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

Summary Store-operated Ca2+ entry (SOCE) is a vital process aimed at refilling cellular internal Ca 2+ 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 Ca 2+ 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 Ca 2+ 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. Highlights Loss/absence of SARAF facilitates age-dependent obesity with decreased metabolic rate, lean mass, and locomotion, without affecting food consumption. Loss of SARAF leads to lipid droplet hypertrophy, BAT whitening and age-dependent hepatic steatosis. Mice lacking SARAF expression in the PVN have an increased metabolic rate, decreased BAT whitening, and are protected from sarcopenic obesity. SARAF ablation in hepatocytes increases SOCE, elevates Ca 2+ oscillation in response to vasopressin, and increases the mitochondria’s spare respiratory capacity. Loss of SARAF leads to decreased hippocampal proliferation, sensitized HPA-axis and changes in anxiety-related behavior.