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. 2025 Nov 11;75(1):22–36. doi: 10.2337/db25-0295

miR-432 Exacerbates Obesity-Induced Dysregulation of Glucose and Lipid Homeostasis

Cuizhe Wang 1,2, Yanting Hou 2, Meixiu Zhang 2, Jingzhou Wang 2, Xiaolong Chu 2, Maodi Liang 2, Chaoyue Sun 2, Jianxin Xie 2,✉, Jun Zhang 2,✉, Cong-Yi Wang 1,✉
PMCID: PMC12716619  PMID: 41218910

Abstract

miRNAs are key regulators of metabolic homeostasis, yet their role in obesity-associated dysfunction remains incompletely understood. Here, we identify miR-432 as a driver of systemic metabolic dysregulation. Serum miRNA profiling revealed a positive correlation between miR-432 expression and obesity/type 2 diabetes mellitus. Functionally, adipose-specific miR-432 exacerbated high-fat diet–induced obesity and insulin resistance. Similarly, hepatic-specific miR-432 aggravated hepatic steatosis and systemic glucose dysregulation, while skeletal muscle–specific miR-432 disrupted glucose homeostasis without affecting body composition. Mechanistically, miR-432 disrupted insulin sensitivity by inhibiting the PIK3R3/AKT pathway and perturbed lipid homeostasis by suppressing the PIK3R3/PPAR-α axis. Notably, obesity-induced miR-432 upregulation was predominantly localized in adipocytes and driven by the CDK5/PPAR-γ axis. Furthermore, adipocyte-derived exosomal miR-432 was identified as a mediator of systemic metabolic dysfunction, facilitating intertissue cross talk in obesity. Collectively, our data demonstrate that miR-432 exacerbates obesity-induced dysregulation of glucose and lipid metabolism.

Article Highlights

  • miR-432 overexpression in adipose tissue, liver, and skeletal muscle exacerbates high-fat diet–induced disruption of metabolic homeostasis.

  • miR-432 impairs glucose homeostasis by suppressing the PIK3R3/AKT pathway and disrupts lipid homeostasis via inhibition of the PIK3R3/PPAR-α axis or directly suppressing PPAR-α.

  • Obesity-induced elevation of miR-432 is predominantly localized in adipocytes and driven by the CDK5/PPAR-γ axis.

  • Adipocyte-derived exosomal miR-432 mediates systemic metabolic dysfunction, establishing an intertissue regulatory network.

Graphical Abstract

Alternate Text: A schematic summarises the role of micro R N A 432 in metabolic regulation. In adipocytes, palmitic acid activates CDK5-phosphorylating P P A R gamma pathway to induce micro R N A 432, which is secreted via exosomes. Micro R N A 432 suppresses P I K 3 R 3/A K T pathway to impair glucose uptake and insulin sensitivity, while inhibiting PIK3R3/PPAR alpha axis to decrease fatty acid oxidation and thermogenesis. These actions collectively disrupting glucose and lipid homeostasis in liver, adipose tissue, and muscle.

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Introduction

Obesity is a public health crisis, elevating the risk of chronic metabolic disorders, including type 2 diabetes mellitus (T2DM), dyslipidemia, and metabolic dysfunction–associated steatotic liver disease (1). The primary tissues responsible for regulating glucose and lipid metabolism are adipose tissue, liver, and skeletal muscle (2). Dysregulation of these tissues contributes to obesity-associated metabolic dysfunction, yet the underlying molecular mechanisms remain incompletely understood.

miRNAs are short, endogenous, noncoding RNAs of ∼22 nucleotides that serve as posttranscriptional regulators of gene expression (3). Specific miRNAs, including miR-29a, miR-27a, and miR-99b, have been unequivocally linked to obesity-induced insulin resistance (4). Additionally, miRNAs participate in systemic lipid metabolism, including miR-34a, miR-27b, miR-223, and miR-122 (5). Our recent studies have identified dysregulated miRNAs in obesity and T2DM, such as miR-4431, miR-548ag/ab, and miR-155 (6–8), highlighting their potential as biomarkers and therapeutic targets in metabolic diseases.

Numerous small extracellular vesicles have been discovered to facilitate communication by transporting bioactive molecules to neighboring cells or distant organs (9). In particular, exosomes, a specific type of small extracellular vesicle, facilitate intercellular communication by transporting active biomolecules, including miRNAs (10,11). There is feasible evidence that exosomal miRNAs from adipose tissue contribute to glucose dysregulation and hepatic steatosis, such as miR-222, miR-122, miR-27a, and miR-22-3p (12–15). However, the functional specificity of miRNAs across metabolic tissues and their role in interorgan cross talk is still not fully known.

This study identified miR-432 as a regulator of obesity-associated metabolic dysfunction in adipose tissue, liver, and skeletal muscle. Mechanistically, miR-432 impaired glucose homeostasis by suppressing the phosphoinositide 3-kinase regulatory subunit 3 (PIK3R3)/protein kinase B (AKT) pathway and disrupted lipid homeostasis by inhibiting the PIK3R3/peroxisome proliferator–activated receptor α (PPAR-α) axis. Notably, adipocyte-derived exosomal miR-432, driven by the cyclin dependent kinase 5 (CDK5)/PPAR-γ axis, impaired glucose and lipid homeostasis, underscoring its function as a mediator of obesity-induced metabolic dysfunction.

Research Design and Methods

Human Samples

Serum, visceral adipose tissue, liver, and skeletal muscle samples were collected from individuals with normal weight, obesity, or T2DM at the First Affiliated Hospital of Shihezi University. Fasting insulin, fasting plasma glucose (FPG), and blood lipid levels were measured. The HOMA of insulin resistance was calculated as FPG (mmol/L) × fasting insulin (μU/mL) / 22.5. Inclusion criteria were normal weight (BMI 18.5–24 kg/m2), obesity (BMI ≥30 kg/m2), or T2DM (clinical diagnosis with FPG ≥7.0 mmol/L or postprandial glucose ≥11.1 mmol/L). All studies were approved by the Institutional Review Board of the First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, China (KJ2022-034-01).

Mice

C57BL/6 and db/db male mice were obtained from Hunan SJA Laboratory Animal Co., Ltd. Heterozygous miR-432 knockin (miR-432ki/+) and adiponectin-cre mice were sourced from Cyagen Biosciences Co., Ltd. Heterozygous miR-432ki/+ mice were interbred to generate homozygous miR-432ki/ki mice, which were then crossed with miR-432ki/ki or wild-type (WT) adiponectin-cre mice to produce adipose-specific miR-432 knockin (cKI) mice, including homozygous miR-432ki/ki,cre or heterozygous miR-432ki/+,cre mice. The miR-432ki/ki or miR-432ki/+ mice absent of cre recombinase served as controls. Primers for genotype are provided in Supplementary Table 1. All animal procedures were approved by the First Affiliated Hospital of Shihezi University Animal Care and Use Committee, Shihezi, Xinjiang, China (A2022-042-01).

Cell Culture

Isolation of stromal vascular fraction (SVF) cells was performed as previously described (16). Briefly, the digested adipose tissue was filtered through a 100-μm cell strainer and centrifuged at 1,000 rpm for 5 min to collect SVF cells. Adipocyte and C2C12 myoblast differentiations were performed as previously described (17,18).

Adeno-Associated Virus Injection

Adeno-associated virus 9 (AAV9) vectors encoding miR-432 mimics/inhibitors (ITR-U6-miR-432-CMV-mCherry-hGHpa-ITR), PPAR-α/PIK3R3 (ITR-CMV-human β-globin intron-PPARα/PIK3R3-hGHpA-ITR), and control empty vector were purchased from GenePharma (Shanghai, China). AAV9 was injected (tail vein/tibialis anterior/subcutaneous fat pad, 1 × 1012 vector genomes [vg]/mouse) into mice and monitored by IVIS Spectrum CT (PerkinElmer, Waltham, MA).

Bioinformatic Analysis

Serum miRNA microarray and RNA sequencing analysis were conducted at Shanghai Biotech Co., Ltd. Differentially expressed miRNAs in the serum of participants were analyzed by volcano plots, heat maps, and Venn diagrams. For downstream target gene prediction, TargetScan and miRDB were conducted. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to identify enriched biological pathways.

Cell Transfection

Lipofectamine 2000 and 3000 (Invitrogen, Waltham, MA) were used for transfecting small RNAs (interfering fragments, mimics, and inhibitors) and plasmids, respectively. The sequences of the transfected materials are provided in Supplementary Table 2.

Glucose Intake

Cells, starved for 4 h, were treated with glucose-free and phenol red–free DMEM for 2 h, followed by 100 nmol/L insulin for 10 min, and 100 μmol/L 2-NBDG (MedChemExpress, Monmouth Junction, NJ) for 20 min. Fluorescence intensity was quantitated using a fluorescence microplate reader at excitation and emission wavelengths of 467 nm and 542 nm, respectively.

Exosomes Extraction and Treatment

Serum and cell supernatants were collected and centrifuged at 4°C and 2,000g for 10 min and 10,000g for 30 min, then centrifuged at 120,000g for 90 min. The pellet was resuspended in PBS and centrifuged at 4°C for 90 min. DiD-labeled exosomes (Beyotime, Shanghai, China) were delivered to mice or cells.

Histochemical Staining and Immunofluorescence

Hematoxylin-eosin (H-E) and oil red O staining were performed as previously described (16). For immunofluorescence, samples were incubated with GLUT4 antibody (Proteintech, Wuhan, China) at 4°C overnight, and CoraLite488-Conjugated Goat Anti-Mouse IgG(H+L) (Proteintech) for 60 min. Fluorescence was measured using confocal microscopy (Nikon, Tokyo, Japan). All images were processed using Fiji software.

Glucose Tolerance and Insulin Tolerance Tests

For the glucose tolerance test (GTT), following a 12-h fast, mice received intraperitoneal glucose (2 g/kg), followed by blood glucose measurements at 0, 30, 60, 90, and 120 min. For the insulin tolerance test (ITT), after a 4-h fast, mice were injected with insulin (0.5 IU/kg), followed by glucose measurements at 0, 30, 60, 90, and 120 min.

Metabolic Cage

The PhenoMaster multifunctional metabolism analysis system (TSE Systems, Berlin, Germany) was used. Mice were housed in metabolic cages for 24 h (12-h light/12-h dark cycle) with continuous measurements of drinking, food intake, Vo2, Vco2, and heat production.

Real-Time Quantitative PCR

Total RNA was isolated using the TRIzol reagent (Invitrogen). Real-time quantitative PCR (RT-qPCR) for mRNA or miRNA was performed as described previously (19). GAPDH served as an internal reference for cells/tissues and cel-miR-39 as an external reference for serum/exosomes. All primer sequences are listed in Supplementary Table 3.

Western Blot Analysis

Protein extraction and Western blot analysis were performed as described previously (20). Antibodies are listed in Supplementary Table 4.

Ago2 RNA Immunoprecipitation

Lysates were centrifuged at 4°C for 15 min at 15,000g, and 10% of the lysates were used as input. Protein G/A Magnetic Beads were incubated with anti-Ago2 or anti-IgG antibodies (Proteintech) for 4 h. The complexes were rotated with the lysates overnight at 4°C. TRIzol was added to detect mRNA enrichment.

Dual-Luciferase Reporter Assay

HEK-293 cells transfected with miR-432 mimic (50 nmol/L) and WT/mutant PIK3R3/PPAR-α 3′ untranslated region (UTR). The activities of firefly and Renilla luciferase were measured using the Dual-Luciferase Assay System (Beyotime, Beijing, China).

Chromatin Immunoprecipitation

3T3-L1 adipocytes were transfected with Flag-tagged PPAR-γ WT or S273A mutant to assess its occupancy in miR-432 promoter. Cells were cross linked with nucleic acids and DNA-binding proteins using formaldehyde. Chromatins were fragmented into 200–1,000-base pair (bp) segments. The anti-Flag or anti-IgG antibody (Proteintech) was applied to precipitate the DNA/protein complex. Primer sequences for chromatin immunoprecipitation (ChIP)–PCR are provided in Supplementary Table 5.

Statistical Analysis

Data analysis was performed using the GraphPad Prism 8.0 software. The results are presented as mean ± SD or mean ± SEM. Student t tests were used for comparisons between groups with normally distributed data and nonparametric tests for nonnormally distributed data. One-way ANOVA was used to compare three groups. Two-way repeated-measures ANOVA was used to assess interaction effects between factors. Correlations were evaluated using Pearson product moment correlation analysis. Statistical significance was defined as P < 0.05 or P < 0.01.

Data and Resource Availability

All data generated or analyzed during this study are included in the published article (and its online supplementary files).

Results

miR-432 Is Associated With Increased Susceptibility to Obesity and T2DM

Differential expression analysis of miRNA profiles identified 40 upregulated and 73 downregulated miRNAs in the serum of individuals in the obesity group and 48 upregulated and 31 downregulated miRNAs in individuals in the T2DM group compared with the normal weight group (Fig. 1A and B and Supplementary Table 6). Principal component analysis indicated similarities between the obesity and T2DM groups (Fig. 1C). Venn diagram analysis characterized 22 upregulated and 18 downregulated miRNAs in both the obesity and T2DM groups (Fig. 1D). A heat map of the 40 miRNAs highlighted hsa-miR-4538, hsa-miR-6871-5p, hsa-miR-432-5p, and hsa-miR-4493 as having the highest fold changes (Fig. 1E).

Figure 1.

A multi-panel figure illustrates differential expression and pathway analysis of micro R N A data comparing obesity, type 2 diabetes mellitus, and normal weight conditions. Panels A and B show volcano plots of significant gene expression changes; C presents principal component analysis clustering; D and G display Venn diagrams of overlapping genes; E shows a heatmap of expression levels; F highlights micro R N A sequence alignment; H and I depict pathway enrichment analyses; J to O show expression comparisons across tissues and groups, with elevated micro R N A 432 expression linked to obesity and diabetes.

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miR-432 was identified to be positively correlated with obesity and T2DM. A and B: Volcano plots of serum miRNA profiles of obesity/T2DM vs. normal weight (NW) (fold change [FC] >2, P < 0.01). C: Principal component (PC) analysis of NW, obesity, and T2DM groups. D: Venn diagram of highly (left) or lowly (right) expressed miRNAs in the obesity and T2DM groups. E: Heat map of 40 differentially expressed miRNAs in D. F: Sequence alignment of mmu-miR-432, hsa-miR-432-5p, and hsa-miR-432-3p. G: Target genes of hsa-miR-432-5p and mmu-miR-432 predicted by TargetScan (version 8.0) and miRDB (2020). H and I: KEGG pathway enrichment analysis (cloud; Oebiotech) in G. J: Serum miR-432 levels quantified by RT-qPCR in NW (n = 60), obesity (n = 60), and T2DM (n = 60) groups. K: Correlation between serum miR-432 and metabolic parameters (weight, BMI, FPG, lipids, etc.) in pooled cohorts (n = 180). L and M: Tissue miR-432 expression in C57BL/6 J mice fed an ND or HFD (60% kcal fat) for 22 weeks (n = 4–6). N: miR-432 levels (RT-qPCR) in epiWAT, skeletal muscle, and liver of 12-week-old m/m and db/db mice (n = 6). O: miR-432 levels (RT-qPCR) in visceral adipose tissue, skeletal muscle, and liver of individuals with NW or overweight/obesity (n = 6). Statistical analyses included t tests for comparisons between groups with normally distributed data or nonparametric tests for data that did not follow a normal distribution. One-way ANOVA was used to compare the three groups. Pearson product moment correlation was used for correlation analysis. *P < 0.05, **P < 0.01. DEG, differentially expressed gene; HDL-C, HDL cholesterol; HOMA-IR, HOMA of insulin resistance; LDL-C, LDL cholesterol; OB, obesity.

A significant enrichment of hsa-miR-432-5p target genes was identified in insulin resistance pathways (Fig. 1G and H), whereas no such enrichment was observed for hsa-miR-4538, hsa-miR-6871-5p, or hsa-miR-4493 (Supplementary Fig. 1A–C). Although the mature sequences of hsa-miR-432-3p and hsa-miR-432-5p are derived from the same pre–miR-312 restriction enzyme digestion product, their mature sequences are distinct (Fig. 1F), resulting in a lack of enrichment of their downstream target genes in the insulin signaling pathway (Supplementary Fig. 1D). Notably, matured mmu-miR-432 only differed by 4 bases (80% sequence identity) as did that of hsa-miR-432-5p with a consistent seed sequence CUUGGA (Fig. 1F). Moreover, KEGG pathway enrichment analysis of predicted target genes for mmu-miR-432 confirmed its enrichment in insulin resistance pathways (Fig. 1G–I). Based on these findings, we embarked on hsa-miR-432-5p and mmu-miR-432 (collectively defined as miR-432) for further investigation.

Consistent with the microarray results, significantly higher levels of miR-432 were detected in the serum of individuals in the obesity and T2DM groups compared with the normal weight group (Supplementary Table 7 and Fig. 1J), which was positively correlated with metabolic markers (weight, BMI, FPG, etc.) but negatively with HDL cholesterol (Fig. 1K). In mice, miR-432 is most abundantly expressed in epididymal white adipose tissue (epiWAT) (Fig. 1L). Sustained high-fat diet (HFD) insult induced ectopic miR-432 expression in adipose tissue, skeletal muscle, and liver (Supplementary Fig. 2A–E and Fig. 1M), a finding corroborated in db/db mice (Fig. 1N and Supplementary Fig. 2F and G). Individuals in the obesity group also manifested significantly higher miR-432 expression in these tissues (Fig. 1O). Together, miR-432 may be involved in the pathogenesis of obesity-related metabolic dysregulation.

miR-432 Exacerbates HFD-Induced Metabolic Dysregulation in Adipose Tissue, Liver, and Skeletal Muscle

Genotyping confirmed the WT, miR-432ki/+, control, and cKI mice (Fig. 2A and B). HFD-fed cKI mice developed increased body weight and adiposity (Fig. 2C–F), despite normal drinking and food intake (Fig. 2G and H). Besides, cKI mice revealed adipocyte hypertrophy (Fig. 2I) and reduced GLUT4 expression in epiWAT (Fig. 2J and K). GTT and ITT indicated impaired glucose tolerance and insulin sensitivity (Fig. 2L and M). Metabolic cage analysis demonstrated that cKI mice exhibited significantly reduced Vo2, Vco2, and heat production compared with control mice (Fig. 2N–Q). Similar metabolic phenotype alterations were observed in heterozygous cKI mice (Supplementary Fig. 3A–I). In contrast, local subcutaneous injection of AAV9-mCherry-miR-432 inhibitor markedly ameliorated these metabolic phenotypes (Supplementary Fig. 4A–F).

Figure 2.

A composite figure demonstrates the effects of adipocyte-specific micro R N A 432 knock-in in mice. It includes the gene targeting strategy, genotyping confirmation, body weight progression, tissue morphology, and metabolic outcomes. Knock-in mice show increased weight, adiposity, and reduced glucose tolerance and insulin sensitivity. Immunostaining and western blot reveal reduced G L U T 4 in adipose tissue. Metabolic chamber data show lower oxygen consumption, carbon dioxide production, and heat generation, indicating impaired energy expenditure.

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cKI mice disrupt systemic metabolic homeostasis. A: Schematic of miR-432 knockin mouse construction. cKI mice were generated by crossing miR-432ki/ki mice with adiponectin-cre, miR-432ki/ki mice. Control (ctrl) mice were miR-432ki/ki but lacking adiponectin-cre. B: Genotyping of WT, miR-432ki/+, miR-432ki/ki (ctrl), and miR-432ki/ki,cre (cKI) mice. C: Body weight of ctrl and cKI mice (n = 8). D: Gross and adipose tissue appearance of ctrl and cKI mice. E: Tissue weight of ctrl and cKI mice (n = 8). F: Adipose index of ctrl and cKI mice ([adipose mass / body mass] × 100) (n = 8). G and H: Daily drinking and food intake measured via metabolic cages of ctrl and cKI mice over 24 h (n = 6). I: H-E staining of epiWAT, iWAT, and BAT from ctrl and cKI mice (scale bar: 500 μm). J: Immunofluorescence of GLUT4 in epiWAT of ctrl and cKI mice (scale bar: 100 μm and 30 μm, respectively). L and M: Intraperitoneal GTT (2 g/kg glucose after 12 h of fasting) and ITT (0.5 units/kg premixed 30R after 4 h of fasting) (n = 8) of ctrl and cKI mice. N–Q: Metabolic parameters of ctrl and cKI mice for 24 h (12-h light/12-h dark cycle): Vo2, Vco2, and heat production (n = 6). Statistical analysis was performed using t test or nonparametric test, depending on data distribution. Two-way repeated-measures ANOVA was used to assess interaction effects between factors. *P < 0.05, **P < 0.01. AUC, area under the curve; BGH pA, bovine growth hormone polyadenylation; visWAT, visceral white adipose tissue; WRPE, woodchuck hepatitis virus posttranscriptional regulatory element.

C57BL/6 mice were placed on an 8-week HFD and subsequently administered tail vein injections of AAV9-mCherry-NC, miR-432 mimic, or inhibitor (Fig. 3A). Fluorescence imaging and mCherry protein expression confirmed predominant hepatic localization of AAV9-mCherry (Fig. 3B and C). While no significant differences in body weight or adipose tissue mass were observed (Fig. 3D–F), mice treated with the miR-432 mimic exhibited a significant increase in liver weight (Fig. 3G). Indeed, miR-432 mimic exacerbated hepatic steatosis, exhibited a notable increase of serum triglyceride (TG) levels, and impaired insulin sensitivity (Fig. 3H–L), while miR-432 inhibitor improved these effects (Fig. 3G–L).

Figure 3.

A multi-panel figure shows the effects of micro R N A 432 modulation in high-fat diet-fed mice. It includes experimental design, imaging, protein expression, and metabolic analyses. Micro R N A 432 mimic increases weight gain, hepatic steatosis, and glucose intolerance, while its inhibition reduces these effects. Liver staining and western blot confirm reduced fat accumulation and restored P I K 3 R 3 and phosphorylated A K T expression with inhibition, indicating improved insulin sensitivity and lipid metabolism.

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Hepatic miR-432 exacerbates HFD-induced metabolic dysregulation. A: Eight-week-old C57BL/6 mice were fed an ND and HFD (60% kcal fat) for 8 weeks, followed by injection of AAV9-mCherry (the empty vector, NC), AAV9-mCherry-miR-432 mimic (mimic), or AAV9-mCherry-miR-432 inhibitor (inhibitor) into the tail vein (1 × 1012 vg/mouse) (n = 8) for an additional 8 weeks. B: In vivo fluorescence imaging (IVIS Spectrum CT) of mice described in A. C: mCherry protein expression in liver. D: Gross and adipose tissue appearance. E–G: Body and tissue weight (n = 8). H: Oil red O and H-E staining of liver (scale bar: 100 μm). I and J: Serum TG and TC content (n = 6). K and L: GTT and ITT (n = 6). M: miR-432 expression in tissues (n = 7). N–Q: PIK3R3 protein (n = 3) and mRNA (n = 7) levels in liver. R and S: AKT phosphorylation (p-AKT) (n = 3) in liver. Statistical analysis was performed using t test or nonparametric test, depending on data distribution. One-way ANOVA was used to compare the groups. Two-way repeated-measures ANOVA was used to assess interaction effects between factors. *P < 0.05, **P < 0.01. AUC, area under the curve; Max, maximum; Min, minimum; perWAT, perirenal white adipose tissue; t-AKT, total AKT; visWAT, visceral white adipose tissue.

Following a similar approach, AAV9-mCherry location within the skeletal muscle was confirmed (Fig. 4A–C). Administration of miR-432 mimic/inhibitor did not cause a change in weight (Fig. 4D–F) and serum TG/total cholesterol (TC) levels (Fig. 4G and H). However, miR-432 mimic significantly exacerbated glucose intolerance along with impaired insulin sensitivity, while an opposite effect was noted for mice receiving the miR-432 inhibitor (Fig. 4I and J). These results demonstrate that miR-432 exacerbates HFD-induced metabolic dysregulation in adipose tissue, liver, and skeletal muscle.

Figure 4.

A composite figure illustrates effects of micro R N A 432 modulation on skeletal muscle metabolism in high-fat diet-fed mice. Experimental design and imaging show successful vector delivery and altered muscle appearance. Mice with micro R N A 432 inhibition exhibit improved glucose tolerance, insulin sensitivity, and reduced triglyceride levels compared with mimic-treated mice. Western blot analysis reveals restored P I K 3 R 3 and phosphorylated A K T expression in skeletal muscle, indicating enhanced insulin signalling and metabolic regulation.

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Skeletal muscle miR-432 exacerbates HFD-induced metabolic dysregulation. A: Eight-week-old C57BL/6 mice were fed an ND and HFD (60% kcal fat) for 8 weeks, followed by injection of AAV9-mCherry (the empty vector, NC), AAV9-mCherry-miR-432 mimic (mimic), or AAV9-mCherry-miR-432 inhibitor (inhibitor) into the tibialis anterior (1 × 1012 vg/mouse) (n = 8) for an additional 8 weeks. B: In vivo fluorescence imaging of mice described in A. C: mCherry protein expression in skeletal muscle. D: Gross and adipose tissue appearance. E and F: Body and tissue weights (n = 8). G and H: Serum TG and TC content (n = 6). I and J: GTT and ITT (n = 6). K: miR-432 expression in tissues (n = 7). L–O: PIK3R3 protein (n = 3) and mRNA (n = 7) levels in skeletal muscle. P and Q: AKT phosphorylation (p-AKT) in skeletal muscle (n = 3). Statistical analysis was performed using t test or nonparametric test, depending on data distribution. One-way ANOVA was used to compare the groups. Two-way repeated-measures ANOVA was used to assess interaction effects between factors. *P < 0.05, **P < 0.01. AUC, area under the curve; Max, maximum; Min, minimum; perWAT, perirenal white adipose tissue; t-AKT, total AKT; visWAT, visceral white adipose tissue.

miR-432 Impairs Glucose Homeostasis Via the PIK3R3/AKT Pathway in Insulin Resistance

As illustrated in Fig. 1G, potential target genes of hsa-miR-432-5p and mmu-miR-432 were predicted using TargetScan and miRDB, respectively. The analysis identified 425 common target genes for hsa-miR-432-5p and 299 for mmu-miR-432. To evaluate the conservation of target genes across species and to assess the translational relevance of murine models to human mechanisms, a Venn diagram was constructed to visualize overlapping targets coregulated by both human and mouse miR-432. This comparative approach revealed 84 conserved target genes (Supplementary Fig. 5A). Subsequent transfection of miR-432 mimic into 3T3-L1 adipocytes, followed by RNA sequencing and RT-qPCR analyses, revealed that PIK3R3 exhibited the most significant mRNA downregulation among these 84 overlapping genes (Supplementary Fig. 5B and C). As PIK3R3 is a critical component of the insulin signaling pathway (Supplementary Fig. 5D), these findings suggest its role as a downstream mediator of miR-432’s metabolic regulation.

The dual-luciferase reporter assay in HEK-293 cells confirmed that miR-432 directly targeted to the 3′UTR of PIK3R3 (Supplementary Fig. 5E and F). Besides, miR-432 mimic recruited Ago2 to PIK3R3 mRNA in 3T3-L1 adipocytes (Supplementary Fig. 5G). Moreover, miR-432 mimic significantly reduced PIK3R3 levels in 3T3-L1, HepG2, and C2C12 cells (Supplementary Fig. 5H and I), while inhibition of miR-432 enhanced PIK3R3 levels (Supplementary Fig. 5J and K). In addition, miR-432 overexpression impaired insulin-induced AKT phosphorylation in primary adipocytes, primary hepatocytes, and C2C12 cells, while miR-432 inhibition reversed it (Supplementary Fig. 5L and M). Moreover, miR-432 mimic impaired glucose uptake in those cells (Supplementary Fig. 5N).

In vivo experiments showed that HFD-fed cKI mice exhibited elevated miR-432 expression in adipose tissue, liver, and skeletal muscle, accompanied by reduced levels of PIK3R3 and AKT phosphorylation (Fig. 5A–I). Conversely, subcutaneous fat pad injection of an AAV9-miR-432 inhibitor increased PIK3R3 expression in inguinal white adipose tissue (iWAT) (Supplementary Fig. 4G and H). Similarly, miR-432 mimic decreased both PIK3R3 expression and AKT phosphorylation, whereas miR-432 inhibition restored them in the liver (Fig. 3M–S) and skeletal muscle (Fig. 4K–Q). As expected, PIK3R3 overexpression salvaged the reduction in AKT phosphorylation induced by miR-432 mimic (Fig. 5H–J). Inversely, PIK3R3 siRNA effectively reversed the increased PIK3R3 expression and insulin-induced AKT phosphorylation caused by miR-432 inhibitor (Fig. 5K–M). Briefly, miR-432 fosters insulin resistance by repressing the PIK3R3/AKT axis.

Figure 5.

A multi-panel figure shows molecular effects of micro R N A 432 knock-in and inhibition on P I K 3 R 3 and A K T signalling. Expression analysis reveals elevated micro R N A 432 and reduced P I K 3 R 3 messenger R N A and protein in adipose, liver and muscle tissues. Western blots demonstrate decreased phosphorylated A K T in knock-in models and restored levels with micro R N A 432 inhibition. Data from liver, adipose, skeletal muscle, and cultured cells confirm that micro R N A 432 suppresses insulin signalling through P I K 3 R 3 downregulation.

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miR-432 fosters insulin resistance by specifically repressing the PIK3R3/AKT axis. A: miR-432 expression levels in tissues of control (ctrl) and cKI mice (n = 8). B and C: PIK3R3 protein (n = 3) and mRNA (n = 8) expression levels in epiWAT of ctrl and cKI mice. D: AKT phosphorylation (p-AKT) levels in epiWAT of ctrl and cKI mice (n = 3). E and F: PIK3R3 protein (n = 3) and mRNA (n = 8) expression levels in liver/skeletal muscle of ctrl and cKI mice. G: p-AKT levels in liver/skeletal muscle of ctrl and cKI mice (n = 3). H–J: Primary adipocytes, primary hepatocytes, and C2C12 cells were transfected with 1) scramble mimic + empty vector (NC), 2) miR-432 mimic (50 nmol/L) + empty vector (mimic), and 3) miR-432 mimic (50 nmol/L) + pik3r3 plasmid (2 μg/well) (mimic + pik3r3) for 48 h to detect insulin-induced p-AKT (n = 3). K–M: Primary adipocytes, primary hepatocytes, and C2C12 cells were transfected with 1) scramble inhibitor + scramble siRNA (NC), 2) miR-432 inhibitor (100 nmol/L) + scramble siRNA (inhibitor), and 3) miR-432 inhibitor (100 nmol/L) + PIK3R3 siRNA (50 nmol/L) (inhibitor + si-pik3r3) to detect PIK3R3 expression and insulin-induced p-AKT (n = 3). Statistical analysis was performed using t test or nonparametric test, depending on data distribution. **P < 0.01. t-AKT, total AKT.

miR-432 Impairs Lipid Homeostasis by Inhibiting the PIK3R3/PPAR-α Axis

It has been reported that PIK3R3 positively modulates PPAR-α expression (21) and that miR-432 also directly targets the 3′UTR of PPAR-α, suggesting a dual regulatory mechanism through which miR-432 modulates lipid homeostasis (Fig. 6A). The dual-luciferase reporter assay confirmed that miR-432 directly targeted to the 3′UTR of PPAR-α and inhibited peroxisome proliferator response element transcriptional activity (Fig. 6B–D). In HFD-fed miR-432 cKI mice, the expression of PPAR-α and its downstream targets was markedly downregulated in both iWAT and brown adipose tissue (BAT) (Fig. 6E–H). Similar results were found in HFD-fed female (Supplementary Fig. 6A–I) and normal diet (ND)–fed male mice (Supplementary Fig. 7A–K). In contrast, miR-432 inhibitor in iWAT significantly increased PPAR-α expression (Supplementary Fig. 4G and H). In primary white/brown adipocytes, miR-432 inhibited the expression of PPAR-α and its downstream targets (Fig. 6I–L). Conversely, miR-432 inhibitor restored the expression of PPAR-α and uncoupled protein 1 (UCP1) (Fig. 6M and N). Moreover, PIK3R3 overexpression reversed the miR-432 mimic–mediated downregulation of PPAR-α and UCP1, while PIK3R3 siRNA counteracted the miR-432 inhibitor–induced upregulation of PPAR-α and UCP1 (Fig. 6O and P).

Figure 6.

A composite figure illustrates how micro R N A 432 regulates P P A R alpha , affecting lipid metabolism and thermogenesis. Reporter assays confirm direct targeting of P P A R alpha by micro R N A 432. Expression and protein analyses show reduced P P A R alpha and downstream thermogenic genes in adipose tissues and adipocytes of knock-in mice, with reversal after inhibition. Western blots and messenger R N A data from liver, brown, and white adipocytes indicate that micro R N A 432 suppression enhances fatty acid oxidation and thermogenic pathways.

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miR-432 impairs lipid homeostasis by inhibiting the PIK3R3/PPAR-α axis or the independent PPAR-α. A: Schematic of miR-432 dual mechanisms in PPAR-α. B: miR-432 binding sites in PPAR-α 3′UTR (TargetScan version 8.0). C and D: Dual-luciferase reporter assay and peroxisome proliferator response element (PPRE) reporter activity in HEK-293 cells (n = 6). E–H: The expression of PPAR-α (n = 8) and target genes (n = 6) in iWAT and BAT of control (ctrl) and cKI mice. I–L: The expression of PPAR-α and downstream targets in primary white/brown adipocytes from ctrl and cKI mice (n = 3–4). M and N: Protein expression of PPAR-α and UCP1 in primary white/brown adipocytes from cKI mice treated with scramble or miR-432 inhibitor (100 nmol/L) for 48 h (n = 3). O and P: Protein expression of PPAR-α and UCP1 in primary white/brown adipocytes transfected with NC/inhibitor/inhibitor + si-pik3r3 or NC/mimic/mimic + pik3r3 (n = 3). Q and R: The protein (n = 3) and mRNA (n = 8) expression of PPAR-α in liver of ctrl and cKI mice. S–V: Protein (n = 3) and mRNA (n = 3) expression of PPAR-α and target genes in primary hepatocytes transfected with NC/mimic/mimic + pik3r3 or NC/inhibitor/inhibitor + si-pik3r3. Statistical analysis was performed using t test or nonparametric test, depending on data distribution. One-way ANOVA was used to compare the three groups. *P < 0.05, **P < 0.01. MT, mutation.

In the liver, miR-432 mimic exacerbated hepatic steatosis and impaired glucose homeostasis (Supplementary Figs. 8A–K and 10A–E), while its inhibition alleviated these conditions (Supplementary Fig. 9A–K). Hepatic miR-432 mimic significantly downregulated PPAR-α and target genes (Supplementary Figs. 8L and M and 10F and G), whereas miR-432 inhibitor restored their expression (Supplementary Fig. 9L and M). In HFD-fed cKI mice, the expression of PPAR-α was markedly downregulated in liver (Fig. 6Q and R). Coadministration of AAV–PPAR-α and PIK3R3 both effectively rescued the miR-432 mimic–induced metabolic disturbances (Supplementary Figs. 8L and M and 10F and G). In primary hepatocytes, PIK3R3 overexpression reversed the miR-432 mimic–mediated suppression of PPAR-α signaling (Fig. 6S and T), while PIK3R3 knockdown attenuated the miR-432 inhibitor–driven effect (Fig. 6U and V). Collectively, miR-432 impairs lipid homeostasis by inhibiting the PIK3R3/PPAR-α axis.

Obesity-Induced miR-432 Elevation Is Predominantly Localized in Adipocytes, a Process Mediated by the CDK5/PPAR-γ Axis

To demonstrate the origin of miR-432 from adipose tissues, SVF cells and adipocytes were isolated from adipose tissues, revealing that HFD selectively induced miR-432 expression in adipocytes (Supplementary Fig. 11A). Furthermore, the adipose tissue–specific Dicer knockout mice, previously established in prior research (22), presented a significant reduction of miR-432 in epiWAT, liver, and skeletal muscle (Supplementary Fig. 11B). In vitro, palmitic acid (PA) was used to simulate the metabolic conditions associated with obesity (23). It was found that PA insult induced a significant increase of intracellular miR-432 levels in adipocytes, no perceptible difference was observed in SVF cells (Supplementary Fig. 11C and D). Further results revealed that PA promoted the miR-432 content in the exosomes (Supplementary Fig. 11E–H). To summarize, adipocytes are the primary source of miR-432 under obese conditions, and its exosomal secretion contributes to systemic regulation.

TransmiR software identified 59 potential miR-432 regulators, with PPAR-γ emerging as the most obesity-relevant factor (Supplementary Tables 8 and 9). ChIP assays confirmed that PPAR-γ directly binds to the promoter region of miR-432 (Supplementary Table 10 and Fig. 7A–C). PPAR-γ overexpression in adipocytes markedly increased miR-432 expression (Fig. 7D and E). Given that PPAR-γ Ser273 phosphorylation contributes to obesity-related insulin resistance (24), we observed elevated PPAR-γ Ser273 phosphorylation following PA treatment (Supplementary Fig. 11I), which may underlie the concomitant upregulation of miR-432. Notably, the PPAR-γ S273A mutant exhibited significantly reduced binding affinity for the miR-432 promoter compared with WT PPAR-γ (Fig. 7A–E), providing direct evidence that Ser273 phosphorylation enhances PPAR-γ binding to this locus.

Figure 7.

A multi-panel figure shows regulation of micro R N A 432 expression by P P A R gamma phosphorylation in adipocytes. Chromatin and co-immunoprecipitation assays identify P P A R gamma binding regions. Mutation at serine 273 reduces binding and micro R N A 432 expression. Western blots and gene expression analyses demonstrate that blocking P P A R gamma phosphorylation decreases micro R N A 432. Findings link phosphorylated P P A R gamma to elevated micro R N A 432 and impaired adipocyte function.

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PA upregulates miR-432 expression in adipocytes via the CDK5/PPAR-γ axis. A–C: ChIP assay was performed in 3T3-L1 adipocytes transfected with Flag-tagged PPAR-γ WT and PPAR-γ S273A mutant plasmid to assess PPAR-γ occupancy of the miR-432 promoter (n = 3). D and E: miR-432 levels (RT-qPCR) in 3T3-L1 adipocytes transfected with empty vector control (NC), PPAR-γ WT, and S273A mutant plasmid (n = 3). F–H: PPAR-γ Ser273 phosphorylation, GDF3/APN/CD36 expression, and miR-432 expression in primary adipocytes treated with PA (0.2 mmol/L) ± GQ-16 (10 μmol/L, 24 h, n = 3) or BSA + DMSO vehicle as control. I–K: PPAR-γ Ser273 phosphorylation, GDF3/APN/CD36 expression, and miR-432 expression in primary adipocytes treated with PA (0.2 mmol/L) ± SR1664 (10 μmol/L, 24 h, n = 3–4) or BSA + DMSO vehicle as control. L and M: PPAR-γ Ser273 phosphorylation and miR-432 expression in primary adipocytes and iWAT of mice treated with PA (0.2 mmol/L) ± (R)-Roscovitine [R(ROS)] (10 μmol/L, 24 h, n = 3) or BSA + DMSO vehicle as control. N: PPAR-γ Ser273 phosphorylation and miR-432 expression in primary adipocytes transfected with CDK5 plasmid and si-CDK5 interfering fragments (n = 3). Statistical analysis was performed using t test or nonparametric test, depending on data distribution. One-way ANOVA was used to compare the three groups. *P < 0.05, **P < 0.01. IP, immunoprecipitation; TSS, transcription start site.

Building on the reported role of CDK5 in regulating PPAR-γ phosphorylation (25), we tested two inhibitors of CDK5-mediated PPAR-γ phosphorylation, GQ-16 and SR1664 (26,27) in PA-treated adipocytes. Both compounds markedly suppressed PPAR-γ Ser273 phosphorylation; altered PPAR-γ target gene expression, such as CD36, adiponectin (APN), and growth differentiation factor 3 (GDF3) (28); and downregulated miR-432 (Fig. 7F–K). Similar reductions were observed both in adipocytes and the epiWAT of PA-treated mice following administration of (R)-Roscovitine, a CDK5 inhibitor (Fig. 7L and M). To directly assess CDK5’s role, loss- and gain-of-function studies were conducted. CDK5 knockdown markedly reduced both PPAR-γ Ser273 phosphorylation and miR-432 expression, while its overexpression enhanced miR-432 levels (Fig. 7N and O). Together, PA upregulates miR-432 expression in adipocytes via the CDK5/PPAR-γ axis.

Adipocyte-Derived Exosomal miR-432 Impairs Glucose and Lipid Homeostasis

Exosomes isolated from miR-432 mimic–transfected adipocytes showed characteristic morphology, size distribution, and exosomal markers (Fig. 8A and B). The content of miR-432 was significantly increased in the extracted exosomes (Fig. 8C). Subsequently, C57BL/6 mice were fed an HFD for 6 weeks followed by tail vein injection of adipocyte-derived exosomal normal control (adipo-exo NC) or adipocyte-derived exosomal miR-432 mimic (adipo-exo mimic). Fluorescence intensity and miR-432 expression confirmed that exosomal miR-432 could be taken up by liver and skeletal muscle (Fig. 8D and Supplementary Fig. 12A and B). While no significant differences were observed in body weight or adipose tissue mass (Fig. 8E and F), mice receiving adipo-exo mimic exhibited a significant increase in liver weight (Fig. 8G), hepatic steatosis (Fig. 8H), glucose intolerance, and insulin resistance (Fig. 8I–J), as well as elevations in TG/TC levels alongside increased AST/ALT levels (Fig. 8K and L). Consistently, a significant decrease of PIK3R3 expression and AKT phosphorylation were observed in the liver and skeletal muscle of mice receiving adipo-exo mimic (Fig. 8M–P). Moreover, the expression of hepatic PPAR-α and its downstream target genes was significantly decreased (Fig. 8Q–S).

Figure 8.

A composite figure shows that adipocyte-derived exosomes carrying micro R N A 432 mimic impair metabolic function in mice. Characterisation confirms exosome structure and marker proteins. Mice receiving micro R N A 432 mimic exhibit liver fat accumulation, higher triglyceride and transaminase levels, and impaired glucose and insulin tolerance. Liver and muscle show reduced P I K 3 R 3, P P A R alpha, and phosphorylated A K T expression, along with downregulation of fatty acid oxidation genes, indicating that exosomal micro R N A 432 promotes lipid accumulation and insulin resistance.

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Adipocyte exosomal miR-432 exacerbates glucose intolerance and insulin resistance in HFD mice. A and B: Transmission electron microscopy, particle size, and marker protein expression (20 μg/well) of exosomes isolated from scramble or miR-432 mimic–transfected adipocytes (adipo-exo NC or mimic). C: miR-432 contents (RT-qPCR) in exosomes in A and B (n = 4). D: In vivo fluorescence imaging (IVIS Spectrum CT) of DiD-labeled exosome fluorescence of mice, which were fed an HFD for 6 weeks and received weekly intravenous injections of adipo-exo NC (1 × 1010 particles/mouse) or adipo-exo mimic (1 × 1010 particles/mouse) for 4 weeks. E–G: Body/tissue weight (n = 8). H: H-E staining (scale bar: 500 μm) and oil red O staining (scale bar: 50 μm) of liver. I and J: GTT and ITT (n = 8). K: Serum TG, TC, AST, and ALT content (n = 8). L: Liver TG and TC content (n = 8). M: PIK3R3 mRNA expression level in liver and skeletal muscle (n = 8). N–P: PIK3R3 protein expression and AKT phosphorylation (p-AKT) in liver and skeletal muscle (n = 3–4). Q–S: PPAR-α (mRNA, n = 8; protein, n = 3) and its target gene (mRNA, n = 8) expression in liver. Statistical analysis was performed using t test or nonparametric test, depending on data distribution. Two-way repeated-measures ANOVA was used to assess interaction effects between factors. *P < 0.05, **P < 0.01. AUC, area under the curve; gprot, grams protein; FA, fatty acid; Max, maximum; Min, minimum; perWAT, perirenal white adipose tissue; visWAT, visceral white adipose tissue.

In vitro studies demonstrated that miR-432 mimics were successfully delivered via adipocyte-derived culture supernatants and exosomes to HepG2 and C2C12 cells (Supplementary Fig. 13A–F). As expected, coculture with adipo-exo mimic significantly repressed PIK3R3 expression and attenuated insulin-induced AKT phosphorylation in recipient cells (Supplementary Fig. 13G and H). Moreover, addition of GW4869, an exosome release blocker, restored the adipo-exo mimic-induced reduction in AKT phosphorylation (Supplementary Fig. 13H). In addition, coculture with adipo-exo mimic significantly repressed PPAR-α expression, and this effect was rescued by treatment with GW4869 (Supplementary Fig. 13I). Collectively, adipocyte-derived exosomal miR-432 disrupts glucose and lipid homeostasis.

Discussion

This report reveals elevated serum levels of miR-432 in individuals with obesity and T2DM. miR-432 is implicated in various tumorigenic processes, including osteosarcoma, gastric cancer, and colorectal cancer (29–32), and play roles in depression, heart disease, and other disorders (33,34). There is feasible evidence that circulating miR-432 levels are decreased following a low-fat diet (35). In metabolic-related tissues, oar-miR-432 inhibits adipose differentiation (36,37), while mmu-miR-432 suppresses myocyte differentiation by modulating the PI3K/AKT pathway (38,39). Our study revealed that miR-432 overexpression in adipose tissue, liver, and skeletal muscle exacerbates HFD-induced disruption of metabolic homeostasis.

Previous literature has reported that PIK3R3 forms a stable complex with p110 and binds to insulin receptor substrate 1 during insulin stimulation (40). PIK3R3 activates AKT signaling in liver cancer (41) and modulates the AKT/mammalian target of rapamycin (mTOR) pathway to promote colorectal cancer progression (42). Furthermore, PIK3R3-mediated AKT activation regulates the proliferation and apoptosis of sheep hair follicle stem cells (43). Of note, miR-432 inhibits myoblast proliferation by blocking the PIK3R3-controlled PI3K/AKT/mTOR pathway (38). Herein, we found that miR-432 reduced insulin sensitivity by targeting the PIK3R3/AKT axis.

This study highlights that miR-432 promotes obesity and hepatic steatosis through dual effects: 1) indirect disruption of the PIK3R3/PPAR-α axis and 2) direct suppression of PPAR-α. These findings align with prior reports establishing PIK3R3 as a positive regulator of PPAR-α in metabolic dysfunction–associated steatotic liver disease improvement (21). Restoration of PIK3R3 expression substantially ameliorated hepatic steatosis and restored PPAR-α levels along with its targets, which confirms that PIK3R3 suppression may be the primary mechanism underlying miR-432–induced steatosis, although the direct effect of miR-432 on PPAR-α cannot be entirely ruled out. Furthermore, while hepatic miR-432 exacerbates fatty acid β-oxidation and uptake, it had no effect on body weight, suggesting that its metabolic effects are primarily confined to hepatic lipid metabolism rather than systemic energy balance. In contrast, the increase in body weight mediated by miR-432 is largely driven by its impact on adipocyte thermogenesis and energy metabolism. These findings establish miR-432 as a contributor to the regulation of glucose and lipid metabolism, yet its full mechanistic scope and interplay with other metabolic regulators require further elucidation.

Our results demonstrate that HFD feeding induced the most pronounced upregulation of miR-432 expression, specifically in adipocytes. Adipose tissue–specific Dicer knockout mice presented a significant reduction of miR-432 in metabolic tissues. Furthermore, HFD challenge also triggered a significant induction of miR-432 and target genes in the liver and skeletal muscle of cKI mice. These findings collectively underscore the role of adipocyte-derived miR-432 in systemic metabolic regulation. Current findings have indicated that exosomes derived from adipose tissue can trigger cross talk within organs, exacerbating insulin resistance and glucose intolerance (44). This study revealed that PA induced PPAR-γ Ser273 phosphorylation through the CDK5 pathway to promote miR-432 expression in adipocytes. Then, miR-432 can be packaged into exosomes and released into circulation to disrupt glucose and lipid homeostasis, underscoring the critical role of adipocyte-derived exosomal miR-432 in mediating intercellular communication and systemic metabolic regulation.

CDK5-mediated phosphorylation of PPAR-γ at Ser273 has been recognized as a pivotal mechanism impairing metabolic homeostasis (45), which disrupts the expression of specific genes, including CD36, APN, and GDF3 (28). Notably, miR-432 may also participate in this regulatory network. Importantly, the elevated serum levels of miR-432 in individuals with T2DM compared with those with obesity suggest that additional regulatory factors, such as inflammatory cytokines and metabolic hormones, may contribute to miR-432 expression. More direct in vivo tracing strategies, such as cre-loxP–based reporter systems, would be essential to unequivocally demonstrate the transfer of adipocyte-derived miR-432–enriched exosomes, and such approaches should be prioritized in future studies. Delivery of miR-432 antagomirs into engineered exosomes or biodegradable nanomaterials presents a highly promising therapeutic strategy for obesity-related metabolic disorders.

Overall, this study reveals that the CDK5/PPAR-γ/miR-432 axis in adipocytes propagates obesity-induced metabolic dysfunction. Adipocyte-derived exosomal miR-432 impairs glucose homeostasis through the PIK3R3/AKT pathway and disrupts lipid homeostasis by inhibiting the PIK3R3/PPAR-α axis. Collectively, miR-432 is a driver of systemic metabolic dysregulation.

This article contains supplementary material online at https://doi.org/10.2337/figshare.30272776.

Article Information

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. C.W. contributed to the data curation and formal analysis and drafted the manuscript. C.W., Y.H., M.Z., J.W., X.C., M.L., and C.S. contributed to the methodology. J.X. and J.Z. contributed to the project administration. J.X., J.Z., and C.-Y.W. contributed to the conceptualization, acquired funding, and reviewed and edited the manuscript. C.-Y.W. provided supervision. J.Z. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding Statement

This research received funding from National Natural Science Foundation of China grants 82260162, 82160156, and 81960152; Tianshan Talents Training Program of the Autonomous Region grants 2023TSYCQNTJ0032 and 2023TSYCCX0116; and Scientific and Technological Research Project of Xinjiang Production and Construction Corps grants 2022ZD001, 2022AB022, 2021AB028, 2023ZD037, and 2023AB057.

Contributor Information

Jianxin Xie, Email: xiejianxin9017@sina.com.

Jun Zhang, Email: zhangjunyc@163.com.

Cong-Yi Wang, Email: wangcy@tjh.tjmu.edu.cn.

Supporting information

Supplementary Material
db250295_supp.pdf (4.7MB, pdf)

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Supplementary Materials

Supplementary Material
db250295_supp.pdf (4.7MB, pdf)

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