Transferrin receptor levels and its rare variant are associated with human obesity

Aim Iron homeostasis is critical for functional respiratory chain complex of mitochondrial, thus potentially contributing to fat biology and energy homeostasis. Transferrin receptor (Tfrc) binds to transferrin for extracellular iron uptake and is recently reported to be involved in brown fat development and functionality. However, whether TFRC levels and variants are associated with human obesity is unknown. Methods To investigate the association of TFRC levels and variants with human obesity, fat biopsies were obtained from surgery. Exon‐sequencing and genetic assessments were conducted of a case–control study. For TFRC levels assessment in fat biopsy, 9 overweight and 12 lean subjects were involved. For genetic study, obese (n = 1271) and lean subjects (n = 1455) were involved. TFRC levels were compared in abdominal mesenteric fat of pheochromocytoma patients versus control subjects, and overweight versus lean subjects. For genetic study, whole‐exome sequencing of obese and matched control subjects were conducted and analyzed. In addition, the possible disruption in protein stability of TFRC variant was assessed by structural and molecular analysis. Results TFRC levels are increased in human browning adipose tissue and decreased in fat of overweight patients. Besides, TFRC levels are negatively correlated with body mass index and positively correlated with uncoupling protein 1 levels. Furthermore, a rare heterozygous missense variant p.I337V in TFRC shows a tendency to enrich in obese subjects. Structural and functional study reveals impaired protein stability of the TFRC variant compared to wild‐type. Conclusions Reduced TFRC levels and its rare variant p.I337V with protein instability are associated with human obesity. Highlights Evidence for contribution of transferrin receptor (Tfrc) and its variants for human thermogenic fat is limited. TFRC levels is elevated in activated human thermogenic fat from pheochromocytoma patients and downregulated in fat from overweight patients compared to their control subjects, respectively. Whole‐exome sequencing of obese and matched control subjects suggests that a rare heterozygous missense variant p.I337V in TFRC shows a tendency to enrich in young, severely obese subjects. Structural and functional studies reveal impaired protein stability of the TFRC variant p.I337V compared to wild‐type.