Summary
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 leads to preservation of 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 a central and peripheral role for 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 liver 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 increase SOCE, elevate Ca2+ oscillation in response to vasopressin, and increase the mitochondria’s spare respiratory capacity.
Loss of SARAF leads to decreased hippocampal proliferation, sensitized HPA-axis and to changes in anxiety-related behavior.
Competing Interest Statement
The authors have declared no competing interest.