| First Author | Gataulin D | Year | 2023 |
| Journal | PNAS Nexus | Volume | 2 |
| Issue | 3 | Pages | pgad068 |
| PubMed ID | 37007714 | Mgi Jnum | J:337869 |
| Mgi Id | MGI:7506703 | Doi | 10.1093/pnasnexus/pgad068 |
| Citation | Gataulin D, et al. (2023) Store-operated Ca(2+) entry regulatory factor alters murine metabolic state in an age-dependent manner via hypothalamic pathways. PNAS Nexus 2(3):pgad068 |
| abstractText | Store-operated calcium entry (SOCE) is a vital process aimed at refilling cellular internal Ca(2+) stores and a primary cellular signaling driver for transcription factors' entry to the nucleus. SOCE-associated regulatory factor (SARAF)/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 hypothalamus's paraventricular nucleus (PVN) neurons reduces old age-induced obesity and preserves locomotor activity, lean mass, and energy expenditure, suggesting a possible central control with a site-specific role for SARAF. At the cellular level, SARAF ablation in hepatocytes leads to elevated SOCE, elevated vasopressin-induced Ca(2+) oscillations, and an increased mitochondrial spare respiratory capacity (SPC), 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. |
