Abstract
BackgroundObesity and particularly the metabolic syndrome, which is often associated with obesity, combine a major risk for type 2 diabetes and cardiovascular disease. Emerging evidence indicate obesity-associated subclinical inflammation primarily originating from adipose tissue as a common cause for type 2 diabetes and cardiovascular disease. However, a suitable and well-characterized mouse model to simultaneously study obesity-associated metabolic disorders and atherosclerosis is not available yet. Here we established and characterized a murine model combining diet-induced obesity and associated adipose tissue inflammation and metabolic deteriorations as well as atherosclerosis, hence reflecting the human situation of cardio-metabolic disease.MethodsWe compared a common high-fat diet with 0.15% cholesterol (HFC), and a high-fat, high-sucrose diet with 0.15% cholesterol (HFSC) fed to LDL receptor-deficient (LDLR-/-) mice. Insulin resistance, glucose tolerance, atherosclerotic lesion formation, hepatic lipid accumulation, and inflammatory gene expression in adipose tissue and liver were assessed.ResultsAfter 12–16 weeks, LDLR-/- mice fed HFSC or HFC developed significant diet-induced obesity, adipose tissue inflammation, insulin resistance, and impaired glucose tolerance compared to lean controls. Notably, HFSC-fed mice developed significantly higher adipose tissue inflammation in parallel with significantly elevated atherosclerotic lesion area compared to those on HFC. Moreover, LDLR-/- mice on HFSC showed increased insulin resistance and impaired glucose tolerance relative to those on HFC. After prolonged feeding (20 weeks), however, no significant differences in inflammatory and metabolic parameters as well as atherosclerotic lesion formation were detectable any more between LDLR-/- mice fed HFSC or HFC.ConclusionThe use of high sucrose rather than more complex carbohydrates in high-fat diets significantly accelerates development of obesity-driven metabolic complications and atherosclerotic plaque formation parallel to obesity-induced adipose tissue inflammation in LDLR-/- mice. Hence LDLR-/- mice fed high-fat high-sucrose cholesterol-enriched diet appear to be a suitable and time-saving animal model for cardio-metabolic disease. Moreover our results support the suggested interrelation between adipose tissue inflammation and atherosclerotic plaque formation.
Highlights
Obesity and the metabolic syndrome, which is often associated with obesity, combine a major risk for type 2 diabetes and cardiovascular disease
Visceral adipose tissue and liver are the primary source and target of circulating inflammatory mediators in obesity-induced inflammation [6]. In both adipose tissue and liver, macrophages, and other immune cells such as T-cells are a main source of inflammatory cytokines such as tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and osteopontin [7,8,9] which drive the low-grade inflammation by mechanisms which need to be elucidated in more detail
In order to develop and standardize a mouse model reflecting the human situation of metabolic syndrome with diet-induced obesity, adipose tissue inflammation promoting insulin resistance and atherosclerosis we investigated the effect of a common high-fat diet and a sucroseenriched high-fat diet in LDLR−/− mice
Summary
Obesity and the metabolic syndrome, which is often associated with obesity, combine a major risk for type 2 diabetes and cardiovascular disease. Emerging evidence indicate obesity-associated subclinical inflammation primarily originating from adipose tissue as a common cause for type 2 diabetes and cardiovascular disease. We established and characterized a murine model combining diet-induced obesity and associated adipose tissue inflammation and metabolic deteriorations as well as atherosclerosis, reflecting the human situation of cardio-metabolic disease. Obesity is strongly associated with the so-called metabolic syndrome, which comprises a combination of factors conferring risk for type 2 diabetes and cardiovascular disease [1]. Visceral adipose tissue and liver are the primary source and target of circulating inflammatory mediators in obesity-induced inflammation [6]. In both adipose tissue and liver, macrophages, and other immune cells such as T-cells are a main source of inflammatory cytokines such as tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and osteopontin [7,8,9] which drive the low-grade inflammation by mechanisms which need to be elucidated in more detail
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