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Bariatric surgery reverses ORG and exhibits a distinct transcriptomic profiel compared to weight loss through a low-fat diet

ABSTRACT: Weight loss is central to treating obesity-related kidney disease, yet the renal effects of low-fat diet (LFD) versus bariatric surgery (BS) remain incompletely understood. This study compared their impact on obesity-related glomerulopathy (ORG). Twenty-eight male Wistar rats were fed a high-fat diet (HFD) for 10 weeks to induce obesity. Eight rats were sacrificed (HFD group), eight switched to LFD for 10 weeks, and twelve underwent sleeve gastrectomy. Body weight, albuminuria, renal histology, and transcriptomic profiles were analyzed. Weight loss was modest in the LFD group (−1.6%) but substantial after BS (−13.2%), occurring 2.1 times faster. Albuminuria decreased in both interventions compared to HFD (LFD: 7228 ± 514 ng/mL, BS: 6242 ± 418 ng/mL; HFD: 10384 ± 1168 ng/mL; p < 0.01) and correlated strongly with weight loss (R² = 0.78). Glomerular area was reduced in both groups, but only BS achieved complete histological resolution of ORG. Tubular cells in BS-treated rats showed megamitochondria and cristae disruption, while LFD induced milder alterations. Transcriptomics revealed suppression of mitochondrial maintenance genes and upregulation of oxidative stress and immunometabolism pathways. Immune-related genes upregulated in BS clustered into pro-inflammatory/chemotactic and regulatory modules. To the best of our knowledge, this is the first evidence that BS fully reverses ORG, highlighting renal effects beyond weight loss alone.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE314677 | GEO | 2026/01/20

REPOSITORIES: GEO

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Project description:Background:The objective of this study was to investigate obesity-related glomerulopathy (ORG) at a cellular, structural and transcriptomic level. Methods:Thirty Wistar rats were randomized into two groups: control rats(n=15), which were fed a standard diet(SD) and study rats(n=15), which were fed a high-fat diet (HFD). After 10 weeks, weight, parameters of kidney function, renal histological features, transcriptomic changes, miRNA and mRNA isolation were compared. Results:HFD gained more weight(55.8%) than SD(29.2%), p<0.001. Albuminuria was also significantly higher in HFD(10,384.04 ng/ml) compared with SD(5,845.45 ng/ml), p<0.001. HFD showed typical lesions of early stages of ORG, with a predominance of mesangial matrix increase (MMI) and podocyte hypertrophy (PH). All histologic lesions correlated with genes differentially expressed (DE) in kidneys of HFD group and PH, also correlated with specific miRNAs DE in the urine of HFD. The functional analysis showed 4 miRNAs DE in the kidneys of HFD group that negatively regulates PTEN gene, which promotes podocyte endocytosis of lipids in ORG. The electronic microscope confirmed the spaces of lipid vacuoles in the podocytes of HFD. Between those 4 miRNAs DE, miR-205 was also found to be upregulated in the urine of HFD group. Conclusions: Wistar rats fed a HFD developed early-stages of ORG, with a specific targetome of miRNAs and gene expression. The upregulation of miR-205 in kidney and its isolation in urine is associated with lipid endocytosis of podocytes, which could become a plausible biomarker of early-stages of ORG and open new avenues for future therapeutics research. Translational Statement: The findings of the basic research in this study can be replicated in human models of obesity. The results of the study on miRNA in humans may contribute to improving the understanding of the pathophysiology of obesity-related glomerulopathy, aiding in the search for early biomarkers, and exploring new therapeutic targets. Keywords: MicroRNA, Biomarker, targetome, obesity-related glomerulopathy, mesangial matrix increase, podocyte hypertrophy, Wistar rats

Project description:An 8-week high fat palm oil diet causes obesity and insulin resistance in C57BL/6J mice, but induces only small changes in the muscle transcriptome. Introduction: The metabolic syndrome (MS) is a cluster of metabolic abnormalities linked to an increased risk of type 2 diabetes and cardiovascular diseases. Two major characteristics of the MS are obesity and insulin resistance. In the present study we investigated the effect of obesity and insulin resistance on the mouse muscle transcriptome. Methods: C57BL/6J mice were fed a palm oil-based low fat diet (LFD) or high fat diet (HFD) for eight weeks. Microarray analysis was performed by using two complementary strategies: (1) 8-week HFD transcriptome versus 8-week LFD transcriptome and (2) transcriptome of mice sacrificed at the start of the intervention versus 8-week LFD transcriptome and 8-week HFD transcriptome, respectively. Results: HFD mice develop obesity and whole-body insulin resistance. Despite these metabolic disturbances we found that HFD induces relatively small changes in gene expression (< 1.3 fold). Only the up-regulation of FA oxidation and the down-regulation of the MAPK cascade were specific for the HFD intervention. Eight-weeks of aging induced more changed gene expression levels than the HFD, including genes involved in cell-cell interaction and development. Conclusion: Eight weeks of aging induce more pronounced changes in the muscle transcriptome than an HFD. Since only one strategy revealed the transcriptional down-regulation of the MAPK cascade, whereas both strategies showed the up-regulation of FA oxidation we suggest the use of complementary analysis strategies by the genome-wide search of gene expression changes induced by mild interventions, such as an HFD. Keywords: diet intervention and time course In this study, C57BL/6J mice were fed a high fat (HF) diet for 8 weeks to induce obesity and insulin resistance. Plasma levels of the adipokines leptin and adiponectin were measured. To investigate how these metabolic disturbances will influence the skeletal muscle transcriptome we performed whole-genome microarray analysis. Functional implications were assessed by analyses of predefined gene sets based on Gene Ontology, biochemical, metabolic and signaling pathways.

Project description:To profile the expression of circulating miRNAs in a mouse model of diet-induced obesity (DIO) with subsequent weight-reduction with low-fat diet (LFD), eighteen C57BL/6 male mice were grouped into three subgroups as: (1) Control: the mice fed with the standard AIN-76A (fat: 11.5 kcal%) diet for 12 wks; (2) DIO: the mice fed with 58 kcal% high-fat diet for 12 wks; (3) DIO+LFD: the mice fed with high-fat diet for 8 wks to induce obesity, then changed to 10.5 kcal% low-fat diet for subsequent 4 wks. C57BL/6 mice were purchased from BioLasco (Taipei, Taiwan). All housing conditions were maintained, and surgical procedures, including analgesia, were performed in an Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC)-accredited SPF facility according to national and institutional guidelines. In this experiment, eighteen C57BL/6 wild type male mice were randomly grouped into three subgroups (n=6 in each group): (1) Control: the control mice were fed ad libitum a standard AIN-76A (fat: 11.5 kcal%) diet for 12 wks; (2) DIO: the mice were fed ad libitum a 58 kcal% HFD (D12331; Research Diets Inc., New Brunswick, NJ) for 12 wks to induce obesity; (3) DIO+LFD: the mice fed ad libitum a 58 kcal% HFD (D12331) for 8 wks to induce obesity, then continued the feeding of 10.5 kcal% LFD (D 12329; Research Diets Inc.) for additional 4 wks. Weight measurements were performed on a weekly basis to for these three groups of mice. Evaluation of blood glucose levels was performed at the beginning and in the end of the experiment to confirm that the HFD-fed mice developed an obese and insulin resistant phenotype. After the end of experiment at 12w, all mice were killed. The abdominal WAT of each mice was removed and weighted. Paraffin-embedded abdominal WAT was sectioned at 5 M-NM-<m and stained with hematoxylin and eosin to measure mean adipocyte area. A volume of 1 mL of whole blood was collected into a plain tube and allowed to clot for 1 hour. The sera samples were aliquoted after centrifugation at 3,000 M-CM-^W g for 10 minutes and stored at M-bM-^HM-^R80M-BM-0C until further analysis.

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Bariatric surgery reverses ORG and exhibits a distinct transcriptomic profiel compared to weight loss through a low-fat diet

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