The molecular mechanism regulating the cardiomyocyte response to energy stress has been a hot topic in cardiac research in recent years, since this mechanism could be targeted for treatment of patients with
ischemic heart disease. We have shown recently that the activity of RAS homolog enriched in brain (RHEB), a small
GTP binding protein, is inhibited in response to
glucose deprivation (GD) in cardiomyocytes and
ischemia in the mouse heart. This is a physiological adaptation, since it inhibits complex 1 of the mechanistic target of
rapamycin (
MTORC1) and activates autophagy, thereby promoting cell survival during GD and prolonged
ischemia. Importantly, the physiological inhibition of RHEB-MTORC1 signaling during
myocardial ischemia is impaired in the presence of
obesity and
metabolic syndrome caused by high-fat diet (HFD) feeding, leading to a dramatic increase in ischemic injury. Although
MTORC1 and autophagy can be regulated through RHEB-independent mechanisms, such as the AMPK-dependent phosphorylation of RPTOR and ULK1, RHEB appears to be critical in the regulation of
MTORC1 and autophagy during
ischemia in cardiomyocytes, and its dysregulation is relevant to human disease. Here we discuss the biological relevance of the dysregulation of RHEB-MTORC1 signaling and the suppression of autophagy in
obesity and
metabolic syndrome.