Abstract
Chronic inflammation is considered a causal risk factor predisposing to insulin resistance. However, evidence is accumulating that inflammation confined to the liver may not be causal to metabolic dysfunction. To investigate this, we assessed if hepatic inflammation explains the predisposition towards insulin resistance in low-density lipoprotein receptor knock-out (Ldlr −/−) mice. For this, wild type (WT) and Ldlr −/− mice were fed a chow diet, a high fat (HF) diet, or a high fat, high cholesterol (HFC) diet for 2 weeks. Plasma lipid levels were elevated in chow-fed Ldlr −/− mice compared to WT mice. Although short-term HF or HFC feeding did not result in body weight gain and adipose tissue inflammation, dyslipidemia was worsened in Ldlr −/− mice compared to WT mice. In addition, dyslipidemic HF-fed Ldlr −/− mice had a higher hepatic glucose production rate than HF-fed WT mice, while peripheral insulin resistance was unaffected. This suggests that HF-fed Ldlr −/− mice suffered from hepatic insulin resistance. While HFC-fed Ldlr −/− mice displayed the anticipated increased hepatic inflammation, this did neither exacerbate systemic nor hepatic insulin resistance. Therefore, our results show that hepatic insulin resistance is unrelated to cholesterol-induced hepatic inflammation in Ldlr −/− mice, indicating that hepatic inflammation may not contribute to metabolic dysfunction per se.
Highlights
Obesity is linked to many deleterious health consequences, including insulin resistance, type 2 diabetes (T2D) and the metabolic syndrome, a group of metabolic risk factors predisposing to T2D, and cardiovascular disease
Insulin levels were significantly elevated in Ldlr−/− mice fed an high fat (HF) and HFC diet compared to chow-fed Ldlr−/− mice (Figure 1(f)) but were not further increased by cholesterol addition to the HF diet (Figure 1(f))
The homeostasis model assessment of insulin resistance (HOMA-IR) was significantly elevated in Ldlr−/− mice fed an HF and HFC diet compared to both HF- and HFC-fed wild type (WT) mice and chow-fed Ldlr−/− mice (Figure 1(g)), confirming the reported predisposition towards insulin resistance in dyslipidemic Ldlr−/− mice [12]
Summary
Obesity is linked to many deleterious health consequences, including insulin resistance, type 2 diabetes (T2D) and the metabolic syndrome, a group of metabolic risk factors predisposing to T2D, and cardiovascular disease. Dyslipidemia may occur as a result of insulin resistance since hepatic lipogenesis, in contrast to gluconeogenesis, remains sensitive to insulin [11]. The rapid development of dyslipidemia [13, 14] and hepatic inflammation [14, 15] in these mice allows us to investigate their effect on insulin resistance before alterations in body weight occur. We opted to use female mice only as they confer a natural resistance against diet-induced obesity This is of particular importance as adiposity drives the metabolic phenotype in most studies [2] and differences in insulin resistance have been shown to disappear after matching the mice for body weight [16]. Our data show that hepatic inflammation is not a causal factor in the development of hepatic insulin resistance in Ldlr−/− mice. In line with the studies mentioned above, but contrasting with the current dogma, our data do not support a role for hepatic inflammation in triggering insulin resistance
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