Store-operated Ca2+ entry regulatory factor (SARAF) alters murine metabolic state in an age-dependent manner via hypothalamic pathways.

Store-operated Ca2+ entry (SOCE) is a vital process aimed at refilling cellular internal Ca2+ stores, and a primary cellular-signaling driver of transcription factors entry to the nucleus. SARAF (SOCE associated regulatory factor)/TMEM66 is an endoplasmic reticulum (ER) resident transmembrane protein that promotes SOCE inactivation and prevents Ca2+ overfilling of the cell. Here we demonstrate that mice deficient in SARAF develop age-dependent sarcopenic obesity with decreased energy expenditure, lean mass and locomotion without affecting food consumption. Moreover, SARAF ablation reduces hippocampal proliferation, modulates the activity of the hypothalamus-pituitary-adrenal (HPA) axis, and mediates changes in anxiety-related behaviors. Interestingly, selective SARAF ablation in the paraventricular nucleus (PVN) of the hypothalamus protects from old age-induced obesity and preserves locomotion, lean mass and energy expenditure, suggesting an opposing, site-specific role for SARAF. Lastly, SARAF ablation in hepatocytes leads to elevated SOCE, elevated vasopressin-induced Ca2+ oscillations, and an increased mitochondrial spare respiratory capacity, thus providing insights into the cellular mechanisms that may affect the global phenotypes. These effects may be mediated via the liver X receptor (LXR) and IL-1 signaling metabolic regulators explicitly altered in SARAF ablated cells. In short, our work supports both central and peripheral roles of SARAF in regulating metabolic, behavioral, and cellular responses. HighlightsO_LILoss/absence of SARAF facilitates age-dependent obesity with decreased metabolic rate, lean mass, and locomotion, without affecting food consumption. C_LIO_LILoss of SARAF leads to lipid droplet hypertrophy, BAT whitening and age-dependent hepatic steatosis. C_LIO_LIMice lacking SARAF expression in the PVN have an increased metabolic rate, decreased BAT whitening, and are protected from sarcopenic obesity. C_LIO_LISARAF ablation in hepatocytes increases SOCE, elevates Ca2+ oscillation in response to vasopressin, and increases the mitochondrias spare respiratory capacity. C_LIO_LILoss of SARAF leads to decreased hippocampal proliferation, sensitized HPA-axis and changes in anxiety-related behavior. C_LI