Attenuation of hepatic ER stress by bitter melon in high-fat diet-fed mice

Abstract

Nearly 70 percent of the adult population in the United States is obese. Obesity is a growing concern as it is a risk factor for developing metabolic disorders, type II diabetes (T2D) and cardiovascular disease. More than 23 million people in the United States are diagnosed T2D. T2D develops when an individual suffers from chronic insulin resistance, which is due to impaired insulin signaling and reduced insulin sensitivity. During obesity, insulin signaling can be impaired via endoplasmic reticulum (ER) stress. Obesity causes cellular stress, which results in an accumulation of unfolded or misfolded proteins. This accumulation of proteins in the ER leads to ER stress. The cell attempts to decrease ER stress and return to homeostasis through the unfolded protein response (UPR). The UPR increases expression of molecular chaperone Grp78, increased phosphorylation of eukaryotic initiation factor 2α (eIF2α) and upregulation of the activating transcription factor ATF4. These three proteins are central to the UPR and are seen in increasing levels during cellular stress. This ER stress response also activates genes such as c-Jun N-terminal kinase (JNK), which cause the phosphorylation of insulin receptors and decrease levels of insulin signaling. There are various treatments available for T2D, including dietary management, oral medications and insulin injections. Over time, most diabetics become less sensitive to these medications and are required to combine different treatments. As a result, diabetic individuals are 60 percent more likely to use a type of complementary or alternative medicine. Momordica charantia, commonly known as bitter melon (BM), is an alternative medicine that has been traditionally used in Ayurvedic and Chinese medicine to treat diabetes and its complications. Our lab has previously demonstrated that BM decreases weight gain and improves hepatic insulin signaling and resistance. The aim of this study was to investigate the effect of BM on the UPR in mice fed a high-fatdiet (HFD). C57BL/6 mice were randomized into three groups: 1) control, 2) HFD, 3) HFD + BM. After 16 weeks, livers were excised and analyzed for ER stress proteins, Grp78, ATF4 and phosphorylated eIF2α via Western blotting. Data analyses indicate that HFD significantly elevated ER stress associated proteins Grp78, ATF4 and eIF2α-P, while a HFD supplemented with BM significantly decreased eIF2α-P expression and normalized ER stress proteins Grp78 and ATF4. These data indicate that improvement in BM-associated hepatic insulin signaling is in part due to decreased ER stress. Therefore, BM has to potential to be a dietary therapy for reducing HFD-associated diabetes.