A two-strata energy flux system driven by a stress hormone prioritizes cardiac energetics.

The heart, an organ with a continuously high demand for energy, inherently lacks substantial reserves. The precise mechanisms that prioritize energy allocation to cardiac mitochondria, ensuring steady-state ATP production amidst high-energy organs, remain poorly understood. Our study sheds light on this process by identifying a two-strata flux system driven by the starvation hormone FGF21. We demonstrate that systemic disruptions in interorgan metabolite mobilization and transcardiac flux, arising from either adipose lipolysis or hepatic ketogenesis due to FGF21 deficiency, directly impair cardiac energetic performance. Locally, this impairment is linked to compromised intracardiac utilization of various metabolites via ketolysis and oxidation pathways, along with hindered mitochondrial biogenesis, TCA cycle, ETC flow, and OXPHOS. Consequently, the heart shifts to a hypometabolic, glycolytic, and hypoenergy state, with a reduced capacity to cope with physiological stressors such as fasting, starvation, strenuous exercise, endurance training, and cold exposure, leading to a diminished heart rate, contractility, and hemodynamic stability. Pharmacological or genetic restoration of FGF21 ameliorates these defects, reenergizing stress-exhausted hearts. This hierarchical energy-prioritizing mechanism is orchestrated by the LKB1-AMPK-mTOR energy stress response pathways. Disrupting cardiac LKB1 or mTOR pathways, akin to stalling mitochondrial energy conduits, obstructs the FGF21-governed cardiac energetic potential. Our findings reveal an essential two-strata energy flux system critical for cardiac energetic efficiency regulated by FGF21, which spatiotemporally optimizes interorgan and transcardiac metabolite flux and intracardiac mitochondrial energy sufficiency. This discovery informs the design of strategies for treating cardiac diseases linked to mitochondrial or energy deficiencies.