Sex-different hepatic glycogen content and glucose output in rats

Abstract

BackgroundGenes involved in hepatic metabolism have a sex-different expression in rodents. To test whether male and female rat livers differ regarding lipid and carbohydrate metabolism, whole-genome transcript profiles were generated and these were complemented by measurements of hepatic lipid and glycogen content, fatty acid (FA) oxidation rates and hepatic glucose output (HGO). The latter was determined in perfusates from in situ perfusion of male and female rat livers. These perfusates were also analysed using nuclear magnetic resonance (NMR) spectroscopy to identify putative sex-differences in other liver-derived metabolites. Effects of insulin were monitored by analysis of Akt-phosphorylation, gene expression and HGO after s.c. insulin injections.ResultsOut of approximately 3 500 gene products being detected in liver, 11% were significantly higher in females, and 11% were higher in males. Many transcripts for the production of triglycerides (TG), cholesterol and VLDL particles were female-predominant, whereas genes for FA oxidation, gluconeogenesis and glycogen synthesis were male-predominant. Sex-differences in mRNA levels related to metabolism were more pronounced during mild starvation (12 h fasting), as compared to the postabsorptive state (4 h fasting). No sex-differences were observed regarding hepatic TG content, FA oxidation rates or blood levels of ketone bodies or glucose. However, males had higher hepatic glycogen content and higher HGO, as well as higher ratios of insulin to glucagon levels. Based on NMR spectroscopy, liver-derived lactate was also higher in males. HGO was inhibited by insulin in parallel with increased phosphorylation of Akt, without any sex-differences in insulin sensitivity. However, the degree of Thr172-phosphorylated AMP kinase (AMPK) was higher in females, indicating a higher degree of AMPK-dependent actions.ConclusionsTaken together, males had higher ratios of insulin to glucagon levels, higher levels of glycogen, lower degree of AMPK phosphorylation, higher expression of gluconeogenic genes and higher hepatic glucose output. Possibly these sex-differences reflect a higher ability for the healthy male rat liver to respond to increased energy demands.

Sex-dependent hepatic transcripts and metabolites in the development of glucose intolerance and insulin resistance in Zucker diabetic fatty rats

“…On the other hand, these disease-related changes in transcripts and metabolites might only be a consequence of reduced insulin sensitivity and/or hyperglycaemia. However, the sex differences observed in this study are similar to those described in healthy rats, with 50% of the sexdependent genes from this study being similar to those observed in SD rats (Gustavsson et al 2010). These include gene products such as glycerol-3-phosphate acyltransferase and acetyl-coenzyme A synthetase 2 (being female-predominant and reduced upon high-fat feeding) and lactate dehydrogenase A and CPT-1a (being male-predominant and induced upon high-fat feeding).…”

“…Furthermore, a significant difference between males and females developing diabetes as a function of dietary fat content is accompanied by a difference in triglyceride/apolipoprotein B ratios (Corsetti et al 2000), with females secreting more triglyceride-enriched lipoprotein particles. This is in line with results obtained in healthy Sprague-Dawley (SD) rats, with females expressing higher levels of lipogenic genes in their livers (Gustavsson et al 2010) as well as having a greater capacity for hepatic uptake of long-chain fatty acids (FAs), synthesis of triglycerides and assembly of very-low-density lipoprotein (VLDL) particles (SolerArgilaga et al 1975, Soler-Argilaga & Heimberg 1976, Kushlan et al 1981.…”

“…This might lead to a greater production of ROS during situations of increased hepatic lipid load. Furthermore, we have recently shown that healthy SD male rats have a greater hepatic turnover of carbohydrates, including higher levels of glycogen, higher expression of gluconeogenic genes and higher hepatic glucose output (Gustavsson et al 2010). Taken together, it is possible that these differences in hepatic lipid and carbohydrate metabolism might contribute to a higher risk of developing hepatic insulin resistance and hyperglycaemia in males compared with females during situations of increased hepatic fat and/or insufficient insulin production.…”

Acute and Subchronic Toxicity of Mulberry Fruits

“…In addition, our data also demonstrated that the female rats showed trends to increase blood sugar level following mulberry administration much more than male. Based on the previous data which reported the difference in carbohydrate and fat metabolism between male and female (Gustavsson et al, 2010) and high carbohydrate especially fructose content in mulberry fruits, we did suggest that the increase blood sugar level in female rat might be associated with the lower carbohydrate metabolism in female rat. However, all changes observed in this study were still in normal range.…”

Estrogens in the Control of Growth Hormone Actions in Liver

“…As mentioned above, sex hormones imprint a sex-dependent pattern of pituitary GH hormone secretion which is a major player in establishing and maintaining the sexual dimorphism of hepatic gene transcription that emerges in rodents at puberty. Sexdependent expression and GH regulation characterizes several families of hepatic genes involved in endo-and xenobiotic metabolism as well as relevant metabolic functions (e.g., lipid metabolism); 20-30% of all hepatic genes has a sex-specific expression pattern in rodents (Tannenbaum et al, 2001;Stahlberg et al, 2004;Gustavsson et al, 2010). Most of these hepatic sex differences are explained by the female-specific secretion of GH, through the induction of female-predominant transcripts and suppression of male-predominant.…”