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Sex-specific alterations in glucose homeostasis and metabolic parameters during ageing of caspase-2-deficient mice

View Article: PubMed Central - PubMed

ABSTRACT

Gender-specific differences are commonly found in metabolic pathways and in response to nutritional manipulation. Previously, we identified a role for caspase-2 in age-related glucose homeostasis and lipid metabolism using male caspase-2-deficient (Casp2−/−) mice. Here we show that the resistance to age-induced glucose tolerance does not occur in female Casp2−/− mice and it appears to be independent of insulin sensitivity in males. Using fasting (18 h) as a means to further investigate the role of caspase-2 in energy and lipid metabolism, we identified sex-specific differences in the fasting response and lipid mobilization. In aged (18–22 months) male Casp2−/− mice, a significant decrease in fasting liver mass, but not total body weight, was observed while in females, total body weight, but not liver mass, was reduced when compared with wild-type (WT) animals. Fasting-induced lipolysis of adipose tissue was enhanced in male Casp2−/− mice as indicated by a significant reduction in white adipocyte cell size, and increased serum-free fatty acids. In females, white adipocyte cell size was significantly smaller in both fed and fasted Casp2−/− mice. No difference in fasting-induced hepatosteatosis was observed in the absence of caspase-2. Further analysis of white adipose tissue (WAT) indicated that female Casp2−/− mice may have enhanced fatty acid recycling and metabolism with expression of genes involved in glyceroneogenesis and fatty acid oxidation increased. Loss of Casp2 also increased fasting-induced autophagy in both male and female liver and in female skeletal muscle. Our observations suggest that caspase-2 can regulate glucose homeostasis and lipid metabolism in a tissue and sex-specific manner.

No MeSH data available.


Metabolic gene expression in the liver of fed and fasted WT and Casp2−/− mice. Metabolic gene expression in the liver of (a) male and (b) female fed and fasted mice. Values are mean±S.D. (n=4–8). One-way ANOVA: *P<0.05, **P<0.01, ***P<0.001 and ****P<0.0001.
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fig5: Metabolic gene expression in the liver of fed and fasted WT and Casp2−/− mice. Metabolic gene expression in the liver of (a) male and (b) female fed and fasted mice. Values are mean±S.D. (n=4–8). One-way ANOVA: *P<0.05, **P<0.01, ***P<0.001 and ****P<0.0001.

Mentions: Fasting stimulates the liver at the level of gene expression to increase pathways of gluconeogenesis while decreasing lipogenesis.17 Consistent with this, in male and female WT and Casp2−/− mice, fasting decreased hepatic gene expression of lipogenic genes while increasing expression of gluconeogenic PGC1α (Figures 5a and b). In addition, PPARγ was decreased in male WT and male and female Casp2−/− mice but not WT females (Figures 5a and b). Differences between genotypes were minimal, particularly in females, but interestingly in fed Casp2−/− males, hepatic levels of HSL, PPARα and PGC1β were significantly decreased compared to WT mice (Figure 5a). However, as ketone body production is similar to WT mice (Figure 2c), it is unclear if liver FA oxidation is affected. In contrast to gWAT, levels of Cpt1a were not altered in the liver of male Casp2−/− mice (Figure 5a).


Sex-specific alterations in glucose homeostasis and metabolic parameters during ageing of caspase-2-deficient mice
Metabolic gene expression in the liver of fed and fasted WT and Casp2−/− mice. Metabolic gene expression in the liver of (a) male and (b) female fed and fasted mice. Values are mean±S.D. (n=4–8). One-way ANOVA: *P<0.05, **P<0.01, ***P<0.001 and ****P<0.0001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979492&req=5

fig5: Metabolic gene expression in the liver of fed and fasted WT and Casp2−/− mice. Metabolic gene expression in the liver of (a) male and (b) female fed and fasted mice. Values are mean±S.D. (n=4–8). One-way ANOVA: *P<0.05, **P<0.01, ***P<0.001 and ****P<0.0001.
Mentions: Fasting stimulates the liver at the level of gene expression to increase pathways of gluconeogenesis while decreasing lipogenesis.17 Consistent with this, in male and female WT and Casp2−/− mice, fasting decreased hepatic gene expression of lipogenic genes while increasing expression of gluconeogenic PGC1α (Figures 5a and b). In addition, PPARγ was decreased in male WT and male and female Casp2−/− mice but not WT females (Figures 5a and b). Differences between genotypes were minimal, particularly in females, but interestingly in fed Casp2−/− males, hepatic levels of HSL, PPARα and PGC1β were significantly decreased compared to WT mice (Figure 5a). However, as ketone body production is similar to WT mice (Figure 2c), it is unclear if liver FA oxidation is affected. In contrast to gWAT, levels of Cpt1a were not altered in the liver of male Casp2−/− mice (Figure 5a).

View Article: PubMed Central - PubMed

ABSTRACT

Gender-specific differences are commonly found in metabolic pathways and in response to nutritional manipulation. Previously, we identified a role for caspase-2 in age-related glucose homeostasis and lipid metabolism using male caspase-2-deficient (Casp2&minus;/&minus;) mice. Here we show that the resistance to age-induced glucose tolerance does not occur in female Casp2&minus;/&minus; mice and it appears to be independent of insulin sensitivity in males. Using fasting (18&thinsp;h) as a means to further investigate the role of caspase-2 in energy and lipid metabolism, we identified sex-specific differences in the fasting response and lipid mobilization. In aged (18&ndash;22 months) male Casp2&minus;/&minus; mice, a significant decrease in fasting liver mass, but not total body weight, was observed while in females, total body weight, but not liver mass, was reduced when compared with wild-type (WT) animals. Fasting-induced lipolysis of adipose tissue was enhanced in male Casp2&minus;/&minus; mice as indicated by a significant reduction in white adipocyte cell size, and increased serum-free fatty acids. In females, white adipocyte cell size was significantly smaller in both fed and fasted Casp2&minus;/&minus; mice. No difference in fasting-induced hepatosteatosis was observed in the absence of caspase-2. Further analysis of white adipose tissue (WAT) indicated that female Casp2&minus;/&minus; mice may have enhanced fatty acid recycling and metabolism with expression of genes involved in glyceroneogenesis and fatty acid oxidation increased. Loss of Casp2 also increased fasting-induced autophagy in both male and female liver and in female skeletal muscle. Our observations suggest that caspase-2 can regulate glucose homeostasis and lipid metabolism in a tissue and sex-specific manner.

No MeSH data available.