ABSTRACT
AIMS/HYPOTHESIS: While it is well known that diet-induced obesity causes insulin resistance, the precise mechanisms underpinning the initiation of insulin resistance are unclear. To determine factors that may cause insulin resistance, we have performed a detailed time-course study in mice fed a high-fat diet (HFD). METHODS: C57Bl/6 mice were fed chow or an HFD from 3 days to 16 weeks and glucose tolerance and tissue-specific insulin action were determined. Tissue lipid profiles were analysed by mass spectrometry and inflammatory markers were measured in adipose tissue, liver and skeletal muscle. RESULTS: Glucose intolerance developed within 3 days of the HFD and did not deteriorate further in the period to 12 weeks. Whole-body insulin resistance, measured by hyperinsulinaemic-euglycaemic clamp, was detected after 1 week of HFD and was due to hepatic insulin resistance. Adipose tissue was insulin resistant after 1 week, while skeletal muscle displayed insulin resistance at 3 weeks, coinciding with a defect in glucose disposal. Interestingly, no further deterioration in insulin sensitivity was observed in any tissue after this initial defect. Diacylglycerol content was increased in liver and muscle when insulin resistance first developed, while the onset of insulin resistance in adipose tissue was associated with increases in ceramide and sphingomyelin. Adipose tissue inflammation was only detected at 16 weeks of HFD and did not correlate with the induction of insulin resistance. CONCLUSIONS/INTERPRETATION: HFD-induced whole-body insulin resistance is initiated by impaired hepatic insulin action and exacerbated by skeletal muscle insulin resistance and is associated with the accumulation of specific bioactive lipid species.
Subject(s)
Diet, High-Fat/adverse effects , Insulin Resistance/physiology , Adipose Tissue/metabolism , Animals , Blotting, Western , Body Composition/physiology , Enzyme-Linked Immunosorbent Assay , Glucose Clamp Technique , Male , Mice , Mice, Inbred C57BL , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
AIMS/HYPOTHESIS: Recent work has identified the important roles of M1 pro-inflammatory and M2 anti-inflammatory macrophages in the regulation of insulin sensitivity. Specifically, increased numbers of M2 macrophages and a decrease in M1 macrophages within the adipose tissue are associated with a state of enhanced insulin sensitivity. IL-10 is an anti-inflammatory cytokine and is a critical effector molecule of M2 macrophages. METHODS: In the present study, we examined the contribution of haematopoietic-cell-derived IL-10 to the development of obesity-induced inflammation and insulin resistance. We hypothesised that haematopoietic-cell-restricted deletion of IL-10 would exacerbate obesity-induced inflammation and insulin resistance. Lethally irradiated wild-type recipient mice receiving bone marrow from either wild-type or Il10-knockout mice were placed on either a chow or a high-fat diet for a period of 12 weeks and assessed for alterations in body composition, tissue inflammation and glucose and insulin tolerance. RESULTS: Contrary to our hypothesis, neither inflammation, as measured by the activation of pro-inflammatory stress kinases and gene expression of several pro-inflammatory cytokines in the adipose tissue and liver, nor diet-induced obesity and insulin resistance were exacerbated by the deletion of haematopoietic-cell-derived IL-10. Interestingly, however, Il10 mRNA expression and IL-10 protein production in liver and/or adipose tissue were markedly elevated in Il10-knockout bone-marrow-transplanted mice relative to wild-type bone marrow-transplanted mice. CONCLUSIONS/INTERPRETATION: These data show that deletion of IL-10 from the haematopoietic system does not potentiate high-fat diet-induced inflammation or insulin resistance.
Subject(s)
Dietary Fats/adverse effects , Inflammation/metabolism , Interleukin-10/deficiency , Animals , Body Composition/genetics , Body Composition/physiology , Cell Line , Glucose Tolerance Test , Inflammation/chemically induced , Insulin Resistance/genetics , Insulin Resistance/physiology , Interleukin-10/genetics , Interleukin-10/pharmacology , Interleukin-10/physiology , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Polymerase Chain Reaction , Tumor Necrosis Factor-alpha/metabolismABSTRACT
AIMS/HYPOTHESIS: The role of IL-6 in the development of obesity and hepatic insulin resistance is unclear and still the subject of controversy. We aimed to determine whether global deletion of Il6 in mice (Il6 (-/-)) results in standard chow-induced and high-fat diet (HFD)-induced obesity, hepatosteatosis, inflammation and insulin resistance. METHODS: Male, 8-week-old Il6 (-/-) and littermate control mice were fed a standard chow or HFD for 12 weeks and phenotyped accordingly. RESULTS: Il6 (-/-) mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with control mice on a standard chow diet. When fed a HFD, the Il6 (-/-) and control mice had marked, equivalent gains in body weight, fat mass and ectopic lipid deposition in the liver relative to chow-fed animals. Despite this normalisation, the greater liver inflammation, damage and insulin resistance observed in chow-fed Il6 (-/-) mice relative to control persisted when both were fed the HFD. Microarray analysis from livers of mice fed a HFD revealed that genes associated with oxidative phosphorylation, the electron transport chain and tricarboxylic acid cycle were uniformly decreased in Il6 (-/-) relative to control mice. This coincided with reduced maximal activity of the mitochondrial enzyme ß-hydroxyacyl-CoA-dehydrogenase and decreased levels of mitochondrial respiratory chain proteins. CONCLUSIONS/INTERPRETATION: Our data suggest that IL-6 deficiency exacerbates HFD-induced hepatic insulin resistance and inflammation, a process that appears to be related to defects in mitochondrial metabolism.
