This study identifies Notch signaling as a novel regulator of fatty acid transport across the endothelium and as an essential repressor of angiogenesis in the adult heart. The data imply that the endothelium controls cardiomyocyte metabolism and function.

SummaryHuman susceptibility to obesity is mainly genetic, yet the underlying evolutionary drivers causing variation from person to person are not clear. One theory rationalizes that populations that have adapted to warmer climates have reduced their metabolic rates, thereby increasing their propensity to store energy. We uncover here the function of a gene that supports this theory. THADA is one of the genes most strongly selected during evolution as humans settled in different climates. We report here that THADA knockout flies are obese, hyperphagic, have reduced energy production, and are sensitive to the cold. THADA binds the sarco/ER Ca2+ ATPase (SERCA) and acts on it as an uncoupler. Reducing SERCA activity in THADA mutant flies rescues their obesity, pinpointing SERCA as a key effector of THADA function. In sum, this identifies THADA as a regulator of the balance between energy consumption and energy storage, which was selected during human evolution.

The transcriptional repressors Hey1 and Hey2 are primary target genes of Notch signaling in the cardiovascular system and induction of Hey gene expression is often interpreted as activation of Notch signaling. Here we report that treatment of primary human endothelial cells with serum or fresh growth medium led to a strong wave of Hey1 and Hey2 transcription lasting for approximately three hours. Transcription of other Notch target genes (Hes1, Hes5, ephrinB2, Dll4) was however not induced by serum in endothelial cells. Gamma secretase inhibition or expression of dominant-negative MAML1 did not prevent the induction of Hey genes indicating that canonical Notch signaling is dispensable. Pretreatment with soluble BMP receptor Alk1, but not Alk3, abolished Hey gene induction by serum. Consequently, the Alk1 ligand BMP9 stimulated Hey gene induction in endothelial cells. Several other cell types however did not show such a strong BMP signaling and consequently only a very mild induction of Hey genes. Taken together, the experiments revealed that bone morphogenic proteins within the serum of cell culture medium are potent inducers of endothelial Hey1 and Hey2 gene expression within the first few hours after medium change.