The kallikrein–kinin pathway as a mechanism for auto-control of brown adipose tissue activity

Abstract

Brown adipose tissue (BAT) is known to secrete regulatory factors in response to thermogenic stimuli. Components of the BAT secretome may exert local effects that contribute to BAT recruitment and activation. Here, we found that a thermogenic stimulus leads to enhanced secretion of kininogen (Kng) by BAT, owing to induction of kininogen 2 (Kng2) gene expression. Noradrenergic, cAMP-mediated signals induce KNG2 expression and release in brown adipocytes. Conversely, the expression of kinin receptors, that are activated by the Kng products bradykinin and [Des-Arg9]-bradykinin, are repressed by thermogenic activation of BAT in vivo and of brown adipocytes in vitro. Loss-of-function models for Kng (the circulating-Kng-deficient BN/Ka rat) and bradykinin (pharmacological inhibition of kinin receptors, kinin receptor-null mice) signaling were coincident in showing abnormal overactivation of BAT. Studies in vitro indicated that Kng and bradykinin exert repressive effects on brown adipocyte thermogenic activity by interfering the PKA/p38 MAPK pathway of control of Ucp1 gene transcription, whereas impaired kinin receptor expression enhances it. Our findings identify the kallikrein–kinin system as a relevant component of BAT thermogenic regulation that provides auto-regulatory inhibitory signaling to BAT.

A Differential Pattern of Batokine Expression in Perivascular Adipose Tissue Depots From Mice

“…We found that 1 week of cold significantly reduced Vegfa mRNA in BAT, which is consistent with the previous data reporting that short-term, but not long-term, cold exposures induce Vegfa gene expression in BAT (Asano et al, 1997). Enhanced expression levels of Bmp8b, Fgf21, and Kng2 were found in iWAT in association with cold-induced browning, also as previously reported (Fisher et al, 2012;Peyrou et al, 2020). The pattern of cold-induced expression changes in batokine-encoding genes were distinct according to the type of PVAT: Bmp8b, Fgf21, and Kng2 were strongly induced in response to cold both in tPVAT and aPVAT, whereas Gdf15 was only induced in tPVAT (as also seen in BAT).…”

LRG1 is an adipokine that promotes insulin sensitivity and suppresses inflammation

“…BAT, the only adipose tissue pro led in the dataset, formed a cluster of 14 genes (7.9%). As expected, classical adipokines known for highly adipose-speci c expression such as adiponectin (Adipoq) and adipsin (Cfd) belonged to this group, along with a recently described batokine, Kng2 (Peyrou et al, 2020).…”

Maternal obesity programs white and brown adipose tissue transcriptome and lipidome in offspring in a sex-dependent manner

“…In line with this statement, MO has been shown to modulate two major genes involved in adipogenesis (Sfrp4) (Zhang et al, 2020) and in TG synthesis (Dgat2) (Chitraju et al, 2019) in a sex-dependent manner in VAT. Female offspring born from obese mothers promoted Fabp4 expression in SAT, which function as a positive factor in fatty acid signaling (Hertzel and Bernlohr, 1998), and induced BAT activity by repressing Kng2 (blunt thermogenesis) expression (Peyrou et al, 2020) and inducing Elovl3…”

“…In line with this statement, MO has been shown to modulate two major genes involved in adipogenesis ( Sfrp4 ) (Zhang et al, 2020) and in TG synthesis ( Dgat2 ) (Chitraju et al, 2019) in a sex-dependent manner in VAT. Female offspring born from obese mothers promoted Fabp4 expression in SAT, which function as a positive factor in fatty acid signaling (Hertzel and Bernlohr, 1998), and induced BAT activity by repressing Kng2 (blunt thermogenesis) expression (Peyrou et al, 2020) and inducing Elovl3 and Mgll (FA elongation and degradation) expression levels as opposed to males. On the other hand, female but not male offspring born from obese mothers showed reduced Homa index as compared to those born from lean mothers, associated to reduced level of C16:1 FA, a circulating lipokine that modulate insulin sensitivity in the liver (Cao et al, 2008).…”

“…RNA concentration was measured by nanodrop and diluted to 2.17 ng/μl. RNA quality was assessed for 12 out of 39 samples randomly by a 2100 Bioanalyzer using a nano chip (Agilent Biotechnologies), and RIN numbers were between 8.7-9.9. cDNA libraries were prepared for the bulk-RNA sequencing in 384-well plate with triplicates for each RNA sample according to the previously described Smart-Seq2 protocol (Picelli et al, 2014). In brief, mRNA was transcribed into cDNA using oligo(dT) primer and SuperScript II reverse transcriptase (ThermoFisher Scientific).…”