Effect of 8-Methyl Nonanoic Acid, a Degradation By-Product of Dihydrocapsaicin, on Energy and Glucose Homeostasis in Diet-Induced Obese Mice

Abstract

Purpose: Consumption of chili with capsaicinoids, such as dihydrocapsaicin (DHC), offers metabolic benefits to humans. However, their spiciness and rapid degradation prevent it from being used as a treatment for metabolic syndrome (MetS), including obesity, insulin resistance (IR), and hyperglycemia. During the degradation process of capsaicinoids, DHC is metabolized to non-pungent 8-methyl nonanoic acid (8-MNA), a methylated medium-chain fatty acid (MCFA). However, the metabolic functions of 8-MNA and its therapeutic potential for MetS have been unknown in animals. As other MCFAs improve metabolic status when added to obesogenic diets, we hypothesize that 8-MNA may improve energy and glucose metabolism in diet-induced obese (DIO) mice that exhibit MetS-like metabolic derangements. Methods: C57BL/6NJcl mice were fed a normal diet, or a high-fat diet (HFD) supplemented with triacylglycerols, which consisted of 8-MNAs or isocaloric soybean oil (SBO) for 18 weeks. Food intake, body weight, and blood chemicals were assessed, and glucose and insulin tolerance tests (GTT and ITT, respectively) were performed. Tissues and organs collected at the end of the experiments were used for biochemical analyses of metabolic determinants. Results: Compared with HFD + SBO-fed mice, 8-MNA feeding resulted in reduced caloric intake and body weight gain in DIO mice (p<0.05) in association with overall weight loss in several tissues and organs as well as transcriptional downregulation of orexigenic agouti-related protein in the hypothalamus. Despite no improvement in GTT and ITT, during the early experimental period, 8-MNA supplementation delayed the onset of HFD-induced IR. Conclusion: We conclude that 8-MNA slows the development of MetS in DIO mice. Furthermore, these findings suggest that 8-MNA derived from DHC accounts, in part, for the metabolic benefits of consuming chili and may represent a promising non-pungent nutraceutical for preventing MetS. © 2025 Keawsomnuk et al.