Batokines selectively expressed in brown and beige adipocytes remain to be identified and their potential signaling role in adipose thermogenesis are largely unknown. Here we identified a batokine we named as Breg acting as a key regulator for adipose thermogenesis and glucose homeostasis. Breg expression is adipose-specific and highly brown fat-enriched, and its secretion is stimulated by β3-adrenergic activation. Gain-of-functional studies collectively showed that secreted Breg promotes adipose thermogenesis, lowers glucose level, and protects against obesity. Adipose-specific Breg knockout mice are defective in white fat browning, and are susceptible to high fat diet-induced obesity and hyperglycemia, demonstrating the physiological importance of this batokine in energy metabolism. Mechanistically, Breg binds to a putative receptor on adipocyte surface and activates protein kinase A independently of β-adrenergic signaling. These results establish Breg as a major upstream signaling component in thermogenesis and offer a potential avenue for the treatment of obesity and diabetes.

Transcriptional co-activator Prdm16 controls brown fat development and white fat browning, but how this thermogenic function is modulated post-translationally is poorly understood. Here, we report that Cbx4, a Polycomb group protein, is a SUMO E3 ligase for Prdm16 and that Cbx4-mediated sumoylation of Prdm16 is required for thermogenic gene expression. Cbx4 expression is enriched in brown fat and is induced in adipose tissue by acute cold exposure. Sumoylation of Prdm16 at lysine 917 by Cbx4 blocks its ubiquitination-mediated degradation, thereby augmenting its stability and thermogenic function. Moreover, this sumoylation event primes Prdm16 to be further stabilized by methyltransferase Ehmt1. Heterozygous Cbx4-knockout mice develop metabolic phenotypes resembling those of Prdm16-knockout mice. Furthermore, fat-specific Cbx4 knockdown and overexpression produce remarkable, opposite effects on white fat remodeling. Our results identify a modifying enzyme for Prdm16, and they demonstrate a central role of Cbx4 in the control of Prdm16 stability and white fat browning.

Browning of subcutaneous white fat (iWAT) involves several reprograming events, but the underlying mechanisms are incompletely understood. Here we show that the transcription factor Hlx is selectively expressed in brown adipose tissue (BAT) and iWAT, and is translationally upregulated by beta3-adrenergic signaling-mediated suppression of the translational inhibitor 4E-BP1. Hlx interacts with and is co-activated by Prdm16 to control BAT-selective gene expression and mitochondrial biogenesis. Hlx heterozygous knockout mice have defects in brown-like adipocyte formation in iWAT, and develop glucose intolerance and high fat-induced hepatic steatosis. Conversely, transgenic expression of Hlx at a physiological level drives a full program of thermogenesis and converts iWAT to brown-like fat, which improves glucose homeostasis and prevents obesity and hepatic steatosis. The adipose remodeling phenotypes are recapitulated by fat-specific injection of Hlx knockdown and overexpression viruses, respectively. Our studies establish Hlx as a powerful regulator for systematic white adipose tissue browning and offer molecular insights into the underlying transcriptional mechanism.The transcriptional co-activator Prdm16 regulates browning of white adipose tissue (WAT). Here, the authors show that Prdm16 interacts with the transcription factor Hlx, which is stabilized in response to beta3-adrenergic signaling, to increase thermogenic gene expression and mitochondrial biogenesis in subcutaneous WAT.