Ablation of FAM210A in brown adipocytes of mice exacerbates high fat diet induced metabolic dysfunction.

Thermogenesis of brown adipose tissues (BAT) provides metabolic benefits against pathological conditions such as Type 2 diabetes, obesity, cardiovascular diseases, 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 have 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 high-fat diet (HFD). We discovered that HFD suppressed FAM210A expression, associated with excessive OPA1 cleavage in BAT. Ucp1-Cre-driven BAT-specific Fam210a knockout (Fam210aUKO) similarly elevates OPA1 cleavage, accompanied by whitening of BAT. When subjected to HFD, the 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 an overall increased lipid content in both liver and BAT. Additionally, Fam210aUKO leads to inflammation in white adipose tissues. These data demonstrate that FAM210A in BAT is necessary for counteracting HFD-induced metabolic dysfunction but not obesity.