scholarly journals Ganoderma lucidum Extract Reduces Insulin Resistance by Enhancing AMPK Activation in High-Fat Diet-Induced Obese Mice

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3338
Author(s):  
Hyeon A Lee ◽  
Jae-Han Cho ◽  
Qonita Afinanisa ◽  
Gi-Hong An ◽  
Jae-Gu Han ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
High Fat Diet ◽  
Ganoderma Lucidum ◽  
Fatty Acid Synthase ◽  
Metabolic Diseases ◽  
Ampk Activation ◽  
High Fat ◽  
Amp Activated Protein Kinase

Ganoderma lucidum is used widely in oriental medicine to treat obesity and metabolic diseases. Bioactive substances extracted from G. lucidum have been shown to ameliorate dyslipidemia, insulin resistance, and type 2 diabetes in mice via multiple 5′ AMP-activated protein kinase (AMPK)-mediated mechanisms; however, further studies are required to elucidate the anti-obesity effects of G. lucidum in vivo. In this study, we demonstrated that 3% G. lucidum extract powder (GEP) can be used to prevent obesity and insulin resistance in a mouse model. C57BL/6 mice were provided with a normal diet (ND) or a high-fat diet (HFD) supplemented with 1, 3, or 5% GEP for 12 weeks and the effect of GEP on body weight, liver, adipose tissue, adipokines, insulin and glucose tolerance (ITT and GTT), glucose uptake, glucose-metabolism related proteins, and lipogenesis related genes was examined. GEP administration was found to reduce weight gain in the liver and fat tissues of the mice. In addition, serum parameters were significantly lower in the 3% and 5% GEP mice groups than in those fed a HFD alone, whereas adiponectin levels were significantly higher. We also observed that GEP improved glucose metabolism, reduced lipid accumulation in the liver, and reduced adipocyte size. These effects may have been mediated by enhanced AMPK activation, which attenuated the transcription and translation of lipogenic genes such as fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1), and sterol regulatory element-binding protein-1c (SREBP1c). Moreover, AMP-activated protein kinase (AMPK) activation increased acetyl-CoA carboxylase (ACC), insulin receptor (IR), IR substrate 1 (IRS1), and Akt protein expression and activation, as well as glucose transporter type 1/4 (GLUT1/4) protein production, thereby improving insulin sensitivity and glucose metabolism. Together, these findings demonstrate that G. lucidum may effectively prevent obesity and suppress obesity-induced insulin resistance via AMPK activation.

scholarly journals Resveratrol Ameliorates High-Fat-Diet-Induced Abnormalities in Hepatic Glucose Metabolism in Mice via the AMP-Activated Protein Kinase Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Caiping Lu ◽  
Hanying Xing ◽  
Linquan Yang ◽  
Kaiting Chen ◽  
Linyi Shu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
High Fat Diet ◽  
Blood Glucose Concentration ◽  
Glycogen Synthesis ◽  
Liver Fat ◽  
High Fat ◽  
Amp Activated Protein Kinase

Diabetes mellitus is highly prevalent worldwide. High-fat-diet (HFD) consumption can lead to liver fat accumulation, impair hepatic glycometabolism, and cause insulin resistance and the development of diabetes. Resveratrol has been shown to improve the blood glucose concentration of diabetic mice, but its effect on the abnormal hepatic glycometabolism induced by HFD-feeding and the mechanism involved are unknown. In this study, we determined the effects of resveratrol on the insulin resistance of high-fat-diet-fed mice and a hepatocyte model by measuring serum biochemical indexes, key indicators of glycometabolism, glucose uptake, and glycogen synthesis in hepatocytes. We found that resveratrol treatment significantly ameliorated the HFD-induced abnormalities in glucose metabolism in mice, increased glucose absorption and glycogen synthesis, downregulated protein phosphatase 2A (PP2A) and activated Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ), and increased the phosphorylation of AMP-activated protein kinase (AMPK). In insulin-resistant HepG2 cells, the administration of a PP2A activator or CaMKKβ inhibitor attenuated the effects of resveratrol, but the administration of an AMPK inhibitor abolished the effects of resveratrol. Resveratrol significantly ameliorates abnormalities in glycometabolism induced by HFD-feeding and increases glucose uptake and glycogen synthesis in hepatocytes. These effects are mediated through the activation of AMPK by PP2A and CaMKKβ.

scholarly journals Gestational Diabetes Mellitus-Associated Hyperglycemia Impairs Glucose Transporter 3 Trafficking in Trophoblasts Through the Downregulation of AMP-Activated Protein Kinase

2021 ◽  
Vol 9 ◽  
Author(s):  
Li Zhang ◽  
Xinyang Yu ◽  
Yue Wu ◽  
Huijia Fu ◽  
Ping Xu ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
High Fat Diet ◽  
Glucose Transporter ◽  
Ampk Activation ◽  
High Fat ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is an important regulator of glucose metabolism, and glucose transporter 3 (GLUT3) is an efficient glucose transporter in trophoblasts. Whether placental AMPK and GLUT3 respond accordingly to gestational diabetes mellitus (GDM) remains uncertain. Here, we explored the regulatory role of AMPK in the GLUT3-dependent uptake of glucose by placental trophoblasts and the viability of the cells. In this study, the level of glycolysis in normal and GDM-complicated placentas was assessed by LC-MS/MS. The trophoblast hyperglycemia model was induced by the incubation of HTR8/SVneo cells with a high glucose concentration. GDM animal models were generated with db/ + mice and C57BL/6J mice fed a high-fat diet, and AMPK was manipulated by the oral administration of metformin. The uptake of glucose by trophoblasts was assessed using 2-NBDG or 2-deoxy-D-[3H] glucose. The results showed that GDM is associated with impaired glycolysis, AMPK activity, GLUT3 expression in the plasma membrane (PM) and cell survival in the placenta. Hyperglycemia induced similar changes in trophoblasts, and these changes were rescued by AMPK activation. Both hyperglycemic db/ + and high-fat diet-induced GDM mice exhibited a compromised AMPK–GLUT3 axis and suppressed cell viability in the placenta as well as excessive fetal growth, and all of these effects were partially alleviated by metformin. Taken together, our findings support the notion that AMPK activation upregulates trophoblast glucose uptake by stimulating GLUT3 translocation, which is beneficial for viability. Thus, the modulation of glucose metabolism in trophoblasts by targeting AMPK might ameliorate the adverse intrauterine environment caused by GDM.

scholarly journals Emodin, a Naturally Occurring Anthraquinone Derivative, Ameliorates Dyslipidemia by Activating AMP-Activated Protein Kinase in High-Fat-Diet-Fed Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Thing-Fong Tzeng ◽  
Hung-Jen Lu ◽  
Shorong-Shii Liou ◽  
Chia Ju Chang ◽  
I-Min Liu
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
High Fat Diet ◽  
Fatty Acid Synthase ◽  
Risk Index ◽  
Atherogenic Index ◽  
High Fat ◽  
Mitochondrial Fatty Acid ◽  
Regulated Gene Expression ◽  
Amp Activated Protein Kinase

The aim of this study was to investigate the antiobesity and antihyperlipidaemic effects of emodin on high-fat diet (HFD)-induced obese rats, and on the regulation of the expression of the genes involved in lipid metabolism to elucidate the mechanisms. After being fed HFD for two weeks, Wistar rats were dosed orally with emodin (40 and 80 mg kg−1) or pioglitazone (20 mg kg−1), once daily for eight weeks. Emodin (80 mg kg−1per day) displayed similar characteristics to pioglitazone (20 mg kg−1per day) in reducing body weight gain, plasma lipid levels as well as coronary artery risk index and atherogenic index of HFD-fed rats. Emodin also caused dose related reductions in the hepatic triglyceride and cholesterol contents and lowered hepatic lipid droplets accumulation in HFD-fed rats. Emodin and pioglitazone enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase, up-regulated gene expression of carnitine palmitoyl transferase 1, and down-regulated sterol regulatory element binding protein 1 and fatty acid synthase protein levels in hepatocytes of HFD-fed rats. Our findings suggest emodin could attenuate lipid accumulation by decreasing lipogenesis and increasing mitochondrial fatty acidβ-oxidation mediated by activation of the AMPK signaling pathway.

scholarly journals Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1403 ◽  
Author(s):  
Sandip Mukherjee ◽  
Jake Haubner ◽  
Anutosh Chakraborty
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Energy Expenditure ◽  
Fatty Liver ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
High Fat ◽  
Inositol Pyrophosphate ◽  
Potential Target ◽  
Genetic Deletion

In mammals, a family of three inositol hexakisphosphate kinases (IP6Ks) synthesizes the inositol pyrophosphate 5-IP7 from IP6. Genetic deletion of Ip6k1 protects mice from high fat diet induced obesity, insulin resistance and fatty liver. IP6K1 generated 5-IP7 promotes insulin secretion from pancreatic β-cells, whereas it reduces insulin signaling in metabolic tissues by inhibiting the protein kinase Akt. Thus, IP6K1 promotes high fat diet induced hyperinsulinemia and insulin resistance in mice while its deletion has the opposite effects. IP6K1 also promotes fat accumulation in the adipose tissue by inhibiting the protein kinase AMPK mediated energy expenditure. Genetic deletion of Ip6k3 protects mice from age induced fat accumulation and insulin resistance. Accordingly, the pan IP6K inhibitor TNP [N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates obesity, insulin resistance and fatty liver in diet induced obese mice by improving Akt and AMPK mediated insulin sensitivity and energy expenditure. TNP also protects mice from bone loss, myocardial infarction and ischemia reperfusion injury. Thus, the IP6K pathway is a potential target in obesity and other metabolic diseases. Here, we summarize the studies that established IP6Ks as a potential target in metabolic diseases. Further studies will reveal whether inhibition of this pathway has similar pleiotropic benefits on metabolic health of humans.

scholarly journals Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

2014 ◽  
Vol 35 (1) ◽  
pp. 26-40 ◽  
Author(s):  
Ahmed Lawan ◽  
Lei Zhang ◽  
Florian Gatzke ◽  
Kisuk Min ◽  
Michael J. Jurczak ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Energy Homeostasis ◽  
Mitogen Activated Protein Kinase ◽  
Hepatic Insulin Resistance ◽  
Fibroblast Growth Factor 21 ◽  
High Fat ◽  
Mitogen Activated Protein ◽  
Fat Feeding

The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis.

scholarly journals Amyotrophy Induced by a High-Fat Diet Is Closely Related to Inflammation and Protein Degradation Determined by Quantitative Phosphoproteomic Analysis in Skeletal Muscle of C57BL/6 J Mice

2019 ◽  
Vol 150 (2) ◽  
pp. 294-302
Author(s):  
Ya-nan Sun ◽  
Jia-qiang Huang ◽  
Zhong-zhou Chen ◽  
Min Du ◽  
Fa-zheng Ren ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Protein Degradation ◽  
Muscle Atrophy ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Serum Glucose ◽  
High Fat

ABSTRACT Background Ectopic fat accumulation in skeletal muscle results in dysfunction and atrophy, but the underlying molecular mechanisms remain unclear. Objective The aim of this study was to investigate the effects of a high-fat diet (HFD) in modulating the structure and energy metabolism of skeletal muscle and the underlying mechanisms in mice. Methods Four-week-old male C57BL/6 J mice (n = 30) were allowed 1 wk for acclimatization. After 6 mice with low body weight were removed from the study, the remaining 24 mice were fed with a normal-fat diet (NFD; 10% energy from fat, n = 12) or an HFD (60% energy from fat, n = 12) for 24 wk. At the end of the experiment, serum glucose and lipid concentrations were measured, and skeletal muscle was collected for atrophy analysis, inflammation measurements, and phosphoproteomic analysis. Results Compared with the NFD, the HFD increased (P < 0.05) body weight (35.8%), serum glucose (64.5%), and lipid (27.3%) concentrations, along with elevated (P < 0.05) expressions of the atrophy-related proteins muscle ring finger 1 (MURF1; 27.6%) and muscle atrophy F-box (MAFBX; 44.5%) in skeletal muscle. Phosphoproteomic analysis illustrated 64 proteins with differential degrees of phosphorylation between the HFD and NFD groups. These proteins were mainly involved in modulating cytoskeleton [adenylyl cyclase-associated protein 2 (CAP2) and actin-α skeletal muscle (ACTA1)], inflammation [NF-κB-activating protein (NKAP) and serine/threonine-protein kinase RIO3 (RIOK3)], glucose metabolism [Cdc42-interacting protein 4 (TRIP10); protein kinase C, and casein kinase II substrate protein 3 (PACSIN3)], and protein degradation [heat shock protein 90 kDa (HSP90AA1)]. The HFD-induced inhibitions of the insulin signaling pathway and activations of inflammation in skeletal muscle were verified by Western blot analysis. Conclusions Quantitative phosphoproteomic analysis in C57BL/6 J mice fed an NFD or HFD for 24 wk revealed that the phosphorylation of inflammatory proteins and proteins associated with glucose metabolism at specific serine residues may play critical roles in the regulation of skeletal muscle atrophy induced by an HFD. This work provides information regarding underlying molecular mechanisms for inflammation-induced dysfunction and atrophy in skeletal muscle.

scholarly journals Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

2020 ◽  
Vol 295 (31) ◽  
pp. 10842-10856 ◽  
Author(s):  
Wen Liu ◽  
Ye Yin ◽  
Meijing Wang ◽  
Ting Fan ◽  
Yuyu Zhu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Low Grade ◽  
High Fat ◽  
Caspase 1

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

Sign in / Sign up

Export Citation Format

Share Document