miR-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. 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.