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

• Published in: The journal of clinical endocrinology and metabolism Vol. 103; no. 3; pp. 1024 - 1032
• Main Authors: Sommer, Christine, Lee, Sindre, Gulseth, Hanne Løvdal, Jensen, Jørgen, Drevon, Christian A, Birkeland, Kåre Inge
• Format: Journal Article
• Language: English
• Published: United States Copyright Oxford University Press 01-03-2018; Oxford University Press
• Subjects: ADAM10 Protein - blood; ADAM17 Protein - blood; Adipose tissue; Adipose Tissue - metabolism; Adult; Aged; Amyloid Precursor Protein Secretases - blood; Carrier Proteins - blood; Cell surface; Diabetes; Diabetes mellitus (non-insulin dependent); Down-Regulation; Enzyme-Linked Immunosorbent Assay; Exercise - physiology; Exercise Therapy - methods; Gene expression; Glucose; Glucose Clamp Technique; High-Throughput Nucleotide Sequencing; Humans; Inflammation; Insulin; Insulin Resistance - physiology; Intracellular Signaling Peptides and Proteins; Leptin receptors; Male; Membrane Proteins - blood; Metabolic Networks and Pathways - physiology; Metabolic pathways; Metabolism; Middle Aged; Muscle, Skeletal - metabolism; Musculoskeletal system; Next-generation sequencing; Plasma levels; Receptors, Leptin - blood; RNA, Messenger - metabolism; Scandinavian and Nordic Countries; Sedentary Behavior; Skeletal muscle; Up-Regulation; Scandinavian and Nordic Countries
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2017-02126

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.
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.
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.
Baseline plasma sOb-R was strongly associated with baseline glucose infusion rate (GIR) [β (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.
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.