ABSTRACT
The molecular targets and mechanisms of propolis ameliorating metabolic syndrome are not fully understood. Here, we report that Brazilian green propolis reduces fasting blood glucose levels in obese mice by disrupting the formation of CREB/CRTC2 transcriptional complex, a key regulator of hepatic gluconeogenesis. Using a mammalian two-hybrid system based on CREB-CRTC2, we identify artepillin C (APC) from propolis as an inhibitor of CREB-CRTC2 interaction. Without apparent toxicity, APC protects mice from high fat diet-induced obesity, decreases fasting glucose levels, enhances insulin sensitivity and reduces lipid levels in the serum and liver by suppressing CREB/CRTC2-mediated both gluconeogenic and SREBP transcriptions. To develop more potential drugs from APC, we designed and found a novel compound, A57 that exhibits higher inhibitory activity on CREB-CRTC2 association and better capability of improving insulin sensitivity in obese animals, as compared with APC. In this work, our results indicate that CREB/CRTC2 is a suitable target for developing anti-metabolic syndrome drugs.
Subject(s)
CREB-Binding Protein/metabolism , Drug Delivery Systems , Metabolic Syndrome/metabolism , Mice, Obese/metabolism , Propolis/metabolism , Transcription Factors/metabolism , Animals , Blood Glucose , Brazil , CREB-Binding Protein/genetics , Drug Development , Drug Discovery , Gluconeogenesis , Insulin Resistance , Liver/metabolism , Metabolic Syndrome/genetics , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Mice, Obese/genetics , Obesity/metabolism , Propolis/genetics , Transcription Factors/geneticsABSTRACT
C57Bl/6J mice are the gold standard animal model of diet-induced obesity. These animals become obese with higher adiposity, blood fasting glucose, triglycerides, and total cholesterol when fed a high-fat diet (HFD). Conversely, the FVB/N mouse line is thought to be resistant to diet-induced obesity, with low or no weight gain and adiposity in response to a HFD In this study, we investigated whether FVB/N mice are resistant or susceptible to metabolic disorder that is promoted by a HFD Biometric parameters and blood chemistry were analyzed in C57Bl/6J and FVB/N mice that were fed a chow diet or HFD Glucose and insulin sensitivity were assessed by performing the glucose tolerance test and measuring serum insulin/glucose and homeostasis model assessment-insulin resistance. Metabolism-related gene expression was investigated by real-time reverse transcription polymerase chain reaction. Adipocyte morphology and liver steatosis were evaluated using standard histology. FVB/N mice had higher adiposity than C57Bl/6J mice that were fed a chow diet and were glucose intolerant. FVB/N mice that were fed a HFD presented higher insulin resistance and greater liver steatosis. Epididymal white adipose tissue exhibited severe inflammation in FVB/N mice that were fed a HFD The FVB/N mouse strain is suitable for studies of diet-induced obesity, and the apparent lack of a HFD-induced response may reveal several strain-specific events that are triggered by a HFD Further studies of the FVB/N background may shed light on the complex multifactorial symptoms of obesity and metabolic syndrome.
Subject(s)
Diet, High-Fat/adverse effects , Mice, Obese/metabolism , Obesity/etiology , Adiposity , Animals , Blood Glucose/metabolism , Disease Models, Animal , Genetic Background , Male , Mice , Mice, Inbred C57BL , Mice, Obese/genetics , Obesity/geneticsABSTRACT
Despite the increase in obesity prevalence over the last decades, humans show large inter-individual variability for susceptibility to diet-induced obesity. Understanding the biological basis of this susceptibility could identify new therapeutic alternatives against obesity. We characterized behavioral changes associated with propensity to obesity induced by cafeteria (CAF) diet consumption in mice. We show that Balb/c mice fed a CAF diet display a large inter-individual variability in susceptibility to diet-induced obesity, such that based on changes in adiposity we can classify mice as obesity prone (OP) or obesity resistant (OR). Both OP and OR were hyperphagic relative to control-fed mice but caloric intake was similar between OP and OR mice. In contrast, OR had a larger increase in locomotor activity following CAF diet compared to OP mice. Obesity resistant and prone mice showed similar intake of sweet snacks, but OR ate more savory snacks than OP mice. Two bottle sucrose preference tests showed that OP decreased their sucrose preference compared to OR mice after CAF diet feeding. Finally, to test the robustness of the OR phenotype in response to further increases in caloric intake, we fed OR mice with a personalized CAF (CAF-P) diet based on individual snack preferences. When fed a CAF-P diet, OR increased their calorie intake compared to OP mice fed the standard CAF diet, but did not reach adiposity levels observed in OP mice. Together, our data show the contribution of hedonic intake, individual snack preference and physical activity to individual susceptibility to obesity in Balb/c mice fed a standard and personalized cafeteria-style diet.
Subject(s)
Diet , Feeding Behavior/physiology , Food Preferences/physiology , Mice, Inbred BALB C/physiology , Mice, Obese/physiology , Motor Activity/physiology , Animal Feed/adverse effects , Animals , Choice Behavior/physiology , Diet/adverse effects , Diet/psychology , Dietary Sucrose/administration & dosage , Disease Models, Animal , Eating/physiology , Eating/psychology , Feeding Behavior/psychology , Food Preferences/psychology , Genetic Predisposition to Disease , Hyperphagia/etiology , Hyperphagia/physiopathology , Hyperphagia/psychology , Male , Mice, Inbred BALB C/genetics , Mice, Inbred BALB C/psychology , Mice, Obese/genetics , Mice, Obese/psychology , Species SpecificityABSTRACT
Exercise is recognized to prevent and attenuate several metabolic and cardiovascular disorders. Obesity is commonly related to cardiovascular diseases, frequently resulting in heart failure and death. To elucidate the effects of acute exercise in heart tissue from obese animals, 12-week-old C57BL6/J obese (ob/ob) and non-obese (ob/OB) mice were submitted to a single bout of swimming and had their hearts analyzed by proteomic techniques. Mice were divided into three groups: control (ob/ob, n = 3; ob/OB, n = 3); a moderate intensity consisting of 20 min of swimming around 90% of Maximal Lactate Steady State (ob/ob, n = 3; ob/OB, n = 3), and a high intensity exercise performed as an incremental overload test (ob/ob, n = 3; ob/OB, n = 3). Obesity modulations were analyzed by comparing ob/ob and ob/OB control groups. Differential 2-DE analysis revealed that single session of exercise was able to up-regulate: myoglobin (ob/ob), aspartate aminotransferase (ob/OB) and zinc finger protein (ob/OB) and down-regulate: nucleoside diphosphate kinase B (ob/OB), mitochondrial aconitase (ob/ob and ob/OB) and fatty acid binding protein (ob/ob). Zinc finger protein and α-actin were up-regulated by the effect of obesity on heart proteome. These data demonstrate the immediate response of metabolic and stress-related proteins after exercise so as contractile protein by obesity modulation on heart proteome.