A Novel Selective Inhibitor of Delta-5 Desaturase Lowers Insulin Resistance and Reduces Body Weight in Diet-Induced Obese C57BL/6J Mice.
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.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa Japan.
Hiroaki
H
Yashiro
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa Japan.
Shuichi
S
Takagahara
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa Japan.
Yumiko Okano
YO
Tamura
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa Japan.
Ikuo
I
Miyahisa
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa Japan.
Junji
J
Matsui
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa Japan.
Hideo
H
Suzuki
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa Japan.
Shota
S
Ikeda
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa Japan.
Masanori
M
Watanabe
D015126:8,11,14-Eicosatrienoic Acid / Q000097:blood / Q000378:metabolism; D052242:Adiponectin / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000097:blood / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects*; D000090943:Delta-5 Fatty Acid Desaturase; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D044943:Fatty Acid Desaturases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D007333:Insulin Resistance; D020738:Leptin / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D011744:Pyrimidinones / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015431:Weight Loss / Q000187:drug effects; D005466:Fluorocarbons
D015126:8,11,14-Eicosatrienoic Acid; D052242:Adiponectin; D016718:Arachidonic Acid; D000090943:Delta-5 Fatty Acid Desaturase; D004791:Enzyme Inhibitors; D044943:Fatty Acid Desaturases; D020738:Leptin; D011744:Pyrimidinones; D011760:Pyrrolidinones; C000621111:2-(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; D005466:Fluorocarbons