An adiponectin receptor agonist antibody stimulates glucose uptake and fatty-acid oxidation by activating AMP-activated protein kinase

Cytokine. 2020 Feb;126:154863. doi: 10.1016/j.cyto.2019.154863. Epub 2019 Oct 16.

Abstract

Adiponectin (Ad) is a representative adipocytokine that regulates energy homeostasis including glucose transport and lipid oxidation through activation of AMP-activated protein kinase (AMPK) pathways. Plasma levels of Ad are reduced in obesity, which contributes to type 2 diabetes. Therefore, agents that activate the Ad signaling pathway could ameliorate metabolic diseases such as type 2 diabetes. Here, we report the identification of a high-affinitive agonist antibody against Ad receptors. The antibody was selected by using phage display of human combinatorial antibody libraries. The selected antibody induced phosphorylation of the acetyl-CoA carboxylase (ACC) and AMPK in skeletal muscle cells and stimulated glucose uptake and fatty-acid oxidation (FAO) in myotubes. In addition, the antibody significantly lowered blood glucose levels during a glucose challenge in normal mice as well as basal blood glucose levels in a type 2 diabetic mouse model. Taken together, these results suggest that the agonist antibody could be a promising therapeutic agent for the treatment of metabolic syndrome such as type 2 diabetes.

Keywords: AMPK; Adiponectin; Agonist antibody; Diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Acetyl-CoA Carboxylase / metabolism
  • Adiponectin / metabolism
  • Animals
  • Blood Glucose / metabolism
  • Cell Line
  • Diabetes Mellitus, Type 2 / metabolism
  • Fatty Acids / metabolism*
  • Gene Knockdown Techniques
  • Glucose / metabolism*
  • Glucose / pharmacology
  • Humans
  • Lipid Metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism
  • NF-kappa B / metabolism
  • Oxidation-Reduction
  • Phosphorylation
  • RNA, Small Interfering
  • Receptors, Adiponectin / agonists*
  • Receptors, Adiponectin / genetics
  • Receptors, Adiponectin / immunology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • Adiponectin
  • Blood Glucose
  • Fatty Acids
  • NF-kappa B
  • RNA, Small Interfering
  • Receptors, Adiponectin
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase
  • Glucose