Perirenal fat β₃-adrenergic signaling alleviates renal fibrosis via regulating Bcat2/BCAA-TNFα pathway in diabetic kidney disease

Tubulointerstitial fibrosis predicts irreversible kidney function loss in diabetic kidney disease (DKD), but adipose-derived signals that shape fibrogenesis are poorly defined. Here, we show that perirenal fat (PRF), an adipose depot contiguous with the kidney, is enriched for β3-adrenergic receptor (ADRB3) and that ADRB3 expression is reduced in human DKD and male mouse DKD models. In db/db and streptozotocin/high-fat diet mice, increased PRF mass associates with albuminuria and serum creatinine, whereas PRF removal attenuates tubular lipid accumulation, mitochondrial injury and fibrosis. Brown adipocyte-lineage ADRB3 deletion enlarges PRF and increases adipocyte TNFα release by suppressing Bcat2-dependent branched-chain amino-acid catabolism through CREB1/METTL3-mediated m6A regulation. ADRB3 activation or PRF-restricted ADRB3 restoration reduces PRF inflammation and renal fibrosis, while iBAT-restricted restoration does not reproduce this renal protection. These findings identify a PRF ADRB3-Bcat2/BCAA-TNFα pathway that contributes to diabetic renal fibrosis. The authors identify perirenal fat ADRB3 signaling as a regulator of diabetic kidney fibrosis through a Bcat2/BCAA-TNFα pathway, suggesting adipose-kidney crosstalk as a potential therapeutic target.