Introduction: Obesity is characterized by chronic inflammation with recruitment and activation of macrophages in white adipose tissues. High-fat diet (HFD) consumption induces macrophage-mediated chronic inflammation in liver and adipose tissue and impairs energy expenditure. Despite strong evidence for the involvement of inflammation in the pathogenesis of obesity and diabetes, the primary mediator(s) and the site(s) at which the inflammatory response occurs have not yet been established. The immediate early response gene 3 (IER3) is a stress-inducible gene that is highly expressed in macrophages and plays a key role in mitochondrial respiration. We hypothesized that IER3 is required for HFD feeding induced-inflammation leading to insulin resistance and obesity.
Methods and Results: We fed IER3-deficient mice (IER3-/-) and their wild-type (WT) littermates a HFD (60% kCal as fat) or normal chow (ND) for 20 weeks. While WT mice gained ~80% body weight on HFD, IER3-/- mice did only 40% on the same diet (25.3±1.3 to 37.7±2.5 g vs 26.0±0.5 to 50.1±1.5 g, respectively, P<0.01). HFD-fed IER3-/- mice exhibited less inflammation in adipose tissue and liver (assessed by measuring TNF-α, IL-6, and leptin mRNA levels using qRT-PCR), hepatic steatosis (evaluated using histology), and glucose intolerance (measured by intraperitoneal glucose and insulin tolerance tests) than those observed in WT counterpart. Interestingly, IER3-/- mice had greater food consumption and thermogenesis than WT mice. Flow cytometry analysis of adipose tissue macrophages (ATM) revealed that HFD feeding increased the percentage of proinflammatory M1 macrophages (10±1 to 37±1%, p<0.001) while decreasing the percentage of anti-inflammatory M2 cells (39±3 to 13±3%, p<0.001) in WT mice. In sharp contrast, the ratio of M1 to M2 cells in ATM did not differ in IER3-/- mice fed a HFD or ND. In accordance with a high percentage of M2 macrophages, IER3-/- mice exhibited browning of white adipose tissue in subcutaneous fat. This was concomitant with increased thermogenesis and energy expenditure in IER3-/- mice, resulting in the lean phenotype of these mice.
Conclusion: IER3 deficiency protects mice against HFD-induced obesity and inflammation by inducing browning of white adipose tissue and increasing energy expenditure.