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

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.

• Authors: Christine Sommer, Sindre Lee, Hanne Løvdal Gulseth, Jørgen Jensen, Christian A Drevon, Kåre Inge Birkeland
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 103 Issue 3 Pg. 1024-1032 (03 01 2018) ISSN: 1945-7197 [Electronic] United States
• PMID: 29300960 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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