Fig. 8

A mechanistic model for the regulation of heart energy allocation by energy stress hormone FGF21. The heart is an unrelenting bioengine that relies on a robust and uninterrupted influx of energy substates. Under physiologically relevant stressors, cardiomyocyte-derived or endocrine FGF21 acts to maintain heart rate, contractility, and hemodynamic stability by activating a dual energy flux system. Systemically, FGF21 directly promotes lipolysis in white adipose depots, releasing free fatty acids (FFAs) for liver uptake or direct transcardiac uptake via intracardiac microvascular circulation. It also promotes hepatic fatty acid oxidation and subsequent ketogenesis, supplying ketones for intracardiac ketolysis during prolonged fasting or starvation. These interorgan substrate mobilization effects ensure intracardiac energy substrate sufficiency. Locally, FGF21 signaling promotes transcardiac and intracardiac flux of various substrates for oxidative utilization, as well as cardiac mitochondrial biogenesis and respiration (the TCA cycle, ETC and OXPHOS), ensuring intracardiac ATP sufficiency. These processes/effects are mediated by the LKB1–AMPK and mTOR pathways and occur secondary to FGF21’s systemic actions. By coordinating these dual fuel systems, FGF21 signaling prioritizes incessant, robust intracardiac ATP flux, and thereby, cardiac energetic efficiency, particularly under stress. Thus, FGF21 is the first-known signaling factor for prioritizing cardiac energy needs and functional efficiency via a novel two-strata flux system. The image is generated in PowerPoint