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

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.

SUBMITTER: Hampe L

PROVIDER: S-EPMC5715598 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Hampe Lutz L Xu Cheng C Harris Paul W R PWR Chen Jie J Liu Ming M Middleditch Martin M Radjainia Mazdak M Wang Yu Y Mitra Alok K AK

British journal of pharmacology 20171102 23

<h4>Background and purpose</h4>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 p ...[more]

PMID: 28945274

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

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

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