Based on the above observations, we hypothesized that global knockout of FTO would lead to an increased sympathetic excitation of the heart. To test this hypothesis, sympathetic and parasympathetic influences on the heart were assessed during resting and stress conditions via time- and frequency-domain analysis of heart rate variability. We also evaluated whether supposed cardiac sympathetic hyperactivity in FTO knockout mice was associated with increased arrhythmia vulnerability, and investigated potential mediating mechanisms at the electrical and structural level of the heart. A previous study in a mouse model bearing a missense mutation in the FTO gene provided preliminary evidence linking FTO deficiency to increased sympathetic nervous system activity. However, to the best of our knowledge, this study is the first description of the effects of global knockout of FTO on cardiac function and its autonomic neural regulation. In resting conditions, FTO deficient mice were characterized by higher heart rate values than wild-type mice, both during the active and inactive phase of the daily cycle. Likewise, we found signs of elevated body temperature in mice lacking the FTO gene. Clearly, differences in heart rate and body temperature may have been determined by different levels of somatomotor activity, which indeed resulted significantly higher in knockout mice during the active phase of the daily cycle. However, given that heart rate was consistently higher in FTO deficient mice even when somatomotor activity levels were not greater, we believe that autonomic mechanisms concurred to determine higher heart rate in these animals. Supporting this view, HRV analysis revealed that knockout mice were characterized by a lower vagal modulation of heart rate than wild-type counterparts. In addition, the fact that FTO deficient mice showed higher LF to HF ratio is suggestive of a larger contribution of the sympathetic modulation of heart rate in mice lacking the FTO gene. Signs that link FTO deficiency to increased cardiac sympathetic drive were evident during stress conditions. Following the injection of saline and during the restraint test, stress-induced tachycardia was greater in knockout mice, despite similar low levels of vagal modulation between the two groups. This is a clear indication of a larger sympathetic modulation of heart rate in FTO deficient mice, which consequently resulted in a shift of the sympatho-vagal balance towards an exaggerated sympathetic prevalence. Given that high expression of FTO is seen in the paraventricular and dorsomedial nuclei of the hypothalamus, which represent important brain centers for the regulation of autonomic function, especially during stress response, we hypothesize a role of FTO in these brain areas in modulating sympathetic outflow to the heart. Previous studies have demonstrated that b-adrenergic agonists increase the inward sodium current in cardiomyocytes.