Abstract
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. ARTICLE HIGHLIGHTS: 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.