A Key Role for Interferon Regulatory Factors in Mediating Early-Life Metabolic Defects in Male Offspring of Maternal Protein Restricted Rats

Abstract

An adverse intra-uterine environment, induced by maternal consumption of diets high in saturated fat or low in protein have been implicated as a potential trigger for development of metabolic disease in later life. However, the underlying mechanisms responsible for this programming of obesity have yet to be described. Recent studies have demonstrated that interferon regulatory factors 3 (IRF3) and 4 (IRF4) function to repress adipogenesis. We investigated whether impaired IRF3 and IRF4 function may predispose to development of metabolic disease in a model of programmed obesity. Changes in IRF3 and IRF4 levels, adipogenic gene expression, and adiponectin signalling were measured in white adipose tissue from programmed male offspring of rat dams fed a low-protein diet (MLP), which are predisposed to obesity. 3T3L1 adipocytes were used to determine novel regulatory mechanisms governing IRF expression. IRF3 and IRF4 levels were suppressed in MLP rats, together with raised lipogenic and adipogenic gene expression. Adiponectin and adiponectin receptor 1 and 2 mRNA levels were reduced in MLP rats, along with levels of PPARα and activity of AMP-activated protein kinase (AMPK), 2 downstream targets of adiponectin. Further studies determined that both IRF3 and IRF4 are induced by adiponectin, with adiponectin-AMPK and adiponectin-PPARα signalling regulating IRF3 and IRF4, respectively. We have demonstrated that impaired ability to repress adipogenesis and lipogenesis, through dysregulated adiponectin-PPARα-AMPK-IRF signalling, may play a causal role in predisposing MLP offspring to development of obesity and metabolic disease in later life.

Key words

interferon regulatory factor - maternal low protein - adiponectin

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