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

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.

A Novel Orally Available Delta-5 Desaturase Inhibitor Prevents Atherosclerotic Lesions Accompanied by Changes in Fatty Acid Composition and Eicosanoid Production in ApoE Knockout Mice

“…5). As we previously reported (Yashiro et al, 2016), compound-326-treated mice were dose-dependently leaner than the vehicle-treated mice (Fig. 6).…”

“…We previously reported that compound-326 (Suzuki et al, 2010), a newly discovered orally available, potent, and selective D5D inhibitor, ameliorated insulin resistance and obesity in a high fat diet-induced obese mouse model accompanied by alterations in the balance between DGLA and AA in the blood (Yashiro et al, 2016). In the present study, we evaluated the antiatherosclerotic effects of compound-326 in Western-diet fed ApoE KO mice.…”

“…Compound-326 potently and selectively inhibits D5D activity, whereas it has almost no inhibitory effects on delta-6 and delta-9 desaturase activity (Yashiro et al, 2016). Its selectivity was investigated using a Cerep/PanLab selectivity profiling panel (Eurofins Discovery, St. Charles, MO) for 94 targets at 10 mM of compound-326.…”

Comparison of Fatty Acid and Gene Profiles in Skeletal Muscle in Normal and Obese C57BL/6J Mice before and after Blunt Muscle Injury

“…AA is a crucial cell membrane component of cells involved in modulating the magnitude and period of inflammatory responses. It exhibits its functions via the synthesis of mostly pro-inflammatory eicosanoids (Calder, 2010 ; Markworth and Cameron-Smith, 2012 ; Yashiro et al, 2016 ). Our phospholipid fraction data show, that the amount of DHGL is negatively influenced by injury in obese mice, while normal weight animals do not show a significant impact, despite higher content.…”

Biological Role of Unsaturated Fatty Acid Desaturases in Health and Disease

“…Interestingly, the same SNP in the European population was associated with the lower fasting plasma glucose level in a normal physiological range, but not with pathological glucose levels [179]. Data from multiple experiments on mice suggest that the development of selective desaturases inhibitors can be beneficial in the treatment of human diabetes, obesity, and atherosclerotic cardiovascular disease [180][181][182]. Mice with D6D knockdown developed resistance against high-fat diet induced obesity, so maybe some metabolic benefits for obese people can be gained with D6D inhibitors [183].…”