Draft:Breg (ADISSP)

Breg, also named ADISSP, is a 19kd small polypeptide and an adipokine; it was discovered and named by Qingbo Chen, Yongxu Wang, and published with the name "Breg" on bioRxiv first, on August 16, 2022. And finally published online with the name ADISSP on December 10, 2022, in the journal Nature Communications. Under normal basal condition (without any external stimuli), it is largely secreted by the brown fat cell; and in turn activate thermogenic function in brown fat cell. In mouse, Breg can efficiently decrease blood glucose and combat obesity. It’s a thermogenic molecule that initiate thermogenesis programs in brown adipose tissue (BAT) and promote browning in inguinal white adipose tissue (iWAT). Human adults with low level Breg are obese.

In mouse, Breg is mainly expressed in the classic inter-scapular BAT, followed in the iWAT, and with lowest expression in the epididymal white adipose tissue (eWAT). Most importantly, under basal culture condition, without any external stimuli, Breg is automatically and largely secreted, at least, by the brown fat cell, and it activates thermogenic function; it means that both the secretion and function of Breg are in a cell-autonomous way. Breg is essential for both β3-Adrenergic receptor agonist, CL316,243 (CL), and acute cold to normally activate thermogenic programs. Breg systemically maintain energy homeostasis even under warm conditions. It is needed in cold, normal and warm temperature conditions.

The human homozygous of Breg is C20orf27; in 2020, it was reported that human Breg can promote cell growth and proliferation of colorectal cancer via the TGFβR-TAK1-NFĸB pathway. Breg amino acids sequence shares 90.2% identity between human and mice

Gene expression and secretion

Breg is mainly expressed in the classic inter-scapular BAT, followed in the iWAT, and with lowest expression in the epididymal white adipose tissue (eWAT) and these is some expression in the brain. In human, Breg largely expression in bone marrow, followed in the fat tissues, and with less expression level in spleen, lung, small intestine, colon, stomach, liver, heart, kidney.

Under basal level, Breg can be secreted by the brown fat cell in a cell autonomy manner. This imply that, under basal conditions, the brown fat maintain its thermogenic (intrinsic thermogenesis) function could through automatically and largely secretion of molecules, like Breg. Interesting, CL can strongly induce Breg secretion in vitro.

Physical function and mechanisms

For obesity

Breg can burn energy through activation the PKA pathway, increase cAMP level, and induce lipolysis and thermogenesis programs in brown fat. Physiologically, fat tissues specifically loss or over-expression of Breg can't result any body weight changes under both normal diet. However, over-expression Breg can remarkably combat obesity when mice fed on a high fat diet for a long time. High-fat diet fed for 20 weeks, Breg Transgenic mice reduced about 66.5% diet-induced obesity (DIO) and without any changes to food intake. Especially combine treatment with Breg+CL can increase UCP1 mRNA level 2 fold than CL treatment alone. Breg can be secreted into the circulation system, and largely induce thermogenesis, hence it can re-build the BAT thermogenic function at least partially.

For blood glucose

Breg robustly promotes glucose uptake, primary and specifically, in the iWAT through the AKT2 pathway. More importantly, all elevated Breg level mice models, including transgenic mice and circulation elevated Breg level by Adenovirus or AAV8 target delivery to liver tissue, or by tail vein deliver the purified Breg protein, show less lipid accumulation in BAT and liver, and the white fat tissues mass are remarkably decreased. This means that high Breg levels promote glucose uptake in the iWAT is not stored, or the lipolysis program is much strong than the De Novo Lipogenesis program. Comparing to combat obesity, the function of Breg to reduce blood glucose is priority, especially when Breg level is not high enough. It's very different with insulin. And it means that Breg decreases blood glucose in an insulin independent way.

Therapeutic function

Breg can exert its thermogenic function independent of both central nervous system and sympathetic nervous system, beyond of this, it can activate beneficial function independent of any external stimuli too. More, the secretion of Breg is largely induced by CL; and thermogenic function of Breg is independent of β-Adrenergic receptor signal pathways. It means that Breg is a downstream effector of CL, it can do what CL dose for thermogenesis, and meanwhile with low or no side effects of CL to non-fat tissues.

Side effects prediction

Breg can largely reduce blood glucose, so super high Breg level could result in hypoglycemia. Besides, as an effect of the β-Adrenergic receptor signal pathway, Breg could temporarily increase the fat acids level, especially at the early treatment stage