Synthetic peptides designed to modulate adiponectin assembly improve obesity-related metabolic disorders

Br J Pharmacol. 2017 Dec;174(23):4478-4492. doi: 10.1111/bph.14050. Epub 2017 Nov 2.

Abstract

Background and purpose: Adiponectin, an adipokine possessing profound insulin-sensitizing and anti-inflammatory properties, is a potent biotherapeutic agent . The trimeric adiponectin subunit assembles into hexameric and functionally important higher molecular weight (HMW) forms, controlled by the endoplasmic reticulum protein 44 (ERp44). Obesity-induced ER stress decreases the HMW form in serum, contributing to the development of insulin resistance and Type 2 diabetes. In this study, a panel of synthetic peptides, designed to target ERp44-adiponectin interactions, were tested for their effects on circulating levels of HMW adiponectin.

Experimental approach: Peptides derived from the ERp44 binding region of adiponectin and immunoglobulin IgM were synthesized with or without a cell-penetrating sequence. Cultures of 3T3-L1 adipocytes were incubated with the peptides for assessing the assembly and secretion of HMW adiponectin. Mice given standard chow or a high-fat diet were treated acutely or chronically, with the peptides to investigate the therapeutic effects on insulin sensitivity and energy metabolism.

Results: The designed peptides interfered with ERp44-adiponectin interactions and modulated adiponectin assembly and release from adipocytes. In particular, IgM-derived peptides facilitated the release of endogenous adiponectin (especially the HMW form) from adipose tissue, enhanced its circulating level and the ratio of HMW-to-total-adiponectin in obese mice. Long-term treatment of mice fed with high-fat diet by IgM-derived peptides reduced the circulating lipid levels and improved insulin sensitivity.

Conclusions and implications: Targeting ERp44-adiponectin interactions with short peptides represents an effective strategy to treat of obesity-related metabolic disorders, such as insulin resistance and Type 2 diabetes.

MeSH terms

  • 3T3-L1 Cells
  • Adiponectin / metabolism*
  • Animals
  • Diabetes Mellitus, Type 2 / etiology
  • Disease Models, Animal
  • Drug Design
  • Endoplasmic Reticulum Stress / drug effects
  • Energy Metabolism / drug effects
  • Insulin Resistance
  • Male
  • Membrane Proteins / metabolism
  • Metabolic Diseases / drug therapy*
  • Metabolic Diseases / etiology
  • Mice
  • Mice, Inbred C57BL
  • Molecular Chaperones / metabolism
  • Molecular Weight
  • Obesity / complications*
  • Peptides / chemical synthesis
  • Peptides / pharmacology*

Substances

  • Adiponectin
  • ERp44 protein, mouse
  • Membrane Proteins
  • Molecular Chaperones
  • Peptides