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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.


Fasting-induced hepatosteatosis develops in WT and Casp2−/− mice. Histological analysis of liver from (a) male and (b) female fed and fasted WT and Casp2−/− mice (×20 magnification). Inset boxes display zoomed in region of image. Bar graphs show liver triglyceride levels as measured by biochemical assay. Values are mean±S.D. (n=4–8). Values are mean±S.D. (n=4–8). Unpaired t-test: ***P<0.001 and ****P<0.0001. Scale bar, 100 μm.
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fig4: Fasting-induced hepatosteatosis develops in WT and Casp2−/− mice. Histological analysis of liver from (a) male and (b) female fed and fasted WT and Casp2−/− mice (×20 magnification). Inset boxes display zoomed in region of image. Bar graphs show liver triglyceride levels as measured by biochemical assay. Values are mean±S.D. (n=4–8). Values are mean±S.D. (n=4–8). Unpaired t-test: ***P<0.001 and ****P<0.0001. Scale bar, 100 μm.

Mentions: Prolonged fasting in mice is known to reduce hepatocyte cell size and liver mass.26 Although this may be accounted for by a decrease in protein liver content, we first wanted to determine other possible reasons for why fasting liver mass differed between male WT and Casp2−/− mice. Histological analysis of liver, demonstrating lipid droplet accumulation in fasted hepatocytes, and measurement of liver triglycerides showed no difference between genotypes (Figures 4a and b). This indicates that Casp2 does not affect fasting-induced hepatosteatosis in male and female mice. Glycogen content can also influence liver mass and was therefore determined in male mice; however, there was high variability with no difference between genotypes (data not shown). These results indicate that the difference in fasted male liver mass is not due to altered glycogen content or altered lipid uptake.


Sex-specific alterations in glucose homeostasis and metabolic parameters during ageing of caspase-2-deficient mice
Fasting-induced hepatosteatosis develops in WT and Casp2−/− mice. Histological analysis of liver from (a) male and (b) female fed and fasted WT and Casp2−/− mice (×20 magnification). Inset boxes display zoomed in region of image. Bar graphs show liver triglyceride levels as measured by biochemical assay. Values are mean±S.D. (n=4–8). Values are mean±S.D. (n=4–8). Unpaired t-test: ***P<0.001 and ****P<0.0001. Scale bar, 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Fasting-induced hepatosteatosis develops in WT and Casp2−/− mice. Histological analysis of liver from (a) male and (b) female fed and fasted WT and Casp2−/− mice (×20 magnification). Inset boxes display zoomed in region of image. Bar graphs show liver triglyceride levels as measured by biochemical assay. Values are mean±S.D. (n=4–8). Values are mean±S.D. (n=4–8). Unpaired t-test: ***P<0.001 and ****P<0.0001. Scale bar, 100 μm.
Mentions: Prolonged fasting in mice is known to reduce hepatocyte cell size and liver mass.26 Although this may be accounted for by a decrease in protein liver content, we first wanted to determine other possible reasons for why fasting liver mass differed between male WT and Casp2−/− mice. Histological analysis of liver, demonstrating lipid droplet accumulation in fasted hepatocytes, and measurement of liver triglycerides showed no difference between genotypes (Figures 4a and b). This indicates that Casp2 does not affect fasting-induced hepatosteatosis in male and female mice. Glycogen content can also influence liver mass and was therefore determined in male mice; however, there was high variability with no difference between genotypes (data not shown). These results indicate that the difference in fasted male liver mass is not due to altered glycogen content or altered lipid uptake.

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.