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Background: Endurance training induces physiological cardiac hypertrophy and elevates adipose tissue lipolysis. Results: Adipose-specific adipose triglyceride lipase (Atgl)-knock-out mice exhibit attenuated exercise-induced cardiac hypertrophy likely mediated by the lack of C16:1n7 palmitoleate actions on the heart. Conclusion: Atgl-mediated adipose lipolysis regulates physiological cardiac hypertrophy. Significance: Adipose-derived lipokines may serve as important molecular mediators of cardiac physiology and pathology.