Inactivation of C/ebp Homologous Protein-driven ImmuneMetabolic Interactions Exacerbate Obesity and Adipose Tissue Leukocytosis

Background: C/ebp homologous protein contributes to ER stress-induced inflammatory cytokine secretion and apoptosis. Results: Loss of Chop increases obesity, insulin resistance, and adipose tissue leukocytosis and inflammation. Conclusion: ER stress signaling through Chop is necessary for adaptation to a high fat diet. Significance: Although in obesity ER stress may impair metabolic health, inactivation of Chop promotes obesity-associated inflammation. Successful adaptation to periods of chronic caloric excess is a highly coordinated event that is critical to the survival and propagation of species. Transcription factor C/ebp homologous protein (Chop) is thought to be an important molecular mediator that integrates nutrient signals to endoplasmic reticulum (ER) stress and innate immune activation. Given that aberrant ER stress response is implicated in inducing metabolic inflammation and insulin resistance, we hypothesized that ER stress target gene Chop integrates immune and metabolic systems to adapt to chronic positive energy balance. Here we report that inactivation of Chop in mice fed a high fat diet led to significant increase in obesity caused by a reduction in energy expenditure without any change in food intake. Importantly, ablation of Chop does not induce metabolically healthy obesity, because Chop-deficient mice fed a high fat diet had increased hepatic steatosis with significantly higher insulin resistance. Quantification of adipose tissue leukocytosis revealed that elimination of Chop during obesity led to substantial increase in number of adipose tissue T and B lymphocytes. In addition, deficiency of Chop led to increase in total number of myeloid subpopulations like neutrophils and F4/80(+) adipose tissue macrophages without any alterations in the frequency of M1- or M2-like adipose tissue macrophages. Further investigation of inflammatory mechanisms revealed that ablation of Chop increases the sensitivity of macrophages to inflammasome-induced activation of IL- in macrophages. Our findings indicate that regulated expression of Chop during obesity is critical for adaptation to chronic caloric excess and maintenance of energy homeostasis via integration of metabolic and immune systems.