Synthetic peptides designed to modulate adiponectin assembly improve obesity-related metabolic disorders
| Autor: | Lutz Hampe, Ming Liu, Yu Wang, Jie Chen, Mazdak Radjainia, Cheng Xu, Alok K. Mitra, Martin Middleditch, Paul W. R. Harris |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pharmacology medicine.medical_specialty Adiponectin Chemistry Endoplasmic reticulum Adipokine Adipose tissue Type 2 diabetes medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Endocrinology Insulin resistance Internal medicine medicine Unfolded protein response Secretion 030217 neurology & neurosurgery |
| Zdroj: | British Journal of Pharmacology. 174:4478-4492 |
| ISSN: | 0007-1188 |
| DOI: | 10.1111/bph.14050 |
| Popis: | BACKGROUND AND PURPOSE Adiponectin, an adipokine possessing profound insulin-sensitizing and anti-inflammatory properties, is a potent biotherapeutic. The trimeric adiponectin subunit assembles into hexameric and functionally important higher-molecular-weight (HMW) forms, tightly controlled by the endoplasmic reticulum protein 44 (ERp44). Obesity-induced ER stress leads to a reduction of the HMW form in serum, contributing to the development of insulin resistance and type2 diabetes. In this study, a panel of designed peptides, targeting ERp44-adiponectin interactions were tested for their effects on the circulating level 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 under standard chow or high fat diet were subjected to acute or chronic treatment 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. CONCLUSION AND IMPLICATIONS Targeting ERp44-adiponectin interactions with short peptides represents an effective strategy for the treatment of obesity-related metabolic disorders, such as insulin resistance and type 2 diabetes. |
| Databáze: | OpenAIRE |
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