ESPE Yearbook of Paediatric Endocrinology

Brief summary: This pooled study, including five cross-sectional or intervention studies (n=24–823) and using publicly available data from genome-wide association studies (GWAS) to perform Mendelian randomization, investigated the influence of glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity on serum soluble leptin receptor (sOb-R) levels. The authors showed that insulin and BMI were associated with decreased serum sOb-R levels, whereas physical activity and food intake acutely increased sOb-R levels, suggesting an involvement in the short-term regulation of leptin signalling.

Membrane-bound leptin receptors (Ob-R) are important to mediate the effects of leptin on hunger and satiety. The human Ob-R can be spliced into six different isoforms with identical extracellular domains but distinct intracellular domains that differ in length and mode of signalling (1). sOb-R is produced by shedding of the extracellular domain of membrane-bound Ob-R (2). It is therefore suggested that sOb-R levels reflect the amount of membrane-bound Ob-Rs, act as a soluble receptor, and prolong the half-life of circulating leptin (3). The regulation and function of sOb-R is largely unknown, but previous studies have found a strong inverse association between sOb-R levels and insulin sensitivity, suggesting a protective effect against the development of type 2 diabetes (4,5).

The strength of this study lies in the use of pooled data from several independent studies. The results strongly support an inverse association between sOb-R and insulin, which may contribute to a lower risk of type 2 diabetes. However, the results should be interpreted with caution, as the exact role and mechanism by which the sOb-R might mediate these effects is still unknown. The study highlights the great interest in understanding the mechanism and clinical implication of sOb-R in humans, which remains to be elucidated in future studies.

References: 1. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, u. a. Abnormal splicing of the leptin receptor in diabetic mice. Nature. Februar 1996;379(6566):632–5. 2. Ge H, Huang L, Pourbahrami T, Li C. Generation of soluble leptin receptor by ectodomain shedding of membrane-spanning receptors in vitro and in vivo. J Biol Chem. November 2002;277(48):45898–903. 3. Lammert A, Kiess W, Bottner A, Glasow A, Kratzsch J. Soluble leptin receptor represents the main leptin binding activity in human blood. Biochem Biophys Res Commun. Mai 2001;283(4):982–8. 4. Sommer C, Lee S, Gulseth HL, Jensen J, Drevon CA, Birkeland KI. Soluble leptin receptor predicts insulin sensitivity and correlates with upregulation of metabolic pathways in men. J Clin Endocrinol Metab. 1. März 2018;103(3):1024–32. 5. Sun Q, Van Dam RM, Meigs JB, Franco OH, Mantzoros CS, Hu FB. Leptin and soluble leptin receptor levels in plasma and risk of type 2 diabetes in U.S. women. Diabetes. 1. März 2010;59(3):611–8.