biostudies-literatureWang CScientific and Technological Research Project of Xinjiang Production and Construction CorpsTraining Program of the Autonomous RegionNational Natural Science Foundation of China22-36https://www.ebi.ac.uk/biostudies/studies/S-EPMC12716619biostudies-literatureUnknown75(1)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.<h4>Article highlights</h4>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.DiabetesmiR-432 Exacerbates Obesity-Induced Dysregulation of Glucose and Lipid Homeostasis.PMC1271661982260162819601522022AB0222023ZD0372023AB0572021AB028821601562023TSYCCX01162022ZD0012023TSYCQNTJ0032Wang CYZhang JWang CSun CXie JChu XZhang MLiang MHou YWang JfalsemiR-432 Exacerbates Obesity-Induced Dysregulation of Glucose and Lipid Homeostasis.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.<h4>Article highlights</h4>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.2026-01-01T00:00:00Z2026 Jan2026-06-08T05:29:53.499Z2026-06-08T03:08:27.15ZS-EPMC127166194121891010.2337/db25-0295