Gene-by-Sex Interactions in Mitochondrial Functions and Cardio-Metabolic Traits

Norheim, Frode; Hasin-Brumshtein, Yehudit; Vergnes, Laurent; Krishnan, Karthickeyan Chella; Pan, Calvin; Seldin, Marcus M.; Hui, Simon T.; Mehrabian, Margarete; Zhou, Zhiqiang; Gupta, Sonul; Parks, Brian W.; Walch, Axel; Reue, Karen; Hofmann, Susanna M.; Arnold, Arthur P.; Lusis, Aldons J.

doi:10.1016/j.cmet.2018.12.013

Cited by 88 publications

(102 citation statements)

References 88 publications

(118 reference statements)

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“…Strikingly, male and female flies showed a vastly different response to wild-type and mutant Lipin with an overlap of only about 20% of the genes that responded at least 1.5fold in both sexes. This result is in accordance with an increasing number of studies that find substantial differences in metabolic gene expression between the sexes (54)(55)(56).…”

Section: Discussionsupporting

confidence: 91%

Nuclear translocation ability of Lipin differentially affects gene expression and survival in fed and fasting Drosophila

Hood

Kofler

Chen

et al. 2020

Journal of Lipid Research

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Lipins are eukaryotic proteins with functions in lipid synthesis and the homeostatic control of energy balance. They execute these functions by acting as phosphatidate phosphatase enzymes in the cytoplasm and by changing gene expression after translocation into the cell nucleus, in particular under fasting conditions. Here, we asked whether nuclear translocation and enzymatic activity of Drosophila Lipin serve essential functions and how gene expression changes, under both fed and fasting conditions, when nuclear translocation is impaired. To address these questions, we created a Lipin null mutant, a mutant expressing Lipin lacking a nuclear localization signal (LipinΔNLS), and a mutant expressing enzymatically dead Lipin. Our data support the conclusion that the enzymatic, but not the nuclear gene regulatory activity of Lipin, is essential for survival. Notably, adult LipinΔNLS flies were not only viable but also exhibited improved life expectancy. In contrast, they were highly susceptible to starvation. Both the improved life expectancy in the fed state and the decreased survival in the fasting state correlated with changes in metabolic gene expression. Moreover, increased life expectancy of fed flies was associated with a decreased metabolic rate. Interestingly, in addition to metabolic genes, genes involved in feeding behavior and the immune response were mis-regulated in LipinΔNLS flies. Combined, our data suggest that nuclear activity of Lipin influences the genomic response to nutrient availability with effects on life expectancy and starvation resistance. Thus, nutritional or therapeutic approaches that aim at lowering nuclear translocation of lipins in humans may be worth exploring.

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Section: Discussionsupporting

confidence: 91%

Nuclear translocation ability of Lipin differentially affects gene expression and survival in fed and fasting Drosophila

Hood

Kofler

Chen

et al. 2020

Journal of Lipid Research

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“…Accordingly, upon the recent study of sex differences in cardio-metabolic traits in a large panel of inbred mouse strains, males were found to have reduced mitochondrial function in adipose tissues, which was associated with an increased susceptibility to obesity and metabolic disorders. These sex differences correlated with the expression of a cluster of genes involved in adipose tissue 'beiging' and mitochondrial functions in adipose tissues [28].…”

Section: Biological Sex As a Determinant Of Energy Balance And Body Cmentioning

confidence: 93%

Sex differences in metabolic regulation and diabetes susceptibility

et al. 2019

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Gender and biological sex impact the pathogenesis of numerous diseases, including metabolic disorders such as diabetes. In most parts of the world, diabetes is more prevalent in men than in women, especially in middle-aged populations. In line with this, considering almost all animal models, males are more likely to develop obesity, insulin resistance and hyperglycaemia than females in response to nutritional challenges. As summarised in this review, it is now obvious that many aspects of energy balance and glucose metabolism are regulated differently in males and females and influence their predisposition to type 2 diabetes. During their reproductive life, women exhibit specificities in energy partitioning as compared with men, with carbohydrate and lipid utilisation as fuel sources that favour energy storage in subcutaneous adipose tissues and preserve them from visceral and ectopic fat accumulation. Insulin sensitivity is higher in women, who are also characterised by higher capacities for insulin secretion and incretin responses than men; although, these sex advantages all disappear when glucose tolerance deteriorates towards diabetes. Clinical and experimental observations evidence the protective actions of endogenous oestrogens, mainly through oestrogen receptor α activation in various tissues, including the brain, the liver, skeletal muscle, adipose tissue and pancreatic beta cells. However, beside sex steroids, underlying mechanisms need to be further investigated, especially the role of sex chromosomes, fetal/neonatal programming and epigenetic modifications. On the path to precision medicine, further deciphering sex-specific traits in energy balance and glucose homeostasis is indeed a priority topic to optimise individual approaches in type 2 diabetes prevention and treatment.

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“…To tackle this issue, a panel of over 100 inbred strains of mice, known as the Hybrid Mouse Diversity Panel was generated by the Lusis laboratory (143). This panel offers important insights into genetically-derived differences in phenotype among inbred mice, and has been used to show that plasma TGs in mice fed a high fat/high sucrose diet are regulated by different quantitative trait loci (QTLs) on mouse chromosome 7 in male and female mice (144). Mice made hyperlipidemic by expression of human APOE-Leiden and human cholesteryl ester transfer protein (CETP) revealed that plasma TG levels varied widely in the different genetic backgrounds (from ∼100 to 1,500 mg/dL) and highlighted a TG locus on chromosome 1, containing several genes with unknown functions in TG metabolism (145).…”

Section: Mouse Population Models and Models Of Secondary Hypertriglycmentioning

confidence: 99%

Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

Basu

Bornfeldt

2020

Front. Endocrinol.

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Human studies support a strong association between hypertriglyceridemia and atherosclerotic cardiovascular disease (CVD). However, whether a causal relationship exists between hypertriglyceridemia and increased CVD risk is still unclear. One plausible explanation for the difficulty establishing a clear causal role for hypertriglyceridemia in CVD risk is that lipolysis products of triglyceride-rich lipoproteins (TRLs), rather than the TRLs themselves, are the likely mediators of increased CVD risk. This hypothesis is supported by studies of rare mutations in humans resulting in impaired clearance of such lipolysis products (remnant lipoprotein particles; RLPs). Several animal models of hypertriglyceridemia support this hypothesis and have provided additional mechanistic understanding. Mice deficient in lipoprotein lipase (LPL), the major vascular enzyme responsible for TRL lipolysis and generation of RLPs, or its endothelial anchor GPIHBP1, are severely hypertriglyceridemic but develop only minimal atherosclerosis as compared with animal models deficient in apolipoprotein (APO) E, which is required to clear TRLs and RLPs. Likewise, animal models convincingly show that increased clearance of TRLs and RLPs by LPL activation (achieved by inhibition of APOC3, ANGPTL3, or ANGPTL4 action, or increased APOA5) results in protection from atherosclerosis. Mechanistic studies suggest that RLPs are more atherogenic than large TRLs because they more readily enter the artery wall, and because they are enriched in cholesterol relative to triglycerides, which promotes pro-atherogenic effects in lesional cells. Other mechanistic studies show that hepatic receptors (LDLR and LRP1) and APOE are critical for RLP clearance. Thus, studies in animal models have provided additional mechanistic insight and generally agree with the hypothesis that RLPs derived from TRLs are highly atherogenic whereas hypertriglyceridemia due to accumulation of very large TRLs in plasma is not markedly atherogenic in the absence of TRL lipolysis products.

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Gene-by-Sex Interactions in Mitochondrial Functions and Cardio-Metabolic Traits

Cited by 88 publications

References 88 publications

Nuclear translocation ability of Lipin differentially affects gene expression and survival in fed and fasting Drosophila

Nuclear translocation ability of Lipin differentially affects gene expression and survival in fed and fasting Drosophila

Sex differences in metabolic regulation and diabetes susceptibility

Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

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