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Pharmacological activation of brown adipose tissue (BAT) is an attractive approach for increasing energy expenditure to counteract obesity. Given the side-effects of known activators of BAT, we studied inhibitors of BAT as a novel, alternative concept to regulate energy expenditure. We focused on G-protein-coupled receptors that are one of the major targets of clinically used drugs. Here, we identify GPR183, also known as EBI2, as the most highly expressed inhibitory G-protein-coupled receptor in BAT among the receptors examined. Activation of EBI2 using its endogenous ligand 7α,25-dihydroxycholesterol significantly decreases BAT-mediated energy expenditure in mice. In contrast, mice deficient for EBI2 show increased energy dissipation in response to cold. Interestingly, only thermogenic adipose tissue depots — BAT and subcutaneous white adipose tissue —respond to 7α,25-dihydroxycholesterol treatment/EBI2 activation but not gonadal white fat, which has the lowest thermogenic capacity. EBI2 activation in brown adipocytes significantly reduces norepinephrine-induced cAMP production, whereas pharmacological inhibition or genetic ablation of EBI2 results in an increased response. Importantly, EBI2 significantly inhibits norepinephrine-induced activation of human brown adipocytes. Our data identify the 7α,25-dihydroxycholesterol/EBI2 signaling pathway as a so far unknown BAT inhibitor. Understanding the inhibitory regulation of BAT might lead to novel pharmacological approaches to increase the activity of thermogenic adipose tissue and whole body energy expenditure in humans. Francesca Copperi et al. evaluate the role of the Gi-protein coupled receptor, EBI2, on regulation of thermogenic activity in murine and human adipocytes. They report that loss of Ebi2 in mice increases brown adipocyte energy expenditure in response to cold exposure, providing insight into ways to potentially modulate energy expenditure in humans. [ABSTRACT FROM AUTHOR]

B cells play a central role in immune system function. Deregulation of normal B cell maturation can lead to the development of autoimmune syndromes as well as B cell malignancies. Elucidation of the molecular features of normal B cell development is important for the development of new target therapies for autoimmune diseases and B cell malignancies. Employing B cell-specific conditional knockout mice, we have demonstrated here that the transcription factor leukemia/lymphoma-related factor (LRF) forms an obligate dimer in B cells and regulates mature B cell lineage fate and humoral immune responses via distinctive mechanisms. Moreover, LRF inactivation in transformed B cells attenuated their growth rate. These studies identify what we believe to be a new key factor for mature B cell development and provide a rationale for targeting LRF dimers for the treatment of autoimmune diseases and B cell malignancies. [ABSTRACT FROM AUTHOR]