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A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity

Miki Okada-Iwabu1, Toshimasa Yamauchi, Masato Iwabu

  • 11] Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan [2] Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-0033, Japan [3] Department of Molecular Medicinal Sciences on Metabolic Regulation, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-0033, Japan [4].

Nature
|November 1, 2013
PubMed

Insights

New synthetic agonists targeting adiponectin receptors (AdipoR1 and AdipoR2) show promise for treating type 2 diabetes and obesity. These compounds mimic adiponectin

Area of Science:

  • Metabolic diseases
  • Endocrinology
  • Pharmacology

Background:

  • Adiponectin, an adipocyte-secreted hormone, regulates glucose and lipid metabolism via AdipoR1 and AdipoR2.
  • Reduced adiponectin levels in obesity are linked to insulin resistance and type 2 diabetes.
  • Targeting AdipoRs with small molecules offers a potential therapeutic strategy for metabolic disorders.

Purpose of the Study:

  • To identify and characterize orally active small-molecule agonists of AdipoR1 and AdipoR2.
  • To evaluate the therapeutic potential of these agonists in preclinical models of obesity and type 2 diabetes.

Main Methods:

  • In vitro binding assays to confirm AdipoR1 and AdipoR2 activation by synthetic agonists.
  • In vivo studies using high-fat diet-induced obese mice and genetically obese db/db mice.
  • Assessment of insulin sensitivity, glucose tolerance, and lifespan in response to treatment.

Main Results:

  • A novel compound, AdipoRon, demonstrated in vitro binding to both AdipoR1 and AdipoR2.
  • AdipoRon replicated adiponectin's effects on AMPK and PPAR-α pathways in muscle and liver.
  • AdipoRon ameliorated insulin resistance, glucose intolerance, and diabetes in rodent models, and extended lifespan.
  • These effects were dependent on AdipoR1 and AdipoR2 expression.

Conclusions:

  • Orally active AdipoR agonists, exemplified by AdipoRon, represent a promising therapeutic avenue.
  • These compounds effectively target key pathways involved in metabolic regulation.
  • AdipoR agonists hold potential for treating obesity-related diseases, including type 2 diabetes.

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