Soluble Leptin Receptor Predicts Insulin Sensitivity and Correlates With Upregulation of Metabolic Pathways in Men

Context: Plasma soluble leptin receptor (sOb-R) seems protective of gestational and type 2 diabetes in observational studies, but the mechanisms are unknown. sOb-R is formed by ectodomain shedding of membrane-bound leptin receptors (Ob-Rs), but its associations with messenger RNA (mRNA) expression are scarcely explored. Objective: To explore associations between plasma levels of sOb-R and (1) insulin sensitivity, (2) mRNA pathways in adipose tissue and skeletal muscle, and (3) mRNA of candidate genes for sOb-R generation in adipose tissue and skeletal muscle. Design and Participants: The MyoGlu study included 26 sedentary, middle-aged men who underwent a 12-week intensive exercise intervention. We measured plasma sOb-R with enzyme-linked immunosorbent assay, insulin sensitivity with a hyperinsulinemic euglycemic clamp, and mRNA in skeletal muscle and adipose tissue with high-throughput sequencing. Results: Baseline plasma sOb-R was strongly associated with baseline glucose infusion rate (GIR) [beta (95% confidence interval), 1.19 (0.57 to 1.82) mg/kg/min, P = 0.0006] and GIR improvement after the exercise intervention [0.58 (0.03 to 1.12) mg/kg/min, P = 0.039], also independently of covariates, including plasma leptin. In pathway analyses, high plasma sOb-R correlated with upregulation of metabolic pathways and downregulation of inflammatory pathways in both adipose tissue and skeletal muscle. In skeletal muscle, mRNA of LEPROT and LEPROTL1 (involved in Ob-R cell surface expression) and ADAM10 and ADAM17 (involved sOb-R-shedding) increased after the exercise intervention. Conclusions: Higher plasma sOb-R was associated with improved GIR, upregulation of metabolic pathways, and downregulation of inflammatory pathways, which may be possible mechanisms for the seemingly protective effect of plasma sOb-R on subsequent risk of gestational and type 2 diabetes found in observational studies.