Sexual dimorphism in hepatic lipids is associated with the evolution of metabolic status in mice

Abstract

Ectopic lipid accumulation in the liver is implicated in metabolic disease in an age-and sex-dependent manner. The role of hepatic lipids has been well established within the scope of metabolic insults in mice, but has been insufficiently characterized under standard housing conditions, where age-related metabolic alterations are known to occur. We studied a total of 10 male and 10 female mice longitudinally. At 3, 7 and 11 months of age, non-invasive 1 H-magnetic resonance spectroscopy ( 1 H-MRS) was used to monitor hepatic lipid content (HLC) and fatty acid composition in vivo, and glucose homeostasis was assessed with glucose and insulin challenges.At the end of the study, hepatic lipids were comprehensively characterized by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometric analyses of liver tissue samples.In males, HLC increased from 1.4 ± 0.1% at 3 months to 2.9 ± 0.3% at 7 months (p < 0.01) and 2.7 ± 0.3% at 11 months (p < 0.05), in correlation with fasting insulin levels (p < 0.01, r = 0.51) and parameters from the insulin tolerance test (ITT; p < 0.001, r = -0.69 versus area under the curve; p < 0.01, r = -0.57 versus blood glucose drop at 1 h post-ITT; p < 0.01, r = 0.55 versus blood glucose at 3 h post-ITT). The metabolic performance of females remained the same throughout the study, and HLC was higher than that of males at 3 months (2.7 ± 0.2%, p < 0.01), but comparable at 7 months (2.2 ± 0.2%) and 11 months (2.2 ± 0.1%). Strong sexual dimorphism in bioactive lipid species, including diacylglycerols (higher in males, p < 0.0001), phosphatidylinositols (higher in females, p < 0.001) and omega-3 polyunsaturated fatty acids (higher in females, p < 0.01), was found to be in good correlation with metabolic scores at 11 months. Therefore, in mice housed under standard conditions, sex-specific composition of bioactive lipids is associated with metabolic protection in females, whose metabolic performance was independent of hepatic cytosolic lipid content.

Increased hepatic fatty acid polyunsaturation precedes ectopic lipid deposition in the liver in adaptation to high-fat diets in mice

“…Insulin resistance was shown to correlate with liver fat in nonalcoholic fatty liver disease patients [35], and in metabolically healthy men, liver fat was found to be closely associated with fasting insulin levels [36]. Similarly, we previously found a good correlation between liver fat in male mice and their metabolic status [37]. Hyperinsulinemia has been suggested to directly contribute to increased FA uptake by the liver [38], an important mechanism by which lipids accumulate in the liver in HFD models [14,15,39].…”

Sex‐specific metabolic responses to 6 hours of fasting during the active phase in young mice

“…However, given the sexual dimorphism in metabolic strategies (Hedrington & Davis, 2015; Mauvais‐Jarvis, 2015; Soares et al . 2017; Della Torre et al . 2018), and the varied response to CR (Mitchell et al .…”

Non‐invasive diagnosis and metabolic consequences of congenital portosystemic shunts in C57BL/6 J mice

“…2 Moreover, in response to the glucose load, the peak time was delayed in PSS mice relative to controls. Because the blood glucose peak is not expected to fluctuate in healthy mice, 13 nor to depend on fasting blood glucose, 29 our observations clearly demonstrate that glucose tolerance is altered in PSS mice. Several insulin-and glucose-mediated hepatic actions contribute to clear glucose from the blood from an oral glucose load, e.g.…”

“…Mice were studied at 6 months of age for shunt size by MRA (nine PSS mice) and MRI (seven PSS mice), and for the determination of the neurochemical profile of the hippocampus by 1 H‐MRS (nine PSS mice and nine control mice), as PSS‐associated metabolic alterations in the brain are consistent within the age range 3–12 months . To avoid possible aging‐associated confounding alterations, mice were studied at 3 months of age for the determination of hepatic lipid content by 1 H‐MRS (five PSS mice and six control mice) and for OGTT (six PSS mice and six control mice). Because some animals underwent more than one type of experiment, a total of nine PSS mice and nine control mice were used overall in these experiments.…”