Abstract
High–fat (HF) diet-induced obesity and insulin insensitivity are associated with inflammation, particularly in white adipose tissue (WAT). However, insulin insensitivity is apparent within days of HF feeding when gains in adiposity and changes in markers of inflammation are relatively minor. To investigate further the effects of HF diet, C57Bl/6J mice were fed either a low (LF) or HF diet for 3 days to 16 weeks, or fed the HF-diet matched to the caloric intake of the LF diet (PF) for 3 days or 1 week, with the time course of glucose tolerance and inflammatory gene expression measured in liver, muscle and WAT. HF fed mice gained adiposity and liver lipid steadily over 16 weeks, but developed glucose intolerance, assessed by intraperitoneal glucose tolerance tests (IPGTT), in two phases. The first phase, after 3 days, resulted in a 50% increase in area under the curve (AUC) for HF and PF mice, which improved to 30% after 1 week and remained stable until 12 weeks. Between 12 and 16 weeks the difference in AUC increased to 60%, when gene markers of inflammation appeared in WAT and muscle but not in liver. Plasma proteomics were used to reveal an acute phase response at day 3. Data from PF mice reveals that glucose intolerance and the acute phase response are the result of the HF composition of the diet and increased caloric intake respectively. Thus, the initial increase in glucose intolerance due to a HF diet occurs concurrently with an acute phase response but these effects are caused by different properties of the diet. The second increase in glucose intolerance occurs between 12 - 16 weeks of HF diet and is correlated with WAT and muscle inflammation. Between these times glucose tolerance remains stable and markers of inflammation are undetectable.
Highlights
Obesity and related metabolic disorders are largely the result of overconsumption of energy dense foods, high in sugar and long chain saturated fats
PF mice showed a drop in body weight after 3 days compared to both LF and HF diets (Fig 1D), after 1 week body weight was similar in the LF and PF groups which were both lower that the HF fed mice (Fig 1E)
The present results show that the inflammatory response to a HF diet develops in distinct stages; the first occurs within 3 days and correlates with an acute phase response, probably resulting from an acute and transient inflammation and activation of Kupffer cells in the liver, and the second between 12 and 16 weeks on the HF diet occurs when inflammation in white adipose tissue (WAT) and muscle becomes apparent
Summary
Obesity and related metabolic disorders are largely the result of overconsumption of energy dense foods, high in sugar and long chain saturated fats. One study looking at both short- and long-term HF diet induced insulin resistance found inflammation increased from day 1 of HF feeding onwards [15], but concluded after looking at the response to HF diet in three different immuno-compromised mouse models, that inflammation was not necessary for the development of short-term but necessary for long-term insulin resistance [15]. If ablation of Kupffer cells takes place after macrophage infiltration of WAT is established it does not improve metabolic health [21], arguing for a role of liver inflammation in the early, but not later, development of insulin insensitivity and adiposity
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