Novel loci influencing circulating leptin levels identified

Novel loci influencing circulating leptin levels identified

Leptin is an adipocyte-secreted hormone that influences long-term regulation of energy homeostasis by informing the brain about the amount of stored body fat. The circulating levels of which correlate closely with overall adiposity such as body fat mass and body mass index (BMI).

Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency that leads to hyperphagia and severe obesity, which can be corrected by exogenous leptin administration, no common loci regulating circulating leptin levels have been uncovered. Therefore, researchers performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals.

They identify five loci robustly associated with leptin levels in/near LEP, SLC32A1GCKRCCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity.

The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight.

Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels.

These findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.