Within the adipokine–myokine network, irisin complements adiponectin, apelin, and omentin in maintaining endothelial NO bioavailability and mitochondrial efficiency; when this signaling is blunted—as in sarcopenic obesity and HFpEF—the result is compounded endothelial dysfunction, energetic inefficiency, and exercise intolerance, hallmarks of adipokine-axis decompensation [77,79,80]. The gene discussed is ITLN1; the disease is obesity due to melanocortin 4 receptor deficiency.