insulin-activated signaling was investigated by Western blot. Liposome-encapsulated clodronate was injected intravenously to deplete macrophages prior to a short-term exposure to high-fat diet. Here, we characterized a short-term high-fat diet model in mice and demonstrated early hepatic insulin resistance and steatosis concurrent with Kupffer cell activation. We demonstrated that selective Kupffer cell depletion obtained by intravenous clodronate, without affecting adipose tissue macrophages, was sufficient to enhance insulin-dependent insulin signaling and significantly improve hepatic insulin sensitivity in vivo in this short-term high-fat diet model. Our study clearly shows that hepatic macrophage response participates to the onset of high-fat diet-induced hepatic insulin resistance and may therefore represent an attractive target for prevention and treatment of diet- and obesity-induced insulin resistance.

A short bout of HFD promotes long-lasting hepatic lipid accumulation

“…The finding of similar body weight after a short-bout of HFD is in line with some 5,17,18 but not all studies [1][2][3][4] examining the effect of short-term HFD on metabolism in mice. Possibly, differences in dietary composition, housing conditions, genetic background or age at dietary intervention may have contributed to observed differences in body weight gain.…”

“…[2][3][4] Here, we provide evidence that such alterations may persist after switching to a standard rodent diet. Accordingly, a recovery feeding period with a chow diet 8 times longer than the HFD exposure did not fully normalize glucose tolerance.…”

“…Although (hepatic) insulin sensitivity was not assessed in this study, it is likely that impaired liver insulin sensitivity in HFD RF mice was responsible for the observed difference in glucose tolerance, as a short-term HFD mainly affects hepatic insulin sensitivity. 1,3,5 Moreover, the fact of increased liver lipid levels in HFD RF mice may further support the assumption of deteriorated hepatic insulin sensitivity, as liver steatosis is often associated with hepatic insulin resistance. 13 The finding of increased FFA levels in the portal vein of HFD RF mice suggest that increased delivery of FFA to the liver contribute to elevated liver lipid levels.…”

“…[1][2][3][4][5] While glucose intolerance mainly results from impaired hepatic insulin sensitivity, increased hepatic fat accumulation upon short-term HFD may evolve due to elevated circulating free fatty acid (FFA) levels provoked by dietary fat supply. 1,3,5,6 Likewise, plasma FFA were shown to be the main source of fatty acids bound in liver triglycerides in manifested obesity. 7 However, in contrast to short-term HFD-induced liver steatosis, adipose tissue lipolysis is thought to be the main source of circulating FFA leading to liver fat accumulation upon chronic caloric surplus.…”

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…Moreover, high plasma levels of CRP have been used as a predictor for the development of NAFLD because patients with NASH are more insulin resistant and have remarkably higher plasma CRP concentrations than overweight nonsteatotic patients with similar visceral adipose tissue mass (Targher et al, 2008). In Addition to elevated pro-inflammatory cytokines, it was observed that metabolic dysfunctions such as insulin resistance are associated with reduced protective adipokines (such as adiponectin (Hotta et al, 2000)), and increased macrophage accumulation in the liver and adipose tissue (Lanthier et al, 2010). In particular, CD4 (þ) and CD8 (þ) T cells infiltration increases in the liver (Gadd et al, 2013).…”