Gene-by-environment modulation of lifespan and weight gain in the murine BXD family

How lifespan and body weight vary as a function of diet and genetic differences is not well understood. Here we quantify the impact of differences in diet on lifespan in a genetically diverse family of female mice, split into matched isogenic cohorts fed a low-fat chow diet (CD, n = 663) or a high-fat diet (HFD, n = 685). We further generate key metabolic data in a parallel cohort euthanized at four time points. HFD feeding shortens lifespan by 12%: equivalent to a decade in humans. Initial body weight and early weight gains account for longevity differences of roughly 4-6 days per gram. At 500 days, animals on a HFD typically gain four times as much weight as control, but variation in weight gain does not correlate with lifespan. Classic serum metabolites, often regarded as health biomarkers, are not necessarily strong predictors of longevity. Our data indicate that responses to a HFD are substantially modulated by gene-by-environment interactions, highlighting the importance of genetic variation in making accurate individualized dietary recommendations. Roy et al. quantify the impact of a high-fat diet across genetically diverse strains of mice, revealing a generally negative effect on lifespan but also a wide variability.

Reduced ech-6 expression attenuates fat-induced lifespan shortening in C. elegans

Wen Gao, Richardus Houtkooper, Yan Liu

Deregulated energy homeostasis represents a hallmark of aging and results from complex gene-by-environment interactions. Here, we discovered that reducing the expression of the gene ech-6 encoding enoyl-CoA hydratase remitted fat diet-induced deleterious effects on lifespan in Caenorhabditis elegans, while a basal expression of ech-6 was important for survival under normal dietary conditions. Lipidomics revealed that supplementation of fat in ech-6-silenced worms had marginal effects on lipid profiles, suggesting an alternative fat utilization for energy production. Transcriptomics further suggest a causal relation between the lysosomal pathway, energy production, and the longevity effect conferred by the interaction between ech-6 and fat diets. Indeed, enhancing energy production from endogenous fat by overexpressing lysosomal lipase lipl-4 recapitulated the lifespan effects of fat diets on ech-6-silenced worms. Collectively, these results suggest that the gene ech-6 is potential modulator of metabolic flexibility and may be a target for promoting metabolic health and longevity.

NATURE PORTFOLIO2022

The phenotypic impact of naturally occurring genetic and molecular mitochondrial variation in a Drosophila Genetic Reference Population

Roel Paulus Josephus Bevers

Genome-wide association (GWA) studies aim to dissect the relationship between genotype and phenotype. So far, the focus has been on nuclear genetic determinants as variation in the mitochondrial genome is often low in the study cohorts. Despite this observation, mitochondrial genomic variants are increasingly linked to metabolic and neurological disorders. Thus, there is much to gain from studying how mitochondrial variation interacts with nuclear variation and/or environment, and how this subsequently affects phenotypes. In my thesis I address these topics using Drosophila melanogaster as a model system, and specifically the Drosophila Genetic Reference Panel (DGRP). The DGRP consists of 200 sequenced and genetically diverse Drosophila populations and has been extensively used to study a wide-range of quantitative traits. However, in all of these studies, researchers have focussed on the influence of nuclear genetic variants in the absence of a high-resolution map of mitochondrial variants. To address this problem, we have developed a high-throughput method to specifically sequence mitochondrial DNA that enabled us to characterize mitochondrial genomic variation to an unprecedented depth. On average, each DGRP line had 25 mitochondrial variants (1 in 600 bp) and that most of the variants detected were unique for each line. However, we also found that some variants are more prevalent and show they can be used to construct mitochondrial haplotypes. We then used these haplotypes to test whether mitochondrial variation affected previously published phenotypes. We detected significant associations with 12 out of 259 publicly accessible phenotypes and found that these were mostly related to metabolism and responses to environmental cues. We selected one of the significant phenotypes, food intake in males, to verify our findings. We demonstrated the effect of mitochondrial haplotypes on the phenotype by swapping mitochondria from ¿high food intake¿ lines with mitochondria from ¿low food intake¿ lines and vice versa. We observed that, largely independent of the nuclear background, DGRP lines with a ¿high food intake mitochondria¿ consumed more food and concomitantly, DGRP lines with the ¿low food intake mitochondria¿ consumed less food. Furthermore, we investigated the influence of natural genetic variation was on the response to a high-fat diet. We designed a control and a high-fat diet and fed this to >100 DGRP lines and measured the lifespan on each diet. On average, lifespan was decreased by 48% on a high-fat diet, however this ranged from an increase of 2% to a decrease of 60% accentuating the complexity of the underlying genetic architecture. Our dataset was relatively small and limited our genome-wide and mitochondrial haplotype association analyses. Nonetheless, our GWA analysis detected variants related to genes involved in lipid metabolism and mitochondria but we did not detect significant associations with mitochondrial haplotypes. This suggests that while mitochondrial function may be important for the response to a high-fat diet, it is not dependent on the mitochondrial haplotype. Taken together, the work described in my thesis demonstrates the significance of accounting for mitochondrial haplotypes in phenotype association analyses. By doing so, it can open up new insights into genotype-to-phenotype relationships and gene regulation.

EPFL2018

Genetic, metabolic, and molecular insights into the diverse outcomes of diet-induced obesity in mouse

Alexis Maximilien Bachmann

Overweight and obesity are increasingly common public health issues worldwide, leading to a wide range of diseases from metabolic syndrome to steatohepatitis and cardiovascular diseases. While the increase in the prevalence of obesity is partly attributable to changes in lifestyle (i.e. increased sedentarity and changes in eating behaviour), the metabolic and clinical impacts of these obesogenic conditions varies between sexes and genetic backgrounds. The conception of personalised treatments of obesity and its complications require a thorough understanding of the diversity of responses to environmental stimuli such as high-fat diet intake. In this thesis, by analysing nine genetically diverse mouse strains, we show that much like humans, mice respond to high-fat diet in a genetic- and sex-dependent manner. Physiological and molecular responses to high-fat diet are associated with the expression of genes involved in immunity and mitochondrial function. Finally, we find that mitochondrial function and mitochondrial supercomplex assembly may explain part of the diversity of physiological responses. By exploring the complex interactions between genetics and metabolic phenotypes via gene expression and molecular traits, we shed light on the importance of genetic background and sex in determining metabolic outcomes. In addition to providing the community with an extensive resource for optimizing future experiments, this work serves as an exemplary design for more generalizable translational studies.

EPFL2021

The phenotypic impact of naturally occurring genetic and molecular mitochondrial variation in a Drosophila Genetic Reference Population

Roel Paulus Josephus Bevers

EPFL2018