The High-Fat Diet–Fed Mouse

Abstract

This study characterizes the high-fat diet-fed mouse as a model for impaired glucose tolerance (IGT) and type 2 diabetes. Female C57BL/6J mice were fed a high-fat diet (58% energy by fat) or a normal diet (11% fat). Body weight was higher in mice fed the high-fat diet already after the first week, due to higher dietary intake in combination with lower metabolic efficiency. Circulating glucose increased after 1 week on high-fat diet and remained elevated at a level of ϳ1 mmol/l throughout the 12-month study period. In contrast, circulating insulin increased progressively by time. Intravenous glucose challenge revealed a severely compromised insulin response in association with marked glucose intolerance already after 1 week. To illustrate the usefulness of this model for the development of new treatment, mice were fed an orally active inhibitor of dipeptidyl peptidase-IV (LAF237) in the drinking water (0.3 mg/ ml) for 4 weeks. This normalized glucose tolerance, as judged by an oral glucose tolerance test, in association with augmented insulin secretion. We conclude that the high-fat diet-fed C57BL/6J mouse model is a robust model for IGT and early type 2 diabetes, which may be used for studies on pathophysiology and development of new treatment. Diabetes 53 (Suppl. 3):S215-S219, 2004 T here is a need for new treatment modalities of type 2 diabetes in view of the progressive deterioration of metabolic control that occurs in spite of intense treatment with existing modalities (1). New treatment should aim at normalizing the basic defects in the disease, which are islet dysfunction in combination with insulin resistance (2). There is, however, also a need for more knowledge of the molecular mechanisms underlying these basic defects. These two needs require reliable and clinically relevant experimental models. Most animal models do not, however, fulfill such requirements, since they are based on monogenic disorders of little relevance for human diabetes (3-5) or on chemical destruction of ␤-cells, which is also of less clinical relevance (6,7). An important and relevant model, however, is the high-fat diet-fed C57BL/6J mouse model. This model was originally introduced by Surwit et al. in 1988 (8). The model has shown to be accompanied by insulin resistance, as determined by intravenous glucose tolerance tests, and of insufficient islet compensation to the insulin resistance (9). The model has, accordingly, been used in studies on pathophysiology of impaired glucose tolerance (IGT) and type 2 diabetes (10 -12) and for development of new treatments (13-16). Here we report the characteristics of this model and illustrate its relevance in studies on developing new treatment modes by showing beneficial influences of a novel and efficient orally active inhibitor of dipeptidyl peptidase-IV (DPP-IV), which is a new mode for treating type 2 diabetes by preventing the degradation of glucagon-like peptide-1 (GLP-1) (17-19). RESEARCH DESIGN AND METHODSFemale C57BL/6J mice were purchased from Taconic (Skensved, Denmark). The ani...

Metabolic and behavioral responses to high-fat feeding in mice selectively bred for high wheel-running activity

“…Food intake usually decreases when animals are switched to an HFD, and they apparently require less calories as fat to maintain energy balance compared with calories from carbohydrates. 6,29 In the control males and females, and to a lesser extent also observed in the selected males, the decrease in intake of HFD was not sufficient to prevent the gain of body fat mass. The selected females, however, showed an entirely different response to the HFD: their food intake actually slightly increased, whereas body mass remained constant (see Figure 1).…”

“…[3][4][5][6] This study investigated whether and how such an effect may be influenced by physical activity. For this Mean and s.e.m.…”

“…[3][4][5][6][7] In particular, the use of selectively bred and genetically for example, previously reported that spontaneous wheel running behavior was able to treat DIO. In addition, Patterson et al 14 observed that 3 weeks of wheel running behavior at the juvenile stage delays DIO in selectively bred DIO-prone rats, probably by favorably altering hypothalamic pathways controlling energy balance.…”

“…[3][4][5][6][7] In particular, the use of selectively bred and genetically engineered rodents that display diet-induced obesity (DIO) or obesity resistance has provided considerable insight about underlying mechanisms (for reviews, see Caroll et al 8 and Tschop and Heiman 9 ) Reports on whether and how physical activity could be involved in preventing dietary fat-induced obesity and associated metabolic derangements are less abundant. In part, this is attributable to the methodological problems that can arise when animals are 'forced' to be active.…”

High‐fat diet protects the blood–brain barrier in an Alzheimer's disease mouse model

“…High‐fat diet (HFD) is a well‐established model for generating impaired glucose tolerance and insulin resistance (Winzell & Ahren, 2004). The effect of HFD on the BBB is not well understood; data are limited, and the techniques to measure BBB functionality vary.…”