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.
Highlights
Obesity is a common metabolic disorder that is rapidly becoming a global public health in adult and pediatric populations, affecting more than 500 million people worldwide in 2013 [1]
We examined the effects of SR4 on hepatic and adipose AMPK activation, adipose hypertrophy, liver steatosis, as well as analyzed the effects of the compound on various genes associated with hepatic lipid and glucose metabolism
Analysis of the food intake showed that SR4-treated high fat diet (HFD) mice had similar amount of food consumption per day as that of vehicle-treated HFD mice, suggesting that the body weight and fat mass reduction in SR4-treated HFD mice were not associated with less caloric intake (Fig. 1D)
Summary
Obesity is a common metabolic disorder that is rapidly becoming a global public health in adult and pediatric populations, affecting more than 500 million people worldwide in 2013 [1] It is associated with an increased risk of several life-threatening diseases such as type 2 diabetes (T2D), cardiovascular diseases, renal diseases, and multiple types of cancer and may represent a leading preventable cause of death [2,3]. Among them is 59 adenosine monophosphate-activated protein kinase (AMPK), an energy-sensing enzyme that integrates nutrients, hormones, and stress signals to maintain whole body energy homeostasis [7,8]. AMPK regulates several proteins involved in glucose and lipid metabolism, including phosphorylation and inactivation of enzymes of fatty acid and cholesterol synthesis, as well as activating ATPgenerating processes, including the uptake and oxidation of glucose and fatty acids [9,10,11]. Due to its involvement in the regulation of a variety of metabolic processes and its central role in glucose and lipid homeostasis, AMPK has become an attractive drug target for the treatment of obesity, T2D, fatty liver disease, cancer, and other metabolic diseases [11,16,17,18]
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