Biology subjects

Chaix, A.

Publications and source records attributed to Chaix, A..

8 recordsLinked to original sources

bioRxiv2025

Time-Restricted Feeding Attenuates Kidney Damage and Preserves Renal Function in Mouse Model of Chronic Kidney Disease

Chronic kidney disease (CKD) is a highly disabling and potentially deadly condition for which there is no cure. With renal damage risk factors such as hypertension, metabolic syndrome and type 2 diabetes on the rise, the prevalence of CKD is increasing worldwide. New therapeutic approaches to CKD management are thus warranted. Time-restricted feeding, a dietary intervention in which daily food intake is limited to a consistent time window, has shown benefits in the context of metabolic disease management. Boolean implication network model of human CKD gene expression data and data from mouse TRF kidney implied TRF could attenuate kidney injury from CKD. We tested the effect of TRF in mouse models of kidney damage under high-fat high-sucrose feeding to induce a metabolic-disease prone environment. Using gold standard pre-clinical models of renal fibrosis, we discovered that TRF protected from kidney damage and clinical features of CKD. At the molecular level, the effects of TRF were pleiotropic with benefits in pathways involved in renal inflammation, fibrosis, and ER stress. Importantly, our results also suggest that TRF can confer early protection from metabolic alterations implicated in kidney damage.

pathology↗

bioRxiv2025

N-acetylcarnosine attenuates age-associated declines in multi-organ systems to improve survival

Histidine containing dipeptides (HCDs) such as N-acetylcarnosine are endogenous metabolites that are ergogenic and mitigate metabolic dysfunction. We previously demonstrated that short-term N-acetylcarnosine treatment is highly efficacious in protecting muscle atrophy induced by disuse. Here we demonstrate that a 6-months treatment of N-acetylcarnosine attenuates a broad spectrum of age-associated maladies and improved survival by [~]50% in female mice. A comprehensive survey of organ systems revealed that N-acetylcarnosine prevents decline in adiposity, diastolic function, vasodilation, muscle strength, and bone density. Together, N-acetylcarnosine substantially delays the onset of system-wide end-stage pathology to prolong lifespan. As an endogenously present metabolite, treatment with N-acetylcarnosine may be a safe and promising intervention to promote healthy aging in humans.

physiology↗

bioRxiv2025

Hyperlipidemia drives tumor growth in a mouse model of obesity-accelerated breast cancer growth.

Obesity is an established risk factor for breast cancer (BC), yet the specific mechanisms driving this association remain unclear. Dysregulated lipid metabolism has emerged as a key factor in cancer cell biology. While obesity is often accompanied by hyperlipidemia, the isolated impact of elevated lipid levels on BC growth has not been experimentally tested. Using the E0771 orthotopic model of obesity-accelerated BC growth in immune-competent mice, we investigated the direct role of systemic lipids in tumor growth. Combining dietary and genetic mouse models, we show that elevated circulating lipids are sufficient to accelerate BC tumor growth even in the absence of obesity or alterations in blood glucose and/or insulin levels. Pharmacological lowering of systemic lipid levels attenuates BC growth in obese mice, suggesting a direct role for lipids in fueling tumor expansion. Notably, we also show that weight loss alone, without a corresponding reduction in lipid levels such as that induced by a ketogenic diet, fails to protect against BC, highlighting the necessity of targeting lipid metabolism in obesity-associated BC. Our findings establish hyperlipidemia as a critical driver of BC progression and suggest that lipid-lowering interventions may be a promising strategy to mitigate BC risk in obese individuals.

cancer biology↗

bioRxiv2024

Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle

ObjectiveGlucagon-like peptide 1 receptor agonists (e.g. semaglutide) potently induce weight loss and thereby reducing obesity-related complications. However, weight regain occurs when treatment is discontinued. An increase in skeletal muscle oxidative phosphorylation (OXPHOS) efficiency upon diet-mediated weight loss has been described, which may contribute to reduced systemic energy expenditure and weight regain. We set out to determine the unknown effect of semaglutide on muscle OXPHOS efficiency. MethodsC57BL/6J mice were fed a high-fat diet for 12 weeks before receiving semaglutide or vehicle for 1 or 3 weeks. The rate of ATP production and O2 consumption were measured by a high-resolution respirometry and fluorometry to determine OXPHOS efficiency in skeletal muscle at these 2 timepoints. ResultsSemaglutide treatment led to significant reductions in fat and lean mass. Semaglutide improved skeletal muscle OXPHOS efficiency, measured as ATP produced per O2 consumed (P/O) in permeabilized muscle fibers. Mitochondrial proteomic analysis revealed changes restricted to two proteins linked to complex III assembly (Lyrm7 and Ttc1, p <0.05 without multiple corrections) without substantial changes in the abundance of OXPHOS subunits. ConclusionsThese data indicate that weight loss with semaglutide treatment increases skeletal muscle mitochondrial efficiency. Future studies could test whether it contributes to weight regain.

physiology↗

bioRxiv2024

Conserved Noncoding Cis-Elements Associated with Hibernation Modulate Metabolic and Behavioral Adaptations in Mice

Our study elucidates functional roles for conserved cis-elements associated with the evolution of mammalian hibernation. Genomic analyses found topologically associated domains (TADs) that disproportionately accumulated convergent genomic changes in hibernators, including the TAD for the Fat Mass & Obesity (Fto) locus. Some hibernation-linked cis-elements in this TAD form regulatory contacts with multiple neighboring genes. Knockout mice for these cis-elements exhibit Fto, Irx3, and Irx5 gene expression changes, impacting hundreds of genes downstream. Profiles of pre-torpor, torpor, and post-torpor phenotypes found distinct roles for each cis-element in metabolic control, while a high caloric diet uncovered different obesogenic effects. One cis-element promoting a lean phenotype influences foraging behaviors throughout life, affecting specific behavioral sequences. Thus, convergent evolution in hibernators pinpoints functional genetic mechanisms of mammalian metabolic control. One-sentence summaryDeletions of conserved cis-elements tied to hibernator evolution causes diverse metabolic traits in mice.

genomics↗

bioRxiv2024

Long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin trafficking and secretion in mice

A ketogenic diet (KD) is a very low-carbohydrate, very high-fat diet proposed to treat obesity and type 2 diabetes. While KD grows in popularity, its effects on metabolic health are understudied. Here we show that, in male and female mice, while KD protects against weight gain and induces weight loss, over long-term, mice develop hyperlipidemia, hepatic steatosis, and severe glucose intolerance. Unlike high fat diet-fed mice, KD mice are not insulin resistant and have low levels of insulin. Hyperglycemic clamp and ex vivo GSIS revealed cell-autonomous and whole-body impairments in insulin secretion. Major ER/Golgi stress and disrupted ER-Golgi protein trafficking was indicated by transcriptomic profiling of KD islets and confirmed by electron micrographs showing a dilated Golgi network likely responsible for impaired insulin granule trafficking and secretion. Overall, our results suggest long-term KD leads to multiple aberrations of metabolic parameters that caution its systematic use as a health promoting dietary intervention.

physiology↗

bioRxiv2022

Weight loss improves skeletal muscle mitochondrial energy efficiency

Weight loss is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight-regain. Evidence suggests that this energetic mismatch originates from lean tissue. Although this phenomenon is well documented, the mechanisms have remained elusive. We hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight loss. Wildtype male C57BL6/N mice were fed with high-fat diet for 10 wks, followed by a subset of mice that were maintained on the obesogenic diet (OB) or switched to standard chow to promote weight loss (WL) for additional 6 wks. Mitochondrial energy efficiency was evaluated using high-resolution respirometry and fluorometry. Mass spectrometric analyses were employed to describe the mitochondrial proteome and lipidome. Weight loss promoted ~50% increase in the efficiency of oxidative phosphorylation (ATP produced per O2 consumed, or P/O) in skeletal muscle. However, weight loss did not appear to induce significant changes in mitochondrial proteome, nor any changes in respiratory supercomplex formation. Instead, it accelerated the remodeling of mitochondrial cardiolipin (CL) acyl-chains to increase tetralinoleoyl CL (TLCL) content, a species of lipids thought to be functionally critical for the respiratory enzymes. We further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight gain. These findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.

physiology↗

bioRxiv2022

Cross regulation between the molecular clock and kidney inflammatory, metabolic and fibrotic responses

Chronic kidney disease is a highly prevalent condition that remains a major clinical and biomedical challenge. Tubulo-interstitial fibrosis is the common pathological substrate for many causes that lead to chronic kidney disease. It is characterized by profound derangements in metabolic and inflammatory responses, whereby functional tissue is replaced with extracellular matrix, leading to the suppression of renal function. Perturbations in the circadian rhythm have been associated with many human pathologies, including renal disease. However, the role of the molecular clock in the instauration of fibrosis remains incompletely understood. We investigated the relationship between the molecular clock and renal damage in experimental models of injury and fibrosis (UUO, FAN and adenine toxicity), employing genetically-modified mice with selective deficiencies of the clock components Bmal1, Clock and Cry. We found that UUO induced a marked increase in the expression of Bmal1. In human tubular epithelial cells, the pro-fibrotic mediator, TGF-{beta}, significantly altered the expression of core clock components. We further observed that the absence of Cry drastically aggravated kidney fibrosis, while both Cry and Clock played a role in the neutrophil and macrophage mediated inflammatory response, respectively. Suppression of Cry1/2 was associated with a major shift in the expression of metabolism-related genes, underscoring the importance of metabolic dysfunction in fibrosis. These results support a reciprocal interaction between the circadian clock and the response to kidney injury. Translational statementChronic kidney disease (CKD) is a highly prevalent clinical syndrome that still poses major clinical challenges. Kidney fibrosis underlies many cases of CKD and therapies against it are of very limited efficacy. Alterations in circadian rhythms (CR) are relevant in patients with CKD, but very little is known about the relationship between CKD and CR. Our study shows that disruption of the molecular clock can impact kidney inflammation and fibrosis and that, reciprocally, kidney fibrosis can alter the expression of clock components. A better understanding of this crosstalk could open new therapeutic avenues for the prevention and treatment of CR-related CKD.

physiology↗