IRF1 in Adipocytes Is Associated with Insulin Signaling and Mitochondrial Homeostasis in Diet-Induced Obesity

Abstract

Obesity-associated metabolic disorders are characterized by impaired glucose and lipid metabolism, insulin resistance, and adipose tissue dysfunction. Interferon regulatory factor 1 (IRF1) is a transcription factor primarily involved in immune regulation; however, its role in adipocyte metabolic regulation remains incompletely understood. In this study, adipocyte-specific Irf1 knockout (Irf1 AKO) mice were generated using the Cre/loxP system and subjected to either a regular chow diet or a high-fat diet (HFD). Metabolic phenotyping, insulin signaling analysis, mitochondrial homeostasis-related assessment, and in vitro adipocyte experiments were performed. Adipocyte-specific IRF1 deficiency improved insulin-stimulated AKT phosphorylation in white adipose tissues and enhanced glucose tolerance and insulin sensitivity under HFD conditions. These metabolic improvements were accompanied by reduced oxygen consumption, energy expenditure, heat production, β3-adrenergic-induced lipolytic response, and cold tolerance. At the molecular level, IRF1 deficiency was associated with reduced TOMM20 expression, decreased mtDNA content, downregulation of oxidative phosphorylation-related genes, and reduced ATP levels in adipose tissues, suggesting altered mitochondrial homeostasis. In 3T3-L1 adipocytes, IRF1 knockdown increased insulin-stimulated AKT activation, glucose uptake, and lipid accumulation, whereas IRF1 overexpression showed opposite trends. Collectively, these findings suggest that adipocyte IRF1 is associated with insulin signaling, lipid metabolic remodeling, and mitochondrial homeostasis, and highlight a potential dissociation between improved insulin responsiveness and reduced energy expenditure in diet-induced obesity.