Perirenal Fat beta3-Adrenergic Signaling Alleviates Renal Fibrosis via Regulating Bcat2/BCAA-TNFalpha Pathway in Diabetic Kidney Disease
Tubulointerstitial fibrosis is the classic histopathologic predictor of irreversible kidney function loss in diabetic kidney disease (DKD), yet upstream drivers of fibrogenesis remain incompletely defined. We have recently reported that perirenal fat (PRF), a brown/white adipose depot contiguous with the kidney, expands in diabetes and predicts DKD risk, therefore the preset study sought to investigate whether PRF signals modulate renal injury. We found that the beta3-adrenergic receptor (ADRB3) is highly expressed in PRF, but markedly downregulated in murine and human DKD. Across db/db and streptozotocin/high-fat diet (STZ/HFD) DKD mouse models, greater PRF mass correlated with worse albuminuria and serum creatinine. Interestingly, surgical PRF removal improved renal function, attenuated tubular lipid accumulation, restored mitochondrial indices, and reduced renal fibrosis. To probe mechanism, we generated brown fat-specific ADRB3 knockout mice (ADRB3BKO). ADRB3 loss enlarged PRF, which markedly increased adipocyte TNFalpha secretion through inhibiting Bcat2 mRNA stability and thereby suppressing Bcat2-dependent branched-chain amino acid (BCAA) catabolism via promoting METTL3-mediated m6A methylation. Conditioned media from ADRB3-deficient adipocytes triggered mitochondrial dysfunction, lipid loading, and profibrotic responses in primary tubular epithelial cells, whereas ADRB3 agonism (BRL 37344) or Bcat2 re-expression blunted these effects. ADRB3BKO exacerbated DKD tubular injury and interstitial fibrosis in vivo, while pharmacologic ADRB3 activation reduced PRF inflammation and mitigated renal pathology without altering glycemia. Importantly, systemic TNFalpha neutralization largely reversed the augmented fibrosis and functional decline in ADRB3BKO DKD mice and normalized tubular bioenergetics. These findings define a PRF-kidney axis in which diminished ADRB3 signaling converts perirenal brown fat into an inflammatory source of TNFalpha that accelerates diabetic renal fibrosis through Bcat2/BCAA pathway. Targeting ADRB3, restoring PRF metabolic health, or selectively intercepting TNFalpha may represent tractable strategies to complement current DKD therapies.