Biology subjects

Auwerx, J.

Publications and source records attributed to Auwerx, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Proteome-wide QTL mapping enables gene-protein-phenotype metabolic network construction in a genetically diverse MASLD mouse model

The limited treatment options available for the estimated 38% of adults worldwide affected by Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) are largely due to an incomplete understanding of the complex molecular networks underlying disease pathogenesis. To dissect the genetic architecture and proteomic regulation underlying MASLD, we generated a genetically diverse mouse cohort through a four-way cross of founder strains with varying susceptibility to liver disease, producing 444 F2 mice with a spectrum of phenotypes and genotypes. Utilizing deep proteomic profiling of the livers of this population, we identified quantitative trait loci (QTL) for 2,652 proteins, spanning over 4,000 unique genomic loci, and distinguished cis- and trans-acting regulatory mechanisms. Integrating proteomic, genomic, and phenotypic data reveals key regulatory loci and candidate proteins influencing disease progression, creating a mineable proteogenomic resource for MASLD research. We utilize this resource to identify the E3 ubiquitin ligase Ubr1 as a candidate central regulator connecting proteostasis and lipid metabolism, with genetic polymorphisms that may alter its abundance and predispose to metabolic dysfunction. This study demonstrates how high-throughput, deep proteome profiling integrated with QTL mapping can reveal complex gene-protein networks governing MASLD susceptibility and progression, offering novel insights for biomarker discovery and therapeutic targeting.

systems biology↗

bioRxiv2026

Quicklime-based eradication attempt of Xenopus laevis as a model for controlling pondscape invasions

Aquatic non-native invasive species are notoriously difficult to eradicate, particularly in pondscapes where populations can spread rapidly, persist in unmanaged refugia, and recolonise treated sites. In such contexts, high-intensity management interventions may be justified, balancing short-term collateral impacts against the prevention of permanent establishment and long-term damages. Chemical eradication methods, such as rotenone or herbicide application, can be effective but raise ethical and environmental concerns. Here, we evaluate quicklime (calcium oxide, CaO) application as a more sustainable alternative control tool for pondscape invaders compared to other chemical methods, using the African clawed frog (Xenopus laevis) invasion in Belgium as a case study. When applied to water, quicklime hydrates exothermically to calcium hydroxide (Ca(OH)), which releases OH ions upon dissolution, temporarily and rapidly increasing pH to lethal levels. In winter 2023, three ponds with breeding populations of X. laevis of low ecological value were drained, fenced, and treated with quicklime. Treatment effectiveness was assessed through pH measurements, visual surveys, and environmental DNA (eDNA) quantification. Immediately after treatment, large numbers of deceased post-metamorphic individuals were recovered, indicating treatment-induced mortality. Eight weeks post-treatment, eDNA concentrations were markedly lower in two of the three ponds (reductions of 100% and 80%) compared to those during the same period one year later. Although eDNA concentrations increased again during the following summer suggesting partial population recovery through survival and/or recolonisation, they remained lower than pre-treatment conditions. Water pH returned to near baseline levels within one month. We provide the first field-based preliminary evidence that quicklime can induce large-scale mortality in X. laevis populations in small to medium-sized ponds. We discuss practical considerations, limitations, and broader applicability, proposing quicklime as a high-intensity option within integrated management strategies for pondscape invaders.

ecology↗

bioRxiv2025

Genetic mapping of lifespan and mitochondrial stress response in C. elegans

The mitochondrial unfolded protein response (UPRmt) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role in aging and healthspan remain to be fully elucidated. Here, we activated the UPRmt using doxycycline (Dox) in a genetically diverse C. elegans population comprising 85 strains and observed large variation in Dox-induced lifespan extension across these strains. Through multi-omic data integration, we identified an aging-related molecular signature that was partially reversed by Dox. To identify the mechanisms underlying Dox-induced lifespan extension, we applied quantitative trait locus (QTL) mapping analyses and found one UPRmt modulator, fipp-1/FIP1L1, which was functionally validated in C. elegans and humans. In the human UK Biobank, FIP1L1 was associated with metabolic homeostasis, underscoring its translational relevance. Overall, our findings demonstrate a novel UPRmt modulator across species and provide insights into potential translational research.

genetics↗

bioRxiv2025

Genetic Modulation of Lifespan: Dynamic Effects, Sex Differences, and Body Weight Trade-offs

The dynamics of lifespan are shaped by DNA variants that exert effects at different ages. We have mapped genetic loci that modulate age-specific mortality using an actuarial approach. We started with an initial population of 6,438 pubescent siblings and ended with a survivorship of 559 mice that lived to at least 1100 days. Twenty-nine Vita loci dynamically modulate the mean lifespan of survivorships with strong age- and sex-specific effects. Fourteen have relatively steady effects on mortality while other loci act forcefully only early or late in life and with polarities of effects that invert. A distinct set of 19 Soma loci shape the negative correlation between weights of young adults with their life expectancies--much more strongly so in males than females. Another set of 11 Soma loci shape the positive correlation between weights at older ages with life expectancies. The Vita and Soma loci share 289 age-dependent epistatic interactions (LODs [≥]3.8) but fewer than 4% are common to both sexes. We provide two examples of how to move from maps toward potential mechanisms. Our findings provide an empirical bridge between evolutionary theories on aging and genetic and molecular causes. These loci and their interactions are key to begin to understand the impact of interventions that may extend healthy lifespan in mice and even in humans.

genetics↗

bioRxiv2025

A multiomic network approach uncovers disease modifying mechanisms of inborn errors of metabolism

For many inborn errors of metabolism (IEM) the understanding of disease mechanisms remains limited in part explaining their unmet medical needs. We hypothesize that the expressivity of IEM disease phenotypes is affected by the activity of specific modifier pathways, which is controlled by rare and common polygenic variation. To identify these modulating pathways, we used RNA sequencing to generate molecular signatures of IEM in disease relevant tissues. We then integrated these disease signatures with multiomic data and gene regulatory networks generated from animal and human populations without overt IEM. We identified and subsequently validated glucocorticoid signaling as a candidate modifier of mitochondrial fatty acid oxidation disorders, and we re-capitulated complement signaling as a modifier of inflammation in Gaucher disease. Our work describes a novel approach that can overcome the rare disease-rare data dilemma, and reveal new IEM pathophysiology and potential drug targets using multiomics data in seemingly healthy populations. Take-home message: Multiomic data and gene regulatory networks derived from animal and human populations without overt IEM can be used to study disease mechanisms in inborn errors of metabolism.

genetics↗

bioRxiv2025

Delivery of a chemically modified noncoding RNA domain improves dystrophic myotube function

Fast twitch, type II muscle fibers are particularly prone to degradation in skeletal muscle pathologies, such as sarcopenia and muscular dystrophies. We previously showed that endogenous activation of the exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis. In the present study, we identify an independent pro-myogenic element within human CYTOR and optimize its RNA delivery. In human primary myoblasts exogenous, vector-based CYTORexon 2 recapitulates the effect of full-length CYTOR by enhancing fast-twitch myogenic differentiation. Furthermore, chemically modified CYTORexon 2 RNA{Psi}U (N1-me-PseudoU, 7-methyl guanosine 5Cap, polyA tail) enhanced RNA stability and reduced the immunogenic response to CYTORexon 2 RNA. We demonstrate that viral- or chemically optimized RNA-mediated CYTORexon 2 administration enhances the commitment towards myogenic maturation in Duchenne muscular dystrophy-derived primary myoblasts, induced myogenic progenitor cells and mouse embryonic stem cells. Furthermore, chemically optimized CYTORexon 2 improves key disease characteristics in dystrophic myotubes, including calcium handling and mitochondrial bioenergetics. In summary, our findings identify CYTOR exon 2 as the pro-myogenic domain of CYTOR that can be delivered in a disease context using chemical modifications. This is of particular importance given the susceptibility of type II muscle fibers in different muscle pathologies such as aging and dystrophies, and the reported oncogenic effect of CYTOR exon 1. Our study, therefore, highlights the potential of identifying functional domains in noncoding RNAs. Delivery, or targeting of such RNA domains could constitute next-generation RNA therapeutics.

bioengineering↗

bioRxiv2024

Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2

Selective and controlled expansion of endogenous {beta}-cells has been pursued as a potential therapy for diabetes. Ideally, such therapies would preserve feedback control of {beta}-cell proliferation to avoid excessive {beta}-cell expansion and an increased risk of hypoglycemia. Here, we identified a regulator of {beta}-cell proliferation whose inactivation results in controlled {beta}-cell expansion: the protein deacetylase Sirtuin 2 (SIRT2). Sirt2 deletion in {beta}-cells of mice increased {beta}-cell proliferation during hyperglycemia with little effect in homeostatic conditions, indicating preservation of feedback control of {beta}-cell mass. SIRT2 restrains proliferation of human islet {beta}-cells cultured in glucose concentrations above the glycemic set point, demonstrating conserved SIRT2 function. Analysis of acetylated proteins in islets treated with a SIRT2 inhibitor revealed that SIRT2 deacetylates enzymes involved in oxidative phosphorylation, dampening the adaptive increase in oxygen consumption during hyperglycemia. At the transcriptomic level, Sirt2 inactivation has context-dependent effects on {beta}-cells, with Sirt2 controlling how {beta}-cells interpret hyperglycemia as a stress. Finally, we provide proof-of-principle that systemic administration of a GLP1-coupled Sirt2-targeting antisense oligonucleotide achieves {beta}-cell selective Sirt2 inactivation and stimulates {beta}-cell proliferation under hyperglycemic conditions. Overall, these studies identify a therapeutic strategy for increasing {beta}-cell mass in diabetes without circumventing feedback control of {beta}-cell proliferation.

physiology↗

bioRxiv2024

High-content phenotypic analysis of a C. elegans recombinant inbred population identifies genetic and molecular regulators of lifespan

Lifespan is influenced by complex interactions between genetic and environmental factors. Studying those factors in model organisms of a single genetic background limits their translational value for humans. Here, we mapped lifespan determinants in 85 genetically diverse C. elegans recombinant intercross advanced inbred lines (RIAILs). We assessed molecular profiles - transcriptome, proteome, and lipidome - and life-history traits, including lifespan, development, growth dynamics, and reproduction. RIAILs exhibited large variations in lifespan, which positively correlated with developmental time. Among the top candidates obtained from multi-omics data integration and QTL mapping, we validated known and novel longevity modulators, including rict-1, gfm-1 and mltn-1. We translated their relevance to humans using UK Biobank data and showed that variants in RICTOR and GFM1 are associated with an elevated risk of age-related heart disease, dementia, diabetes, kidney, and liver diseases. We organized our dataset as a resource (https://lisp-lms.shinyapps.io/RIAILs/) that allows interactive explorations for new longevity targets.

systems biology↗

bioRxiv2024

Adaptive thermogenesis is mediated by GDF15 via the GFRAL neuronal axis in mice

Adaptive thermogenesis is a key homeostatic mechanism that primarily occurs in brown adipocytes and enables the maintenance of body temperature. Although this process involves coordinated responses in multiple tissues, including the browning of white adipocytes, the precise inter-organ crosstalk underlying adaptive thermogenesis is unclear. Here, we investigate the pivotal role of the GDNF family receptor alpha-like (GFRAL) neuronal axis in modulating compensatory thermogenic responses in brown and white adipose depots under stress conditions, specifically the mitochondrial unfolded protein response resulting from genetic modification and cold exposure. We employed a mouse model with targeted deletion of Crif1 in the mitoribosomes of brown adipocytes, and cold-exposed mice and immortalized adipocytes, to uncover the mechanism by which mitochondrial stress-induced growth differentiation factor 15 (GDF15) expression affects metabolism and facilitates adaptive thermogenesis. We found that Crif1 deletion resulted in browning of inguinal white adipose depots, increased energy expenditure, reduced food intake, and resistance to weight gain. Retrograde neuronal tracing established that GFRAL-positive neurons in the hindbrain and sympathetic preganglionic neurons in the spinal cord mediated the GDF15-associated browning of inguinal white adipose tissue. Intervention studies using antisense oligonucleotides to inhibit Gfral expression blunted the effect of Crif1 deletion on energy expenditure and food intake, further confirming the essential role the GFRAL axis plays in GDF15-driven thermogenic adaptation in white adipose tissue. Our findings suggest that the GFRAL neuronal axis is key in coordinating the adaptive thermogenic response across multiple tissues and adipose depots, thereby ensuring metabolic homeostasis during mitochondrial stress.

molecular biology↗

bioRxiv2023

Inhibition of CERS1 in skeletal muscle exacerbates age-related muscle dysfunction

Age-related muscle wasting and dysfunction render the elderly population vulnerable and incapacitated, while underlying mechanisms are poorly understood. Here, we implicate the CERS1 enzyme of the de novo sphingolipid synthesis pathway in the pathogenesis of age-related skeletal muscle impairment. In humans, CERS1 abundance declines with aging in skeletal muscle cells and, correlates with biological pathways involved in muscle function and myogenesis. Furthermore, CERS1 is upregulated during myogenic differentiation. Pharmacological or genetic inhibition of CERS1 in aged mice blunts myogenesis and deteriorates aged skeletal muscle mass and function, which is associated with the occurrence of morphological features typical of inflammation and fibrosis. Ablation of the CERS1 orthologue lagr-1 in C. elegans similarly exacerbates the age-associated decline in muscle function and integrity. We discover genetic variants reducing CERS1 expression in human skeletal muscle and Mendelian randomization analysis in the UK biobank cohort shows that these variants reduce muscle grip strength and overall health. In summary, our findings link age-related impairments in muscle function to a reduction in CERS1, thereby underlining the importance of the sphingolipid biosynthesis pathway in age-related muscle homeostasis.

physiology↗

bioRxiv2023

Induction of mitophagy reverts age-associated decline of the hematopoietic and immune systems

Aging compromises hematopoietic and immune system functions, making elderly individuals especially susceptible to hematopoietic failure, infections and tumor development and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward myeloid lineage (myeloid-bias). These processes are accompanied by an aberrant accumulation of mitochondria in HSCs. The administration of the mitophagy-inducer Urolithin-A re-establishes the correct mitochondrial homeostasis in HSCs and completely restores the blood reconstitution capability of "old" HSCs. Moreover, Urolithin-A supplemented food restores lymphoid compartments, boosts HSCs function and improves the immune response to viral infection in old mice. Altogether our results demonstrate that targeting mitophagy reverts aging phenotype in the hematopoietic and immune system.

immunology↗

bioRxiv2023

Genetic and dietary modulators of the inflammatory response in the gastro-intestinal tract of the BXD mouse genetic reference population

Inflammatory gut disorders, including inflammatory bowel disease (IBD), can be impacted by dietary, environmental and genetic factors. While the incidence of IBD is increasing worldwide, we still lack a complete understanding of the gene-by-environment interactions underlying inflammation and IBD. Here, we profiled the colon transcriptome of 52 BXD mouse strains fed with a chow or high-fat diet (HFD) and identified a subset of BXD strains that exhibit an IBD-like transcriptome signature on HFD, indicating that an interplay of genetics and diet can significantly affect intestinal inflammation. Using gene co-expression analyses, we identified modules that are enriched for IBD-dysregulated genes and found that these IBD-related modules share cis-regulatory elements that are responsive to the STAT2, SMAD3, and REL transcription factors. We used module quantitative trait locus (ModQTL) analyses to identify genetic loci associated with the expression of these modules. Through a prioritization scheme involving systems genetics in the mouse and integration with external human datasets, we identified Muc4 and Epha6 as the top candidates mediating differences in HFD-driven intestinal inflammation. This work provides insights into the contribution of genetics and diet to IBD risk and identifies two candidate genes, MUC4 and EPHA6, that may mediate IBD susceptibility in humans.

systems biology↗

bioRxiv2023

Loss-of-SIRT7 sensitizes hepatocellular carcinoma to sorafenib through the regulation of ERK Phosphorylation

The FDA-approved oral multi-kinase inhibitor, sorafenib (BAY 43-9006, Nexavar), is the first approved systemic therapy for patients with unresectable hepatocellular carcinoma (HCC). Although it has been shown to significantly improve the overall survival of patients with HCC, drug resistance limits the response rate to this therapeutic. Here, we report that acquired sorafenib resistance is associated with overexpression of the deacetylase, SIRT7, and a high level of ERK phosphorylation. Further, we identify that the hyperactivation of ERK is controlled by SIRT7-mediated deacetylation of DDX3X. The inhibition of SIRT7 combined with sorafenib resulted in a marked reduction of cell viability in vitro and of tumor growth in vivo. It seems plausible that SIRT7 is responsible for the acquired sorafenib resistance and its inhibition is most likely beneficial together in conjunction with sorafenib by suppressing ERK signaling. HighlightsO_LISorafenib resistance in HCC is associated with SIRT7 and ERK hyperactivation. C_LIO_LISuppression of SIRT7 combined with sorafenib restores sensitivity to sorafenib. C_LIO_LISIRT7 controls sorafenib resistance through ERK activation by mediating DDX3X deacetylation. C_LI

cancer biology↗

bioRxiv2022

Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation

Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H+-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPRmt, but not other similar stress responses, such as the UPRER. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from reactive oxygen species (ROS)-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPRmt activation and mitochondrial function resilience.

cell biology↗

bioRxiv2022

Inhibition of GCN5 decreases skeletal muscle fat metabolism during high fat diet feeding

IntroductionGCN5 (Kat2a) is a lysine acetyl transferase capable of acetylating and inhibiting PGC-1 activity. As such, it is described as a negative regulator of PGC-1 and subsequently restricts mitochondrial content. However, elimination of GCN5 in skeletal muscle does not increase mitochondrial content or alter lipid metabolism under normal metabolic conditions. GCN5 levels increase with high-fat diet (HFD) feeding in rodents. Additionally, the GCN5 homolog, PCAF, has previously been shown to also acetylate and inhibit PGC-1 and therefore may possibly compensate for loss of GCN5. ObjectiveThe objective of this study was to examine if with HFD feeding that elimination of GCN5 (Kat2a gene) from skeletal muscle would elicit improvements in mitochondrial and metabolic markers. MethodsSkeletal muscle specific GCN5 knockouts (Gcn5 skm-/-) were fed an HFD. Body composition, cardio-metabolic and physical fitness outcomes were monitored. Additionally, cultured myotubes were treated with a pan-GCN5/PCAF inhibitor and examined for changes in mitochondrial markers. ResultsElimination of skeletal muscle GCN5 did not alter body composition, tissue masses, energy intake, or energy expenditure measurements of mice fed an HFD. Furthermore, whole body glucose homeostasis and cardiac measurements were not altered. There were few differences in lipid metabolism genes, relatively more glucose oxidation versus Gcn5 skm+/+ (wildtype) mice, and a reduction in Pdk4 expression. Exercise capacity and mitochondrial content levels were not altered in Gcn5 skm-/- mice. Further, elimination of GCN5 in skeletal muscle increased Kat2b (PCAF) mRNA expression; however, inhibition of GCN5/PCAF bromodomains in cultured myotubes did not increase oxidative metabolism genes and decreased expression of some mitochondrial genes and Pdk4 mRNA. ConclusionsNeither elimination of GCN5, nor simultaneous inhibition of GCN5 and its homolog PCAF improved skeletal muscle mitochondrial content under normal or HFD-fed conditions. Despite this, GCN5 may play a role in regulating macronutrient preference by regulating Pdk4 content. Thus, HFD/macronutrient excess revealed novel roles of GCN5 in skeletal muscle. Highlights- Skeletal muscle specific elimination of Gcn5/Kat2a decreases fat oxidation without 1) preventing high-fat diet induced weight gain, 2) improving whole body glucose handling, or 3) improving skeletal muscle mitochondrial content. - Inhibition of the GCN5 and PCAF bromodomains and Gcn5 ablation decreases expression of Pdk4. - Expression of Kat2b increases with Gcn5 elimination in skeletal muscle. - Inhibition of the GCN5 and PCAF bromodomains do not result in increased skeletal muscle mitochondrial content.

physiology↗

bioRxiv2022

Hepatic lipid overload potentiates biliary epithelial cell activation via E2Fs

During severe or chronic hepatic injury, biliary epithelial cells (BECs), also known as cholangiocytes, undergo rapid reprogramming and proliferation, a process known as ductular reaction (DR), and allow liver regeneration by differentiating into both functional cholangiocytes and hepatocytes. While DR is a hallmark of chronic liver diseases, including advanced stages of non-alcoholic fatty liver disease (NAFLD), the early events underlying BEC activation are largely unknown. Here, we demonstrate that BECs readily accumulate lipids upon fatty acid (FA) treatment in BEC-derived organoids, and during high-fat diet feeding in mice. Lipid overload induces a metabolic rewiring to support the conversion of adult cholangiocytes into active BECs. Mechanistically, we found that lipid overload unleashes the activation of the E2F transcription factors in BECs, which drives cell cycle progression while promoting glycolytic metabolism. These findings demonstrate that fat overload is sufficient to initiate a DR, without epithelial damage, and provide new insights into the mechanistic basis of BEC activation, revealing unexpected connections between lipid metabolism, stemness, and regeneration.

cell biology↗

bioRxiv2022

A lysosomal surveillance response (LySR) that reduces proteotoxicity and extends healthspan

Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homeostasis and health. Here, we discovered an adaptive lysosomal transcriptional response that we termed the Lysosomal Surveillance Response (LySR). Typified by the induction of a large group of transcripts involved in lysosomal function and proteolysis, the LySR can be triggered by silencing of specific vacuolar H+-ATPase subunits in Caenorhabditis elegans. Notably, LySR activation enhances the clearance of protein aggregates in worm models of Alzheimers and Huntingtons disease and amyotrophic lateral sclerosis, thereby boosting fitness and extending lifespan. The GATA transcription factor, ELT-2, regulates the LySR program as well as its associated beneficial effects. In mammalian cells, overexpression of GATA4/GATA6, the mammalian orthologs of ELT-2, is sufficient to induce the expression of multiple lysosome-specific proteases and alleviate proteotoxicity. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan. HighlightsO_LIRNAi of specific v-ATPase subunits extends C. elegans lifespan and activates LySR C_LIO_LIGATA transcription factor ELT-2 regulates LySR and LySR-associated lifespan extension C_LIO_LILySR activation reduces protein aggregates and extends worm healthspan C_LIO_LIOverexpression of GATA4/GATA6 alleviates amyloid-{beta} proteotoxicity in mammalian cells C_LI

cell biology↗

bioRxiv2021

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

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 conditions such as high-fat diet intake. 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 expression of genes involved in immunity and mitochondrial function. Finally, we find that mitochondrial function 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, our work serves as an exemplary design for more generalizable translational studies.

bioinformatics↗