Fig. 3

The inter-organ crosstalk in diabetic HFpEF. In diabetic HFpEF, gut microbiota dysbiosis and metabolites like IPA, TMAO, SCFAs engage in the gut - heart axis. NASH and HFpEF share lipid-accumulation, inflammation, fibrosis mechanisms. Abnormal liver metabolites (Saa1/4, lipid metabolites) and liver-secreted FXI and FGF21 link liver and heart via metabolic inflammation and fibrosis pathways. EAT, near the heart, directly drives HFpEF pathology through local inflammation, lipotoxicity, and mechanical compression. VAT are indirectly involved via systemic metabolic disorders and inflammation. The hematopoietic system contributes through immune cell activation (macrophages, T-cells) and inflammatory cytokines, perpetuating myocardial injury. AhR, aryl hydrocarbon receptor; BMP, bone morphogenetic protein; EAT, epicardial adipose tissue; FGF21, fibroblast growth factor 21; FFA, free fatty acid; FXI, factor XI; GDF15, growth differentiation factor 15; HFpEF, heart failure with preserved ejection fraction; IL, interleukin; IPA, indole-3-propionic acid; LCFAs, long-chain fatty acids; LPL, lipoprotein lipase; MPO, myeloperoxidase; NAD, nicotinamide adenine dinucleotide; NAM, nicotinamide; NASH, nonalcoholic steatohepatitis; NETs, neutrophil extracellular traps; NLRP3, NOD-like receptor family pyrin domain-containing 3; NNMT, nicotinamide N-methyltransferase; PI3K/AKT, phosphoinositide 3-kinase/protein kinase B; Saa1/4, serum amyloid A1/A4; SCFAs, short-chain fatty acids; SIRT3, sirtuin 3; SMAD1/5, SMAD family member 1/5; TGF-β, transforming growth factor-β; TMAO, trimethylamine N-oxide; TNF-α, tumor necrosis factor-α; TNFR1, tumor necrosis factor receptor 1; VAT, visceral adipose tissue