A Novel Selective Inhibitor of Delta-5 Desaturase Lowers Insulin Resistance and Reduces Body Weight in Diet-Induced Obese C57BL/6J Mice

Hiroaki Yashiro; Shuichi Takagahara; Yumiko Okano Tamura; Ikuo Miyahisa; Junji Matsui; Hideo Suzuki; Shota Ikeda; Masanori Watanabe

doi:10.1371/journal.pone.0166198

A Novel Selective Inhibitor of Delta-5 Desaturase Lowers Insulin Resistance and Reduces Body Weight in Diet-Induced Obese C57BL/6J Mice

PLoS One. 2016 Nov 10;11(11):e0166198. doi: 10.1371/journal.pone.0166198. eCollection 2016.

Authors

Hiroaki Yashiro¹, Shuichi Takagahara¹, Yumiko Okano Tamura¹, Ikuo Miyahisa¹, Junji Matsui¹, Hideo Suzuki¹, Shota Ikeda¹, Masanori Watanabe¹

Affiliation

¹ Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa Japan.

Abstract

Obesity is now recognized as a state of chronic low-grade inflammation and is called as metabolic inflammation. Delta-5 desaturase (D5D) is an enzyme that metabolizes dihomo-γ-linolenic acid (DGLA) to arachidonic acid (AA). Thus, D5D inhibition increases DGLA (precursor to anti-inflammatory eicosanoids) while decreasing AA (precursor to pro-inflammatory eicosanoids), and could result in synergistic improvement in the low-grade inflammatory state. Here, we demonstrate reduced insulin resistance and the anti-obesity effect of a D5D selective inhibitor (compound-326), an orally active small-molecule, in a high-fat diet-induced obese (DIO) mouse model. In vivo D5D inhibition was confirmed by determining changes in blood AA/DGLA profiles. In DIO mice, chronic treatment with compound-326 lowered insulin resistance and caused body weight loss without significant impact on cumulative calorie intake. Decreased macrophage infiltration into adipose tissue was expected from mRNA analysis. Increased daily energy expenditure was also observed following administration of compound-326, in line with sustained body weight loss. These data indicate that the novel D5D selective inhibitor, compound-326, will be a new class of drug for the treatment of obese and diabetic patients.

MeSH terms

8,11,14-Eicosatrienoic Acid / blood
8,11,14-Eicosatrienoic Acid / metabolism
Adiponectin / genetics
Adipose Tissue / drug effects
Adipose Tissue / metabolism
Animals
Arachidonic Acid / blood
Arachidonic Acid / metabolism
Body Weight / drug effects*
Delta-5 Fatty Acid Desaturase
Diet, High-Fat / adverse effects
Energy Metabolism / drug effects
Enzyme Inhibitors / pharmacology*
Fatty Acid Desaturases / antagonists & inhibitors*
Fatty Acid Desaturases / metabolism
Gene Expression / drug effects
Hep G2 Cells
Humans
Inflammation / genetics
Inflammation / metabolism
Inflammation / prevention & control
Insulin Resistance*
Leptin / genetics
Macrophages / drug effects
Macrophages / metabolism
Male
Mice, Inbred C57BL
Obesity / etiology
Obesity / physiopathology
Obesity / prevention & control*
Pyrimidinones / pharmacology*
Pyrrolidinones / pharmacology*
Reverse Transcriptase Polymerase Chain Reaction
Weight Loss / drug effects

Substances

2-(2,2,3,3,3-pentafluoropropoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-5,7-dihydro-3H-pyrrolo(2,3-d)pyrimidine-4,6-dione
Adiponectin
Delta-5 Fatty Acid Desaturase
Enzyme Inhibitors
Leptin
Pyrimidinones
Pyrrolidinones
Arachidonic Acid
Fatty Acid Desaturases
8,11,14-Eicosatrienoic Acid

Grants and funding

This study was financially supported by Takeda Pharmaceutical Company Limited. Employees of Takeda played roles in study design, data collection and analysis, decision to publish, or preparation of the manuscript.