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. 2010 Sep;34(9):1427-33.
doi: 10.1038/ijo.2010.78. Epub 2010 Apr 20.

Sensitivity to the satiating effects of exendin 4 is decreased in obesity-prone Osborne-Mendel rats compared to obesity-resistant S5B/Pl rats

S D Primeaux  1 , M J Barnes, H D Braymer, G A Bray
Affiliations

Sensitivity to the satiating effects of exendin 4 is decreased in obesity-prone Osborne-Mendel rats compared to obesity-resistant S5B/Pl rats

S D Primeaux et al. Int J Obes (Lond). 2010 Sep.

Abstract

Background: Osborne-Mendel (OM) rats are prone to obesity when fed a high-fat diet, whereas S5B/Pl (S5B) rats are resistant to diet-induced obesity when fed the same diet. OM rats have a decreased satiation response to fatty acids infused in the gastrointestinal tract, compared to S5B rats. One possible explanation is that OM rats are less sensitive to the satiating hormone, glucagon-like peptide 1 (GLP-1). GLP-1 is produced in the small intestine and is released in response to a meal. The current experiments examined the role of GLP-1 in OM and S5B rats.

Methods: Experiment 1 examined preproglucagon mRNA expression in the ileum of OM and S5B rats fed a high-fat (55% kcal) or low-fat (10% kcal) diet. Experiment 2 investigated the effects of a 2 h high-fat meal after a 24 h fast in OM and S5B rats on circulating GLP-1 (active) levels. Experiment 3 examined the effects of exendin-4 (GLP-1 receptor agonist) administration on the intake of a high-fat or a low-fat diet in OM and S5B rats.

Results: Preproglucagon mRNA levels were increased in the ileum of OM rats compared to S5B rats and were increased by high-fat diet in OM and S5B rats. OM and S5B rats exhibited a similar meal-initiated increase in circulating GLP-1 (active) levels. Exendin-4 dose dependently decreased food intake to a greater extent in S5B rats compared to OM rats. The intake of low-fat diet, compared to the intake of high-fat diet, was more sensitive to the effects of exendin-4 in these strains.

Conclusions: These results suggest that though OM and S5B rats have similar preproglucagon mRNA expression in the ileum and circulating GLP-1 levels, OM rats are less sensitive to the satiating effects of GLP-1. Therefore, dysregulation of the GLP-1 system may be a mechanism through which OM rats overeat and gain weight.

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Conflict of interest statement

Conflict of interest: The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Daily low fat and high fat food intake was measured for 14 days. OM rats ate more high fat food (HF) than low fat food (LF) throughout the 14 days. S5B rats ate more high fat food (HF) than low fat food (LF) on most days. OM rats consumed more high fat diet than S5B rats from Days 2–13. Data is expressed in kilocalories (kcal) and shown as mean ± SEM. * OM high fat diet vs. OM low fat diet; # S5B high fat diet vs. S5B low fat diet; (p<.05).
Figure 2
Figure 2
A. Weekly body weight change indicated that OM rats fed a high fat diet (HF) gained more weight than OM rats fed a low fat diet (LF). S5B rats fed a high fat diet (HF) gained more weight than S5B rats fed a low fat diet (LF). Data are expressed as the cumulative weekly change from pre-diet body weight and shown as mean ± SEM. * OM high fat diet vs. OM low fat diet; # S5B high fat diet vs. S5B low fat diet; (p<.05). B. OM rats had a higher index of body fat than S5B rats. High fat diet increased the index of body fat in OM rats, but not S5B rats. The index of body fat is based on retroperitoneal and epididymal fat pad weight and shown as mean ± SEM. * OM low fat diet vs. OM high fat diet; # OM vs. S5B: (p<.05).
Figure 3
Figure 3
Preproglucagon mRNA levels were higher in the ileum of OM than S5B rat following 14d access to a high fat or low fat diet. Access to a high fat diet increased preproglucagon mRNA levels in both OM and S5B rats. Preproglucagon mRNA levels were normalized to 18S and are shown as mean ± SEM. * high fat diet vs. low fat diet; # OM vs. S5B; (p<.05).
Figure 4
Figure 4
Plasma GLP-1 (active) levels were measured in OM and S5B rats fed a high fat diet and either fasted for 24h or fasted for 24h and then refed for 2h. In OM and S5B rats, circulating GLP-1 (active) levels were increased following refeeding. Data are shown as mean ± SEM. * Fasted vs. Refed, (p<.05).
Figure 5
Figure 5
A. S5B rats were administered varying doses of Ex-4 following a 24h fast and given access to either low fat or high fat diet. Ex-4 dose dependently decreased high fat and low fat diet intake at 1h, 2h, and 4h. B. Following a 24h fast, OM were administered Ex-4 and low fat and high fat intake were measured. The two highest doses of Ex-4 (5μg/kg and 10μg/kg) decreased low fat diet intake at 1h, 2h, and 4h and high fat diet intake at 1h. The highest dose of Ex-4 decreased high fat food intake at 2h, but not at 4h. Data are expressed as cumulative food intake in kilocalories (kcal) and shown as mean ± SEM. * saline vs. Ex-4, (p<.05).
Figure 6
Figure 6
High fat and low fat food intake was measured 24h following Ex-4 administration. A. In S5B rats, low fat and high fat diet intake was suppressed by Ex- 4 (1μg/kg, 5μg/kg, 10μg/kg and 5μg/kg, 10μg/kg). B. In OM rats, Ex-4 administration suppressed low fat intake and high fat food intake (5μg/kg, 10μg/kg and 10μg/kg). Data are expressed as cumulative food intake in kilocalories (kcal) and shown as mean ± SEM. * saline vs. Ex-4, (p<.05).
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