Qiu Jiamin, Khedr Mennatallah A, Pan Meijin, Ferreira Christina R, Chen Jingjuan, Snyder Madigan M, Ajuwon Kolapo M, Yue Feng, Kuang Shihuan
Department of Animal Sciences, Purdue University, West Lafayette, IN.
Department of Orthopaedic Surgery, School of Medicine, Duke University, Durham, NC.
Diabetes. 2025 Mar 1;74(3):282-294. doi: 10.2337/db24-0294.
Thermogenesis of brown adipose tissue (BAT) provides metabolic benefits against pathologic conditions, such as type 2 diabetes, obesity, cardiovascular disease, and cancer. The thermogenic function of BAT relies on mitochondria, but whether mitochondrial remodeling is required for the beneficial effects of BAT remains unclear. We recently identified FAM210A as a BAT-enriched mitochondrial protein essential for cold-induced thermogenesis through the modulation of OPA1-dependent cristae remodeling. Here, we report a key role of FAM210A in the systemic response to a high-fat diet (HFD). We discovered that an HFD suppressed FAM210A expression, associated with excessive OPA1 cleavage in BAT. Ucp1-Cre-driven BAT-specific Fam210a knockout (Fam210aUKO) similarly elevated OPA1 cleavage, accompanied by whitening of BAT. When subjected to an HFD, Fam210aUKO mice gained similar fat mass as sibling control mice but developed glucose intolerance, insulin resistance, and liver steatosis. The metabolic dysfunction was associated with overall increased lipid content in both the liver and BAT. Additionally, Fam210aUKO leads to inflammation in white adipose tissue. These data demonstrate that FAM210A in BAT is necessary for counteracting HFD-induced metabolic dysfunction but not obesity.
FAM210A regulates cold-induced mitochondrial remodeling through control of OPA1 cleavage, but whether it also plays a role in high-fat diet (HFD)-induced cristae remodeling is unknown. We asked if an HFD would alter the FAM210A level and OPA1 cleavage in brown adipose tissue (BAT) and how FAM210A loss of function would affect diet-induced obesity in mice. We found that an HFD diminished FAM210A expression and accelerated OPA1 cleavage in BAT, and Fam210a knockout exacerbated HFD-induced whitening of BAT, cold intolerance, liver steatosis, white adipose tissue inflammation, and metabolic dysfunction. Our work reveals a physiologic role of FAM210A-mediated BAT mitochondrial remodeling in systemic adaptation to an HFD and suggests that BAT mitochondria may be targeted to treat diet-induced metabolic dysfunction.
棕色脂肪组织（BAT）的产热作用对诸如2型糖尿病、肥胖症、心血管疾病和癌症等病理状况具有代谢益处。BAT的产热功能依赖于线粒体，但线粒体重塑对于BAT的有益作用是否必要仍不清楚。我们最近鉴定出FAM210A是一种富含于BAT的线粒体蛋白，通过调节OPA1依赖性嵴重塑对冷诱导的产热至关重要。在此，我们报告了FAM210A在对高脂饮食（HFD）的全身反应中的关键作用。我们发现高脂饮食抑制了FAM210A的表达，这与BAT中OPA1的过度切割有关。Ucp1-Cre驱动的BAT特异性Fam210a基因敲除（Fam210aUKO）同样提高了OPA1的切割水平，并伴有BAT的白化。在高脂饮食条件下，Fam210aUKO小鼠获得的脂肪量与同窝对照小鼠相似，但出现了葡萄糖不耐受、胰岛素抵抗和肝脂肪变性。代谢功能障碍与肝脏和BAT中脂质含量总体增加有关。此外，Fam210aUKO导致白色脂肪组织炎症。这些数据表明，BAT中的FAM210A对于对抗高脂饮食诱导的代谢功能障碍是必要的，但对肥胖并非如此。
FAM210A通过控制OPA1切割来调节冷诱导的线粒体重塑，但它是否也在高脂饮食（HFD）诱导的嵴重塑中起作用尚不清楚。我们研究了高脂饮食是否会改变棕色脂肪组织（BAT）中的FAM210A水平和OPA1切割，以及FAM210A功能丧失如何影响小鼠饮食诱导的肥胖。我们发现高脂饮食会降低BAT中FAM210A的表达并加速OPA1的切割，而Fam210a基因敲除会加剧高脂饮食诱导的BAT白化、耐寒性降低、肝脂肪变性、白色脂肪组织炎症和代谢功能障碍。我们的工作揭示了FAM210A介导的BAT线粒体重塑在全身适应高脂饮食中的生理作用，并表明BAT线粒体可能是治疗饮食诱导的代谢功能障碍的靶点。
