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

Rolf Gruetter, Ana Francisca Leal Silva Soares, Hongxia Lei, Marc Moniatte, Jonathan Paz Montoya
Wiley-Blackwell, 2017
Journal paper

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.

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Rolf Gruetter, Ana Francisca Leal Silva Soares, Hongxia Lei, Marc Moniatte, Jonathan Paz Montoya
Wiley-Blackwell, 2017
Journal paper

Abstract

Official source

https://infoscience.epfl.ch/record/229401?ln=en

About this result

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Impact of hepatic lipid accumulation and composition on glucose tolerance and insulin sensitivity: a longitudinal study in male and female mice

Rolf Gruetter, Ana Francisca Leal Silva Soares, Hongxia Lei

Background and aims: Metabolic disruptions characterized by high hepatic lipid content (HLC) are associated with impairments in whole body glucose homeostasis. To gain insight on the role of hepatic lipids in the metabolic performance in the absence artificial metabolic stresses we measured non- invasively and longitudinally the HLC and profile in mice during adult devel - opment by Magnetic Resonance (MR) Spectroscopy in vivo . In parallel, mice were challenged with insulin and glucose tolerance tests. Materials and methods: Male (N=10) and female (N=10) C57Bl/6J mice were studied at 3 (3Mo), 7 (7Mo) and 10 months (10Mo) of age. Mice were scanned in a 14.1 T magnet with a 1 H quadrature surface coil over the abdo - men. Localized 1 H spectra were acquired from a 8 μl volume with stimulated echo acquisition mode sequence and the HLC expressed as the percent of to - tal 1 H MR signal, with corrections for spin-spin relaxation effects. Additional spectra were acquired from the same volume with suppression of the water signal to enable the detection and quantification of all the lipid protons. The lipid profile was characterized by the following indices: saturated component (SC); unsaturated fatty acyl chains (UFA); mean number of double bonds per fatty acyl chain (ndb/FA), mean number of poly-unsaturated double bonds per fatty acyl chain (PUdb/FA) and per UFA (PUdb/UFA); mean chain length (MCL). OGTTs (1.5 g/Kg) and i.p. insulin tolerance tests (ITTs) were per - formed after a 6h-fast. Plasma insulin was determined by ELISA and insulin sensitivity estimated with the quantitative insulin check index (QUICKI) as the inverse of the log 10 sum of fasting insulin (μIU/ml) and fasting glucose (mg/dl). Data are expressed as mean ± SEM. Statistical significance was ac - cepted for a P < 0.05 (one-way ANOVA with Newman-Keuls post test) and correlations assessed by the Pearson r coefficient. Results: In males, the HLC at 3Mo was 1.35 ± 0.15%, increasing to 3.06 ± 0.38% at 7Mo, not different from 2.70 ± 0.31% at 10Mo. Females had higher HLC at 3Mo (2.63 ± 0.19%) but no further changes henceforward (2.31 ± 0.20% at 7Mo; 2.36 ± 0.20% at10 Mo). In males, the SC and MCL of hepatic lipids increased with age, with a trend for decreased PUdb/FA and PUdb/ UFA with no changes in ndb/FA or UFA content. Females showed the same trends. Glycemia 3h-post ITT and 2h-post OGTT was lower in females, while QUICKI was higer. These scores were preserved until 10Mo in females. In males, glycemia 2-h post OGTT increased with age and the area above the curve (AAC) for the ITT decreased. In males, but not females, higher body weight correlated with hepatic lipid accumulation ( r = 0.7); worse ITT scores correlated with higher body weight ( r = -0.6) and HLC ( r = -0.7) and lower Pudb/UFA ( r = 0.5); worse OGTT scores correlated with higher HLC ( r = 0.4). Conclusion: In male mice, loss of insulin sensitivity correlated with weight gain, HL accumulation and lower poly-unsaturation. Glucose intolerance was specifically associated with HLC, suggesting a deleterious effect of lipids on the adaptation of hepatic metabolism to the fed state. This behaviour was not observed in females even if they showed similar HLC. In fact, the poly- unsaturation of HL in females didn’t change with HLC, suggesting a positive effect of PUFA on preserving the hepatic metabolic performance.

Springer2014

The role of nicotinamide riboside kinases in mammalian NAD⁺ metabolism

Joanna Ratajczak

NAD+ has emerged as a central metabolic node and an important co-substrate for the activity of various enzymes, including the protein deacetylase SIRT1. Different strategies to increase NAD+ bioavailability have been shown to boost SIRT1 activity, which results in protection against metabolic disease, neurodegenerative disorders and certain types of cancer. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have recently been discovered as new NAD+ precursors. Recent studies have shown that dietary supplementation with NR or NMN prevented against high-fat diet-induced body weight gain. However, the physiological role of NR in mammalian metabolism remains largely unexplored. In this project, we focused on the first step of NR metabolism â the phosphorylation of NR by nicotinamide riboside kinases (NRK1 and NRK2). We have investigated the role of NRKs in the metabolism of NAD+ precursors and mammalian physiology in vivo. The results obtained indicate that NRKs are the rate-limiting and essential step for NR- and NMN-driven NAD+ synthesis in hepatocytes and that NMN has to be extracellularly converted to NR for its use as an NAD+ precursor. Accordingly, animals lacking NRK1 have defects in NR/NMN utilization. We demonstrated that effective NR utilization is key for the maintenance of metabolic homeostasis as NRK1 whole-body KO mice display numerous alterations in glucose and lipid management. Using NRK1 liver-specific KO mice, we demonstrate that NRK1 is required to maintain hepatic NAD+ levels and mitochondrial function upon high-fat feeding. Consequently, NRK1LKO mice are sensitized to diet-induced glucose intolerance and insulin resistance. Finally, we show that both isoforms of NRK are redundant in mediating NR/NMN effects in muscle. Hence, this work identifies NRKs as a novel valuable target in the fight against metabolic disease and indicates that the regulation of NRK will enable us to find novel ways of enhancing NAD+ availability. Moreover, it has unveiled a critical role of NRK1 for the metabolism of diverse forms of Vitamin B3 and highlights how circulating NR is key to preserve metabolic health upon dietary challenges.

EPFL2017

This study demonstrates the suitability of magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) for the imaging of congenital portosystemic shunts (PSS) in mice, a vascular abnormality in which mesenteric blood bypasses the liver and is instead drained directly to the systemic circulation. The non-invasive diagnosis performed in tandem with other experimental assessments permits further characterization of liver, whole-body and brain metabolic defects associated with PSS. Magnetic resonance measurements were performed in a 26-cm, horizontal-bore, 14.1-T magnet. MRA was obtained with a three-dimensional gradient echo sequence (GRE; in-plane resolution, 234 × 250 × 234 μm3 ) using a birdcage coil. Two-dimensional GRE MRI with high spatial resolution (in-plane resolution, 100 × 130 μm2 ; slices, 30 × 0.3 mm) was performed using a surface coil. Brain- (dorsal hippocampus) and liver-localized 1 H magnetic resonance spectroscopy (MRS) was also performed with the surface coil. Whole-body metabolic status was evaluated with an oral glucose tolerance test (OGTT). Both MRA and anatomical MRI allowed the identification of hepatic vessels and the diagnosis of PSS in mice. The incidence of PSS was about 10%. Hepatic lipid content was higher in PSS than in control mice (5.1 ± 2.8% versus 1.8 ± 0.6%, p = 0.02). PSS mice had higher brain glutamine concentration than controls (7.3 ± 1.0 μmol/g versus 2.7 ± 0.6 μmol/g, p < 0.0001) and, conversely, lower myo-inositol (4.2 ± 0.6 μmol/g versus 6.0 ± 0.4 μmol/g, p < 0.0001), taurine (9.7 ± 1.2 μmol/g versus 11.0 ± 0.4 μmol/g, p < 0.01) and total choline (0.9 ± 0.1 μmol/g versus 1.2 ± 0.1 μmol/g, p < 0.001) concentrations. Fasting blood glucose and plasma insulin were lower in PSS than in control mice (4.7 ± 0.5mM versus 8.8 ± 0.6mM, p < 0.0001; and 0.04 ± 0.03 μg/L versus 0.3 ± 0.2 μg/L, p = 0.02, respectively). Glucose clearance during OGTT was delayed and less efficient in PSS mice than in controls. Thus, given the non-negligible incidence of PSS in inbred mice, the undiagnosed presence of PSS will, importantly, have an impact on experimental outcomes, notably in studies addressing brain, liver or whole-body metabolism.

2018