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

J Clin Endocrinol Metab. 2018 Mar 1;103(3):1024-1032. doi: 10.1210/jc.2017-02126.

Abstract

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) [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.

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.

Trial registration: ClinicalTrials.gov NCT01803568.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM10 Protein / blood
  • ADAM17 Protein / blood
  • Adipose Tissue / metabolism
  • Adult
  • Aged
  • Amyloid Precursor Protein Secretases / blood
  • Carrier Proteins / blood
  • Down-Regulation
  • Enzyme-Linked Immunosorbent Assay
  • Exercise / physiology*
  • Exercise Therapy / methods
  • Glucose Clamp Technique
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Insulin Resistance / physiology*
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins / blood
  • Metabolic Networks and Pathways / physiology*
  • Middle Aged
  • Muscle, Skeletal / metabolism
  • RNA, Messenger / metabolism*
  • Receptors, Leptin / blood*
  • Scandinavian and Nordic Countries
  • Sedentary Behavior
  • Up-Regulation

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • LEPROT protein, human
  • Membrane Proteins
  • RNA, Messenger
  • Receptors, Leptin
  • leptin receptor, human
  • Amyloid Precursor Protein Secretases
  • ADAM10 Protein
  • ADAM10 protein, human
  • ADAM17 Protein
  • ADAM17 protein, human

Associated data

  • ClinicalTrials.gov/NCT01803568