The role of the unfolded protein response in adipocyte formation and function

The adipocyte is a highly specialized cell that acts at the center of metabolic homeostasis due to its ability to orchestrate energy supply and demand via lipid storage, mobilization, and a wide repertoire of endocrine functions. The right balance of adiposity is therefore crucial to maintain the health of the organism. Formation of a mature and functionally intact adipocyte is a complex process involving the coordinated action of many synthetic networks, especially those of the endoplasmic reticulum (ER). We hypothesized that the unique challenges of adipocyte function and plasticity would require a robust adaptation of the ER, namely through its adaptive unfolded protein response (UPR). First, we demonstrated that UPR markers are regulated in human obesity and that severe weight loss in obese subjects decreases expression of UPR markers, indicating a relationship between adipocyte metabolic stress and the UPR in both animal models and humans. Second, utilizing mouse models of adipocyte-specific deletion of a main transcriptional mediator of the UPR, X-box binding protein 1 (XBP1), we investigated the consequences of the UPR on adipocyte function. Unexpectedly, even under the stress of obesity XBP1 deletion did not affect the formation of adipocytes, adipose tissue mass, adipokine secretion or systemic glucose and insulin sensitivity. However, under the physiological challenge of lactation, during which adipocytes undergo a dramatic transformation involving severe lipid depletion, deletion of XBP1 disrupted lactational metabolism. Compared to wild type controls, maternal adipose tissue stores were increased in lactating AdX-K0 mice accompanied by a decrease in litter weight Importantly, adipocyte-specificity of the phenotype was confirmed using tissue fractionation, laser capture microdissection, and alternative loxP-Cre models. Investigation of the mammary gland revealed disturbed development at day 1 of lactation and advanced involution at late lactation, accompanied by inflammatory cytokine expression. We propose that ER function is critical to the dramatic transformation of the adipocyte during lactation and compromise of ER function results in the failure of the adipocyte to fully contribute to lactation. Our findings attribute a novel and significant role to the adipocyte in the regulation of lactation, opening up future opportunities for many new insights into lactation and maternal-child health.