Downregulation of plasma insulin levels and hepatic PPARgamma expression during the first week of caloric restriction in mice

Abstract

Calorie restriction extends lifespan by decreasing the rate of tumor formation, an effect occurring within 8 weeks of initiating a restricted diet. Our goal was to define how the first weeks of a calorie restricted diet (60% of ad libitum calories) affects putative mediators of the calorie restriction phenotype, focusing on regulators of fatty acid biosynthesis. In C57Bl/6 mice, insulin decreased over 50% (p<0.05) during the first week of calorie restriction whereas IGF-1 was unaffected. In the liver, PPARgamma mRNA fell to 13% of baseline after 1 week of calorie restriction (p<0.05), whereas hepatic SREBP-1c and SIRT1 mRNA levels were unaffected. No changes in abdominal or subcutaneous adipose tissue were observed until after 4 weeks of caloric restriction. We conclude that calorie restriction-induced decreases in insulin and hepatic PPARgamma are rapid enough to support a role for these molecules in triggering the initial phase of the calorie restriction phenotype.

Figure 1

Body weights in the 4 experimental groups. At 8 weeks of age mice were randomized to one of the 4 experimental groups that started calorie restriction at either 10 weeks of age (16-week calorie restriction group), 22 weeks of age (4-week calorie restriction group), or 25 weeks of age (1-week calorie restriction group). N=9 mice/group

Figure 2

Plasma glucose, insulin and IGF-1 levels measured at the time of sacrifice. Insulin levels were significantly decreased after 1 week of calorie restriction and glucose was significantly decreased after 4 weeks of calorie restriction, while IGF-1 levels did not significantly change from baseline. N=9 at each time point for glucose and 7-8 for insulin and IGF-1 * significantly different from control

Figure 3

Time course for the effects of calorie restriction on liver mRNA levels. The data from real-time PCR were normalized by 18 rRNA and are expressed relative to the control group (0 weeks of calorie restriction). Note that in liver PPARγ was decreased to less than 20% of baseline levels after only one week of a calorie restricted diet. N=4-5 per group * significantly different from control group

Figure 4

Effects of 16 weeks of calorie restriction on SIRT1 protein levels in the liver. N=5 per group

Figure 5

Time course for the effects of calorie restriction on subcutaneous adipose tissue mRNA levels. The data from real-time PCR were normalized by 18 rRNA and are expressed relative to the control group (0 weeks of calorie restriction). Note that PPARγ was unchanged from baseline, but SREBP-1c and FAS were significantly increased after 16 weeks of calorie restriction. N=4-5 per group * significantly different from control group

Figure 6

Time course for the effects of calorie restriction on abdominal adipose tissue mRNA levels. The data from real-time PCR were normalized by 18 rRNA and are expressed relative to the control group (0 weeks of calorie restriction). Note that PPARγ was unchanged from baseline, but SREBP-1c and FAS were significantly increased after 16 weeks of calorie restriction, the same pattern observed in subcutaneous adipose tissue. N=4-5 per group * significantly different from control group