Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C066

Oral Communications

Sex-dependent hepatic response to high fat diet in male and female C57bl/6 mice

J. Lebeck1, J. B. Vegger1, J. S. Thomsen1, A. Brüel1

1. Biomedicine, Aarhus University, Aarhus C, Denmark.


Obesity and secondary development of type-2-diabetes mellitus (T2D) is a major healthcare problem. Sex-differences exist in the prevalence of T2D with men being diagnosed at lower age and body mass index than women (1). Increased hepatic glucose production (HGP) is one of the key elements of the pathophysiology of T2D. Glycerol is a precursor for HGP and hepatic glycerol uptake via the glycerol channel AQP9 is regulated in a sex-specific manner. Similarly, glycerol kinase that phosphorylates glycerol into glycerol-3-phosphate is also influenced by sex (2). In this study we investigate the effect of 12 and 24 weeks of high fat diet (HFD) on hepatic glycerol handling in age-matched male (n=10+10, 10+8) and female (n=10+10, 9+10) mice. At the termination of the experiment the mice were anaesthetised using isoflurane inhalation (induction 4%, maintenance 2% in atmospheric air) and the liver was removed for immunoblotting and histology. Values are means ± S.E.M. and means are compared by either student t-test or ANOVA. After both 12 and 24 weeks of HFD male and female mice had a significantly increased bodyweight (BW) (g) (32.5 ± 0.3 vs. 48.4 ± 0.9, p<0.001 21.9 ± 0.5 vs. 29.5 ± 1.0, p<0.001) and (34.5 ± 0.8 vs. 51.1 ± 1.2, p<0.001, 22.3 ± 0.4 vs. 39.2 ± 2.2, p<0.001) when compared to controls. In male mice blood glucose levels (BG) (mmol/l) were increased after 12 and 24 weeks of HFD (7.7 ± 0.4 vs. 10.7 ± 0.7, p<0.001, 7.5 ± 0.03 vs. 10.2 ± 0.5, p<0.01) when compared to controls. In female mice the BG were only elevated after 24 weeks of HFD (7.0 ± 0.4 vs. 8.3 ± 0.3, ns, 5.5 ± 0.1 vs. 8.7 ± 0.1, p<0.001). Males demonstrated an 80 and 62% increase in liver weight (LW) in response to 12 and 24 weeks of HFD, respectively, when compared to controls. In females a 21 and 40% increase in LW were observed. LW normalized to BW increased after 24 weeks of HFD when compared to controls in male mice, whereas this ratio was decreased in female mice, which suggests a relatively lower hepatic fat accumulation in female than in male mice. This observation was supported by histological analysis of the liver. The hepatic expression of AQP9 remained unaffected by HFD in both male and female mice. However, after both 12 and 24 weeks of HFD female groups demonstrated a markedly higher hepatic AQP9 expression than male control mice (1.00 ± 0.09 vs. 0.20 ± 0.02, p<0.05, 1.15 ± 0.09 vs. 0.20 ± 0.02, p<0.01) and (1.0 ± 0.1 vs. 0.2 ± 0.0, p<0.05, 1.2 ± 0.2 vs 0.2 ± 0.0, p<0.01). The hepatic expression of glycerol kinase was increased after 12 and 24 weeks of HFD in female mice (1.0 ± 0.1 vs. 1.5 ± 0.1, p<0.001, 1.0 ± 0.1 vs. 1.7 ± 0.1, p<0.05) compared with controls, whereas the expression remained unaffected in males. In conclusion, the response to HFD is sex-dependent in C57bl/6 mice. Female mice respond with less hepatic steatosis than males and with an increased expression of glycerol kinase.

Where applicable, experiments conform with Society ethical requirements