COH-SR4 Reduces Body Weight, Improves Glycemic Control and Prevents Hepatic Steatosis in High Fat Diet-Induced Obese Mice

Abstract

Obesity is a chronic metabolic disorder caused by imbalance between energy intake and expenditure, and is one of the principal causative factors in the development of metabolic syndrome, diabetes and cancer. COH-SR4 (“SR4”) is a novel investigational compound that has anti-cancer and anti-adipogenic properties. In this study, the effects of SR4 on metabolic alterations in high fat diet (HFD)-induced obese C57BL/J6 mice were investigated. Oral feeding of SR4 (5 mg/kg body weight.) in HFD mice for 6 weeks significantly reduced body weight, prevented hyperlipidemia and improved glycemic control without affecting food intake. These changes were associated with marked decreases in epididymal fat mass, adipocyte hypertrophy, increased plasma adiponectin and reduced leptin levels. SR4 treatment also decreased liver triglycerides, prevented hepatic steatosis, and normalized liver enzymes. Western blots demonstrated increased AMPK activation in liver and adipose tissues of SR4-treated HFD obese mice, while gene analyses by real time PCR showed COH-SR4 significantly suppressed the mRNA expression of lipogenic genes such as sterol regulatory element binding protein-1c (Srebf1), acetyl-Coenzyme A carboxylase (Acaca), peroxisome proliferator-activated receptor gamma (Pparg), fatty acid synthase (Fasn), stearoyl-Coenzyme A desaturase 1 (Scd1), carnitine palmitoyltransferase 1a (Cpt1a) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (Hmgcr), as well as gluconeogenic genes phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose-6-phosphatase (G6pc) in the liver of obese mice. In vitro, SR4 activates AMPK independent of upstream kinases liver kinase B1 (LKB1) and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ). Together, these data suggest that SR4, a novel AMPK activator, may be a promising therapeutic compound for treatment of obesity, fatty liver disease, and related metabolic disorders.

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

“…The compounds recently studied include a modified version of the classic protonophore, DNP (62), which is structurally similar to salicylate (53,67). These mitochondrial uncouplers result in an increase in energy expenditure similar to that obtained when treating with salsalate/salicylate (present work and previous studies [6,10,11,14,15,[52][53][54][55][56][57][58]) and also improve markers of NAFLD and T2D (62)(63)(64)(65)(66). Therefore, considering that mitochondrial uncouplers improve T2D and NAFLD, and increasing energy expenditure is a potent mechanism to improve T2D and NAFLD (62,63,(68)(69)(70), the present work, together with previous reports in mice and humans, is highly suggestive that salicylate-driven mitochondrial uncoupling is the primary mechanism of action explaining the improvement in T2D and NAFLD associated with salsalate treatment.…”

“…From a therapeutic perspective, the beneficial effects of mitochondrial protonophores (uncouplers) on T2D and NAFLD have been consistently observed (62)(63)(64)(65)(66). The compounds recently studied include a modified version of the classic protonophore, DNP (62), which is structurally similar to salicylate (53,67).…”

Protective and therapeutic potential of ginger (Zingiber officinale) extract and [6]‐gingerol in cancer: A comprehensive review

“…Obesity is associated with the metabolic syndrome and the dysregulation of new fatty acid synthesis, leading to numerous consequences, including tumorigenesis and tumor progression (Ameer, Scandiuzzi, Hasnain, Kalbacher, & Zaidi, 2014). Numerous studies have focused on the effect of natural polyphenols in reducing hepatic fat accumulation, overweight, and obesity to reduce the risk of carcinogenesis without disrupting food appetite (Figarola et al, 2013;Huang et al, 2014;Kang et al, 2013). In order to confer rapid proliferation and survival, cancer reorients acetylcoenzyme A into oxidative phosphorylation to develop overexpression of the de novo synthesis pathway of fatty acids (Rodriguez-Enriquez, Marin-Hernandez, Gallardo-Perez, & Moreno-Sanchez, 2009).…”

Metabolomics and Diabetes: Analytical and Computational Approaches

“…This idea is highlighted by a recent study testing the AMPK activator COH-SR4 (94). Although not using metabolomics directly, Figarola et al (94) identified that COH-SR4 was able to rescue many of the abnormalities associated with metabolic syndrome in an animal model of obesity, including reduction of several metabolic enzymes in pathways previously found to be altered by metabolomics.…”

“…This idea is highlighted by a recent study testing the AMPK activator COH-SR4 (94). Although not using metabolomics directly, Figarola et al (94) identified that COH-SR4 was able to rescue many of the abnormalities associated with metabolic syndrome in an animal model of obesity, including reduction of several metabolic enzymes in pathways previously found to be altered by metabolomics. Additionally, recent exciting discoveries link intestinal microbiota metabolism of dietary-derived saturated fats to cardiovascular disease risk, highlighting these as attractive potential therapeutic targets for complications of obesity/diabetes (95–97).…”