Basic nutritional investigationResistant starch improves insulin resistance and reduces adipose tissue weight and CD11c expression in rat OLETF adipose tissue
Introduction
The number of type 2 diabetes patients continues to increase worldwide. The disease is related to genetic and environmental factors, such as overeating, reduced physical activity, and various kinds of stress. Type 2 diabetes is associated with many complications, especially microvascular and macrovascular diseases [1]. Thus, prevention of type 2 diabetes is important for prolonging a healthy lifespan and maintaining quality of life. An initial stage of type 2 diabetes development is insulin resistance (IR), in which the individual’s blood glucose levels are not adequately reduced, despite maximal insulin secretion. Insulin resistance is frequently associated with obesity. In particular, excess accumulation of fat in adipose tissues is known to induce IR, resulting in chronic hyperglycemia [2]. Therefore, suppression of IR is important for preventing the development and progression of type 2 diabetes and its complications.
The main factors involved in the development of IR in adipose tissues are the induction of oxidant stress and inflammation. Infiltration of macrophages into adipose tissues has been observed in both rodents and humans [3], [4], [5], [6], [7]. The infiltrated macrophages secrete reactive oxygen species (ROS) and inflammatory cytokines such as interleukin (IL)-1 β, IL-6, and tumor neurosis factor (TNF)-α [8], [9], [10]. Furthermore, the infiltration of macrophages is closely associated with the expression of β2-integrin, an adhesion molecule that is expressed in leukocytes as a CD11s/CD18 dimer. The CD11s/CD18 dimers induce monocyte/macrophage infiltration into many tissues, including adipose tissues [11], [12], [13], [14]. In particular, it was reported that CD11c-positive macrophages in adipose tissues are strongly associated with the development of IR, and that experimental deletion of these cells improves IR [15]. CD11c-positive macrophages secrete proinflammatory cytokines, such as TNF-α and IL-6, together with abundant ROS production, whereas CD11c-negative macrophages express anti-inflammatory cytokines, such as IL-10 [4]. Thus, the expression of CD11c on macrophages is important for the progression of inflammation in adipose tissues. However, to our knowledge it has not been elicited whether a reduction of CD11c-positive macrophages by dietary factors can improve or prevent the development of IR.
To prevent IR, it is considered important to reduce excess eating, inhibit postprandial hyperglycemia, and enhance energy utilization. Dietary consumption of resistant starch (RS) instead of regular starch could reduce IR because RS is low in calories [16], [17], [18], [19], [20], reduce postprandial hyperglycemia and insulin secretion [21], [22], [23], [24], and induce liver β-oxidation associated with short-chain fatty acid production by fermentation [25]. Indeed, a previous study demonstrated that Wistar rats fed an RS diet for 14 d underwent significant reductions in weight and mesenteric adipose tissue weight, and reduced expression levels of enzymes related to fatty acid synthesis, such as fatty acid synthase and malic enzyme, in adipose tissues [26]. Additionally, it was previously reported that the intake of RS instead of regular starch in Goto-Kakizaki rats, a model of type 2 diabetes, reduced weight and triacylglycerol levels [27]. However, whether or not RS intake reduces IR at an early stage and the molecular mechanism underlying the amelioration of IR remain unknown.
Based on these issues, we hypothesized that replacing regular starch with RS in the diet would improve IR at an early stage by reducing inflammation associated with the presence of macrophages expressing CD11c in adipose tissues. To explore this hypothesis, we examined whether RS intake reduces the presence of macrophages, especially CD11c-positive macrophages, in adipose tissues and inhibits the development of IR at an early stage in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. These rats exhibit obesity, in addition to late onset of chronic and slowly progressive hyperinsulinemia, hyperglycemia, and hyperlipidemia, which are caused by overeating [28], at the stage of impaired glucose tolerance (IGT).
Section snippets
Animals
Twelve 22-wk-old male OLETF rats (Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan) were divided into two groups and were fed a control (55% α-corn starch; n = 6) or an RS diet (55% RS; n = 6) for 5 wk. Rats in both groups had similar 6-h fasting glucose levels and weights. The weight, as well as 6-h fasting plasma glucose, insulin, triacylglycerol (TAG), and free fatty acid levels did not differ between the two groups (Table 1). The control diet was a modified
Effects of the RS diet on blood biochemical parameters and tissue weights in OLETF rats
The mean body weight did not differ between the two groups. Mesenteric adipose tissue weight was significantly reduced in rats fed the RS diet compared with those fed the control diet (15%; P < 0.05). Plasma glucose, plasma hemoglobin (Hb)A1c, and serum free fatty acid levels did not differ between the two groups. Serum insulin, TAG, glycoalbumin levels, and HOMA-IR were significantly lower in rats fed the RS diet than in those fed the control diet (Table 1).
Effects of the RS diet on insulin sensitivity in OLETF rats
OGTTs were performed after 4 wk of
Discussion
A previous study revealed that feeding an RS diet for 2 wk reduced mesenteric adipose tissue weight and serum TAG levels in Wistar normal rats [26]. Thus, we hypothesized that RS intake for a relatively short time could ameliorate IGT and IR. To explore this hypothesis, we used 22-wk-old OLETF rats, an age associated with moderate IGT, and fed them for 5 wk with an RS diet or a control diet. We found that feeding these rats with the RS diet for 5 wk reduced mesenteric adipose tissue weight and
Acknowledgments
This work was supported by a Grant-in-Aid for Young Scientists (22680054) and for Scientific Research (23300276) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Global COE program, the Center of Excellence for Innovation in Human Health Sciences of the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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Cited by (0)
TH performed the experiments and analyses, and wrote the manuscript. SI and CI assisted with the experiments. KM assisted with the experiments and with drafting the manuscript. TG organized the study. The authors have no conflicts of interest to declare.