N-Octyl Caffeamide, a Caffeic Acid Amide Derivative, Prevents Progression of Diabetes and Hepatic Steatosis in High-Fat Diet Induced Obese Mice

Abstract

The underlying pathological mechanisms of diabetes are complicated and varied in diabetic patients, which may lead to the current medications often failing to maintain glycemic control in the long term. Thus, the discovery of diverse new compounds for developing medicines to treat diabetes and its complications are urgently needed. Polyphenols are metabolites of plants and have been employed in the prevention and treatment of a variety of diseases. Caffeic acid phenethyl ester (CAPE) is a category of compounds structurally similar to polyphenols. In this study, we aimed to investigate the antidiabetic activity and potential molecular mechanisms of a novel synthetic CAPE derivative N-octyl caffeamide (36M) using high-fat (HF) diet induced obese mouse models. Our results demonstrate that 36M prevented the progression of diabetes in the HF diet fed obese mice via increasing phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and inhibiting expression of protein tyrosine phosphatase 1B (PTP1B). We also found that 36M could prevent hepatic lipid storage in the HF diet fed mice via inhibition of fatty acid synthase and lipid droplet proteins, including perilipins and Fsp27. In conclusion, 36M is a potential candidate compound that can be developed as AMPK inhibitor and PTP1B inhibitor for treating diabetes and hepatic steatosis.

Caffeic Acid Phenethyl Ester and Caffeamide Derivatives Suppress Oral Squamous Cell Carcinoma Cells

“…Herein, the lower level of caffeamide derivative 36M treatment for 72 h presented a more potent ability to induce cell toxicity in cancer cells than the corresponding dose level of the CAPE derivative 26G ( Figure 1 A,B). This study indicates that 36M plays critical roles in preventing type 2 diabetes and oral microbes because of its broad resistance to acid, alkali, and high-temperature conditions [ 27 , 28 ]. Furthermore, 36M showed more potent cell cytotoxicity than other CAPE derivatives [ 28 ].…”

“…CAPE and caffeamide derivatives ( 26G , 36C , 36H , 36 K , and 36M ) were synthesized and provided by Dr. Yueh-Hsiung Kuo, and the extraction processes were as reported previously [ 27 , 45 ]. Briefly, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate was dissolved in dichloromethane and added to a mixture of caffeic acid, phenethyl alcohol, corresponding amines, and triethylamine in dimethylformamide.…”

Natural Remedies for the Treatment of Diabetes Mellitus

“…In-vivo studies in highfat-induced obese animal models also evaluated the compound's involvement in slowing diabetes progression via AMPK regulation. This compound indirectly reduces insulin resistance, improves GLUT4 transport, and may work as a potential treatment for Type 2 DM (Wu et al 2022). Numerous CAPE derivatives studied for their cytotoxicity showed a 3-16% drop in viable cells while simultaneously improving glucose absorption by about 70% (Eid et al 2010).…”

Synthesis and Dopaminergic Neuroprotective Activity of the Proposed Structure of Bassiamide A, a Caffeamide Alkaloid Derived from Bassia Indica Wight

“…[4] Caffeic acid derivatives such as caffeic acid ester and caffeamide have been widely used as templates to develop novel therapeutic candidates based on their pluripotent biological activities against diverse human diseases. [5][6][7] In addition to their wide range of therapeutic properties including anti-Parkinson's disease [8] and anti-diabetic effects, [9] natural and synthetic caffeamide derivatives have several advantages over their ester analogs, such as metabolic stability. For instance, Yang et al reported that caffeic acid phenethyl amide, an amide surrogate of caffeic acid phenethyl ester (CAPE), a bioactive component of propolis, showed a prolonged in-vivo half-life by avoiding enzymatic hydrolysis without significant changes in its cytoprotective properties compared to those of CAPE.…”