Transferrin receptor levels and its rare variant are associated with human obesity
Jin Qiu, Zhiyin Zhang, Yepeng Hu, Yuhan Guo, Caizhi Liu, Yanru Chen, Dongmei Wang, Junlei Su, Sainan Wang, Mengshan Ni, Sainan Xu, Jian Yu, Tianhui Hu, Gaojie Song, Xinran Ma, Xuejiang Gu, Jiqiu Wang, Lingyan Xu- Endocrinology, Diabetes and Metabolism
Abstract
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.