Biology subjects

Hadjadj, S.

Publications and source records attributed to Hadjadj, S..

4 recordsLinked to original sources

bioRxiv2026

Keto-gluconeogenic metabolic axis mirrors renal homeostasis and post-injury response in spatial transcriptomics

Metabolic disturbance is a key feature in acute kidney injury (AKI) and chronic kidney disease (CKD). The kidney highly depends on fatty acid metabolism; how renal cells rewire metabolism upon AKI and CKD transition remained unclear. Here, we combine spatial transcriptomics with biochemical analyses to characterize metabolic changes and intercellular interactions during AKI to CKD transition. Using aristolochic acid model of CKD, we spatio-temporally correlated changes in structure and function with metabolic profile during AKI to CKD transition. Surprisingly, keto-gluconeogenic metabolic axis was highly enriched in healthy kidney and paralleled injury phase transitions. Intercellular interaction analysis associated a subtype of macrophage with the drift to chronicity. Online scRNAseq datasets analysis confirmed altered keto-gluconeogenic metabolic pathways in ischemia-reperfusion injured mouse kidneys and AKI and CKD human kidney biopsies compared to healthy controls. This study identifies a metabolic axis transcriptionally mirroring renal homeostasis and injury responses, and tubulo-interstitial interactions that can be targeted to mitigate AKI to CKD transition.

pathology↗

bioRxiv2025

Comparative Transcriptomic Analysis of Obesity and Lipodystrophy Reveals Shared Mechanisms and Novel Targets in Adipose Tissue Dysfunction

The global rise in obesity poses a major public health challenge. While chronic energy surplus is a well-established driver of weight gain and obesity, the mechanisms linking adipose tissue (AT) expansion to cardiometabolic complications remain incompletely understood. In obese individuals, dysfunctional AT loses its capacity to store excess lipids, leading to ectopic fat accumulation and contributing to cardiometabolic complications such as type 2 diabetes. However, the molecular events that drive the transition from healthy to dysfunctional adipocytes are poorly defined. At the opposite end of the adiposity spectrum, lipodystrophies represent a heterogeneous group of disorders characterized by selective loss of AT, often accompanied by severe metabolic disturbances. Despite these contrasting adipose phenotypes, both obesity and lipodystrophy result in similar metabolic complications. In this study, we investigated whether AT in these two contrasting conditions shares a common molecular signature. We performed an unbiased comparative transcriptomic analysis of AT from lipodystrophic BSCL2-deficient and obese mice, identifying a shared signature of 129 genes. Using publicly available datasets, we replicated this signature and refined it to 102 genes whose expression is consistently altered in both obese and lipodystrophic adipose tissue. Correlation network analysis, gene ontology, and literature-based refinement revealed that these genes fall into nine functional categories: lipogenesis, adipocyte differentiation, carbohydrate metabolism, mitochondrial function, amino acid metabolism, reactive oxygen species, metabolic processes, immune response, and a group with no clear functional association. Most of these genes expression levels correlated strongly with insulin sensitivity across lipodystrophic and obese mice, as well as human samples. Finally, 52 genetic loci containing these genes harbor variants associated with type 2 diabetes, including 11 loci where genetic associations directly influence candidate gene expression levels. In conclusion, our findings demonstrate that a shared "energetic collapse" of adipocytes, characterized by profound metabolic inflexibility in pathways spanning glucose utilization, lipogenesis, and amino acid catabolism, represents a common pathogenic mechanism underlying adipose tissue dysfunction in both obesity and lipodystrophy. This convergent molecular signature underscores the critical role of intrinsic adipocyte metabolic health in systemic energy homeostasis and insulin sensitivity.

physiology↗

bioRxiv2025

Tripartite ER-Mitochondria-Lipid Droplets contact sites control adipocyte metabolic flexibility

Obesity is a major risk factor for cardiometabolic diseases, with adipocyte dysfunction playing a central role. Understanding how lipid storage and mobilization are regulated--and disrupted--in adipocytes is key to addressing obesity-associated complications. The ER-anchored protein Seipin controls lipid droplet (LD) biogenesis and maintenance, and its loss disrupts ER-LD contact sites. In humans, Seipin deficiency causes generalized lipodystrophy, a severe form of adipocyte dysfunction. We previously showed that Seipin also localizes at ER-mitochondria contact sites (MAM), where it regulates calcium exchange and mitochondrial function. Here, we examined whether Seipin targeting to MAM and ER-LD sites overlaps functionally. We analyzed subcutaneous adipose tissue (AT) from inducible Seipin-knockout mice using transmission electron microscopy (TEM) and proximity ligation assays (PLA) to quantify membrane contact sites (MCS) involving the ER, LDs, and mitochondria. In control mice, feeding reduced MAMs while increasing ER-LD and mitochondria-LD contacts, whereas Seipin deficiency abolished this remodeling. Specifically, under lipid loading, MAMs located in proximity to LDs--tripartite contact sites known as MAM-LD--were increased in control but not in Seipin-deficient adipocytes. Fluorescence recovery after photobleaching assays revealed that Seipin depletion impairs triglyceride transfer to LDs, an effect rescued by the MAM-LD-reinforcing synthetic peptide Linker-ER-Mi. Importantly, this rescue was abolished by silencing the mitochondrial calcium uniporter, demonstrating that calcium exchange is critical for triglyceride storage in LDs. We further investigated how MAM-LD remodeling influences adipocyte metabolic flexibility. Using TEM and PLA, we monitored two MAM subtypes: those forming MAM-LD and those engaging cytosolic mitochondria (MAM-CM). During adipogenesis, MAM-LD frequency increased while MAM-CM decreased. Similarly, in mouse AT and 3T3-L1 adipocytes, lipid loading selectively promoted MAM-LD. Notably, this adaptive remodeling of membrane contact sites was blunted in the adipose tissue of diet-induced obese mice. Genetic disruption of MCS in 3T3-L1 adipocytes altered lipid flux, impaired lipolysis, and reduced insulin signaling. Together, our findings identify MAM-LD contacts as key regulators of adipocyte lipid handling and metabolic flexibility, whose disruption may underlie the metabolic inflexibility of obesity.

cell biology↗

bioRxiv2018

Exome-wide association study on Albuminuria identifies a novel rare variant in CUBN and additional genes, in 33,985 Europeans with and without diabetes

Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease (CKD) and end-stage renal disease which are highly prevalent in patients with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited with the majority of studies focusing on common variants.\n\nWe performed an exome-wide association study to identify coding variants in a two phase (discovery and replication) approach, totaling to 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and further testing in Greenlanders (n = 2,605). We identify a rare (MAF: 0.8%) missense (A1690V) variant in CUBN (rs141640975, {beta}=0.27, p=1.3 x 10-11) associated with albuminuria as a continuous measure in the combined European meta-analyses. Presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had 3 times stronger effect in individuals with diabetes compared to those without (pinteraction: 5.4 x 10-4, {beta}DM: 0.69, {beta}nonDM: 0.20) in the discovery meta-analyses. Geneaggregate tests based on rare and common variants identify three additional genes associated with albuminuria (HES1, CDC73, and GRM5) after multiple testing correction (P_bonferroni<2.7 x 10-6).\n\nThe current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. These findings provide new insights into the genetic architecture of albuminuria and highlight novel target genes and pathways for prevention of diabetes-related kidney disease.\n\nSignificance statementIncreased albuminuria is a key manifestation of major health burdens, including chronic kidney disease and/or cardiovascular disease. Although being partially heritable, there is a lack of knowledge on rare genetic variants that contribute to albuminuria. The current study describes the discovery and validation, of a new rare gene mutation (~1%) in the CUBN gene which associates with increased albuminuria. Its effect multiplies 3 folds among diabetes cases compared to non diabetic individuals. The study further uncovers 3 additional genes modulating albuminuria levels in humans. Thus the current study findings provide new insights into the genetic architecture of albuminuria and highlight novel genes/pathways for prevention of diabetes related kidney disease.

genetics↗