The Role of Adipocyte XBP1 in Metabolic Regulation during Lactation

Abstract

Summary The adipocyte is central to organismal metabolism and exhibits significant functional and morphological plasticity during its formation and lifespan. Remarkable transformations of this organ occur during obesity and lactation, two metabolic processes where a better understanding of adipocyte function is essential. Considering the critical importance of the cellular organelle endoplasmic reticulum (ER) in adapting to fluctuations in synthetic processes, we explored the role of XBP1, a central regulator of ER adaptive responses, in adipocyte formation and function. Unexpectedly, deletion of adipocyte-XBP1 in vivo in mice (XBP1ΔAd) had no effect on adipocyte formation or systemic homeostatic metabolism on regular or high fat diet. However, during lactation XBP1ΔAd dams displayed increased adiposity, decreased milk production, and decreased litter growth compared to control dams. Moreover, we demonstrate that XBP1 is regulated during lactation, where it responds to prolactin to alter lipogenic gene expression. These results demonstrate a previously unrecognized role for adipocyte-XBP1 in regulation of lactational metabolism.

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…Importantly, XBP1 is not the only factor involved in ER stress. Nevertheless, it is a central regulator of ER adaptive responses (Gregor et al, 2013).…”

Mammary gland development: cell fate specification, stem cells and the microenvironment

“…The dense fat pad precursor, which is observable at E14, develops throughout embryogenesis, yet conversion to typical white fat tissue is not observed until two to three days after birth (Sakakura, 1987). During pregnancy and lactation, adipocytes with reduced lipid content are observed, suggesting that this reservoir of fat is necessary for the metabolically demanding process of milk production (Gregor et al, 2013;Hovey and Aimo, 2010). Adipocytes also serve an endocrine function in the gland: they are thought to regulate epithelial growth and mammary epithelium function, as well as to communicate with other cell types in the mammary gland (Bartley et al, 1981;Hovey and Aimo, 2010).…”

Epithelial Xbp1 Is Required for Cellular Proliferation and Differentiation during Mammary Gland Development

“…In the second study, adipocyte Xbp1 was proven to be essential for the activity of the lactating gland, and Xbp1 splicing in adipocytes was induced by the lactogenic hormone prolactin. However, these changes in Xbp1 splicing in adipocytes did not alter the milk composition, mammary lipogenic activity, or mammary function, as assessed by determination of the level of Stat5 phosphorylation or expression of prolactin or the ErbB4 receptor (10). Accordingly, the contribution of mammary epithelium Xbp1 to breast epithelial cell function and development is unknown.…”

“…It is produced as an RNA that is regulated by IRE1␣-mediated cytoplasmic splicing of Xbp1 mRNA, resulting in a frameshift that then creates an mRNA that encodes a transcriptionally active protein (spliced Xbp1 [sXbp1]). Spliced Xbp1 regulates the transcription of a number of ER quality control genes and is essential for the development, survival, and function of intestinal epithelial cells, immune cells, and hepatocytes (9) and of adipocytes (10) as well as for the development of professional secretory cells, such as B cells, hepatocytes, and pancreatic ␤ cells (11,12). Two recent studies have characterized the contribution of the UPR to lactation.…”