The aim of this study was to evaluate the inhibitory potential of aqueous extracts from coffee silverskin (CSE) and husk (CHE) and their main phenolics on adipogenesis, obesity-related inflammation, mitochondrial dysfunction, and insulin resistance, in vitro. Coffee by-products extracts (31-500 mu g mL(-1)) and pure phenolics (100 mu mol L-1 ) reduced lipid accumulation and increased mitochondrial activity in 3T3-L1 adipocytes. Also reduced the expression of inducible nitric oxide synthase and cyclooxygenase-2 and diminished secretion of proinflammatory factors in LPS-stimulated RAW2643.7 macrophages. Cytokine release diminished (tumor necrosis factor alpha: 23-57%; monocyte chemoattractant protein 1: 42-60%; interleukin-6: 30-39%) and adiponectin increased (7-13- fold) in adipocytes treated with macrophage-conditioned media. ROS scavenging and activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha pathway counteracted mitochondrial dysfunction. Increases in insulin receptor (1.4 to 4-fold), phosphoinositide 3-kinase (2 to 3-fold) and protein kinase B (1.3 to 3-fold) phosphorylation, in conjunction with a decrease in serine phosphorylation of insulin receptor substrate 1, evoked glucose transporter 4 translocation (8-15-fold) and glucose uptake (44-85%). CSE and CHE phenolics inhibited adipogenesis and elicited adipocytes browning. Suppressing macrophages-adipocytes interaction alleviated inflammation-triggered mitochondrial dysfunction and insulin resistance. CSE and CHE are beneficial in reducing adipogenesis and inflammation-related disorders.