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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.


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Improved glucose tolerance in aged Casp2−/− mice does not occur in females and is insulin-independent in males. (a) Insulin tolerance test in aged male and (b) aged female WT and Casp2−/− mice. Values are mean±S.D. (n=8–10). Unpaired t-test: ***P<0.01.
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fig1: Improved glucose tolerance in aged Casp2−/− mice does not occur in females and is insulin-independent in males. (a) Insulin tolerance test in aged male and (b) aged female WT and Casp2−/− mice. Values are mean±S.D. (n=8–10). Unpaired t-test: ***P<0.01.

Mentions: Previously, we observed reduced fed and fasted blood glucose levels in aged male Casp2−/− mice and protection from age-induced glucose intolerance that was observed in WT mice following glucose tolerance testing.10 Although aged Casp2−/− mice have increased oxidative damage, studies have shown that increased ROS in mice can result in enhanced insulin sensitivity.18 To determine if this was a reason for improved glucose tolerance in aged male Casp2−/− mice, insulin tolerance testing was performed following a 6-h fast. Although blood glucose was significantly lower in male Casp2−/− mice (6.29±0.89 mmol/l versus 8.49±1.1 mmol/l in WT mice) following fasting, there was no difference in the response to intraperitoneal (i.p.) injection of insulin (Figure 1a). As our previous findings were in male mice only, we performed glucose tolerance testing on aged female Casp2−/− mice but found no difference compared to WT mice (Figure 1b). These results suggest that caspase-2 influences glucose homeostasis in a sex-specific manner independent of insulin signaling.


Sex-specific alterations in glucose homeostasis and metabolic parameters during ageing of caspase-2-deficient mice
Improved glucose tolerance in aged Casp2−/− mice does not occur in females and is insulin-independent in males. (a) Insulin tolerance test in aged male and (b) aged female WT and Casp2−/− mice. Values are mean±S.D. (n=8–10). Unpaired t-test: ***P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Improved glucose tolerance in aged Casp2−/− mice does not occur in females and is insulin-independent in males. (a) Insulin tolerance test in aged male and (b) aged female WT and Casp2−/− mice. Values are mean±S.D. (n=8–10). Unpaired t-test: ***P<0.01.
Mentions: Previously, we observed reduced fed and fasted blood glucose levels in aged male Casp2−/− mice and protection from age-induced glucose intolerance that was observed in WT mice following glucose tolerance testing.10 Although aged Casp2−/− mice have increased oxidative damage, studies have shown that increased ROS in mice can result in enhanced insulin sensitivity.18 To determine if this was a reason for improved glucose tolerance in aged male Casp2−/− mice, insulin tolerance testing was performed following a 6-h fast. Although blood glucose was significantly lower in male Casp2−/− mice (6.29±0.89 mmol/l versus 8.49±1.1 mmol/l in WT mice) following fasting, there was no difference in the response to intraperitoneal (i.p.) injection of insulin (Figure 1a). As our previous findings were in male mice only, we performed glucose tolerance testing on aged female Casp2−/− mice but found no difference compared to WT mice (Figure 1b). These results suggest that caspase-2 influences glucose homeostasis in a sex-specific manner independent of insulin signaling.

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.


Related in: MedlinePlus