Scope This study aims to investigate the metabolic phenotype and mechanism of 40% calorie restriction (CR) in mice. Methods and results CR mice exhibit super‐stable blood glucose, as evidenced by increased fasting blood glucose (FBG), decreased postprandial blood glucose, and reduced glucose fluctuations. Additionally, both fasting plasma insulin and the homeostasis model assessment of insulin resistance increase significantly in CR mice. Compared with control, the phosphorylation of insulin receptor substrates‐1 and serine/threonine kinase decreases in liver and fat but increases in muscle of CR mice after insulin administration, indicating hepatic and adipose insulin resistance, and muscle insulin sensitization. CR reduces visceral fat much more than subcutaneous fat. The elevated FBG is negatively correlated with low‐level fasting β‐hydroxybutyrate, which may result from insufficient free fatty acids and diminishes ketogenic ability in CR mice. Furthermore, liver glycogen increases dramatically in CR mice. Analysis of glycogen metabolism related proteins indicates active glycogen synthesis and decomposition. Additionally, CR elevates plasma corticosterone and hypothalamic orexigenic gene expression. Conclusion CR induces lipid insufficiency and stress, resulting in global physiological insulin resistance except muscle and enhances glycogen metabolism, culminating in the stability of blood glucose manifests in increased FBG, which compensates for insufficient blood ketones.

Resting B cell dependence on the B cell antigen receptor (BCR) has been attributed solely to its signaling competence. We have recently shown that the presence of the BCR is vital for endoplasmic reticulum (ER) homeostasis and mitochondrial function both in primary B cells and Burkitt lymphoma (BL) cell lines. Unexpectedly, in BL Ramos cells this role has been shown to be independent of BCR signals from the cell membrane. Now, we provide evidence that also in mouse resting B cells ER-resident immunoglobulin (Ig) heavy chains control ER homeostasis, calcium storage and mitochondrial homeostasis through ER-mitochondria contacts. These findings demonstrate that BCR expression shapes cellular fitness already at the stage of assembly in the ER and uncover a new layer of B cell dependence on the production of Ig heavy chains in the ER. Sensing protein expression in the ER, with counterselection of compromised cells, might well operate also in other differentiated cells.