Red Pepper (Capsicum annuum L.) Seed Extract Improves Glycemic Control by Inhibiting Hepatic Gluconeogenesis via Phosphorylation of FOXO1 and AMPK in Obese Diabetic db/db Mice.

Obesity is a notable risk factor for developing type 2 diabetes, augmenting the concern of obese diabetes (ObD). Anti-obesity and antioxidant effects of red pepper seeds extract (RPSE) have increased our expectations that RPSE would also improve the pathological phenotypes of obese diabetes. Therefore, we hypothesized that RPSE would have an anti-diabetic effect in ObD mice. Animals were assigned either as follows: (1) db/+, (2) db/db control, (3) RPSE (200 mg/kg bw), or (4) a comparative control (metformin 150 mg/kg bw). RPSE was orally administered daily for 8 weeks. As a result, RPSE supplementation improved diabetic phenotypes, including fasting glucose, hemoglobin (HbA1c), and insulin levels. Pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), and triglycerides were reduced in RPSE-treated mice. RPSE supplementation also diminished the rate-limiting enzymes of gluconeogenesis, including glucose 6-phosphatas (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), in the liver. RPSE supplementation increased the phosphorylation of forkhead box protein O1 (FOXO1) and AMP-activated protein kinase (AMPK), which underlined the mechanism of the anti-diabetic effects of RPSE. Taken together, RPSE has the potential to improve glycemic control by repressing hepatic gluconeogenesis via the phosphorylation of FOXO1 and AMPK in ObD mice.

Maternal selenium status is profoundly involved in metabolic fetal programming by modulating insulin resistance, oxidative balance and energy homeostasis.

PURPOSE: High and low levels of selenium (Se) have been related to metabolic disorders in dams and in their offspring. Their relationship to oxidative balance and to AMP-activated protein kinase (AMPK) is some of the mechanisms proposed. The aim of this study is to acquire information about how Se is involved in metabolic programming. METHODS: Three experimental groups of dam rats were used: control (Se: 0.1 ppm), Se supplemented (Se: 0.5 ppm) and Se deficient (Se: 0.01 ppm). At the end of lactation, the pups' metabolic profile, oxidative balance, Se levels, selenoproteins and IRS-1 hepatic expression, as well as hepatic AMPK activation were measured. RESULTS: The experimental groups present deep changes in Se homeostasis, selenoproteins and IRS-1 hepatic expression, oxidative balance, AMPK activation ratio and insulin levels. They do, however, have different metabolic profiles. CONCLUSIONS: High- and low-Se diets are linked to insulin resistance, yet the mechanisms involved are completely opposite.

The Chinese medicine Chai Hu Li Zhong Tang protects against non-alcoholic fatty liver disease by activating AMPKα.

An effective treatment for non-alcoholic fatty liver disease (NAFLD) is urgently needed. In the present study, we investigated whether the Chinese medicine Chai Hu Li Zhong Tang (CHLZT) could protect against the development of NAFLD. Rats in an animal model of NAFLD were treated with CHLZT, and their serum levels of cholesterol (TC), triglycerides (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were detected with an automatic biochemical analyzer. A cellular model of NAFLD was also established by culturing HepG2 cells in a medium that contained a long chain fat emulsion. Those cells were treated with CHLZT that contained serum from rats. After treatment, the levels of adenylate-activated protein kinase (AMPK) α (AMPKα), p-AMPKα, acetyl coenzyme A carboxylase (ACC) α (ACCα), pACCα, PPARγ, and SREBP-2 were detected. The AMPK agonist, acadesine (AICAR), was used as a positive control compound. Our results showed that CHLZT or AICAR significantly decreased the serum levels of TG, TC, LDL-C, AST, ALT, and insulin in NAFLD rats, and significantly increased their serum HDL-C levels. Treatments with CHLZT or AICAR significantly decreased the numbers of lipid droplets in NAFLD liver tissues and HepG2 cells. CHLZT and AICAR increased the levels of p-AMPKα and PPARγ in the NAFLD liver tissues and HepG2 cells, but decreased the levels of ACC-α, p-ACC-α, SREBP-2, and 3-hydroxyl-3-methylglutaryl-coenzyme A reductase (HMGR). CHLZT protects against NAFLD by activating AMPKα, and also by inhibiting ACC activity, down-regulating SREBP2 and HMGR, and up-regulating PPAR-γ. Our results suggest that CHLZT might be useful for treating NAFLD in the clinic.

Aged garlic extract suppresses inflammation in apolipoprotein E-knockout mice.

SCOPE: Chronic inflammation plays a major role in the formation and progression of atherosclerotic plaques. To clarify the mode of action of aged garlic extract (AGE) to retard atherosclerosis, we investigated whether AGE suppresses the inflammation in apolipoprotein E-knockout (ApoE-KO) mice. METHODS AND RESULTS: ApoE-KO mice were fed standard diet with or without 3% AGE for 12 wk. AGE feeding inhibited the progression of atherosclerotic lesion by 27% and reduced the level of C-reactive protein (CRP) and thromboxane B2 (TXB2 ), a marker of platelet activation, in serum by 39 and 33%, respectively, compared to ApoE-KO mice without AGE treatment. AGE treatment also decreased the level of tumor necrosis factor alpha (TNF-α), a major stimulus inducing CRP production, in the liver by 35%. AGE decreased the level of interleukin-1 receptor-associated kinase 4 (IRAK4) by 60% and almost doubled the level of phospho-AMP-activated protein kinase (p-AMPK) in the liver. CONCLUSION: The anti-atherosclerotic effect of AGE involves the suppression of inflammation by reducing the serum level of CRP and TXB2 , and the protein level of TNF-α and IRAK4, and increasing AMPK activity in liver.

Tang-Nai-Kang alleviates pre-diabetes and metabolic disorders and induces a gene expression switch toward fatty acid oxidation in SHR.Cg-Leprcp/NDmcr rats.

Increased energy intake and reduced physical activity can lead to obesity, diabetes and metabolic syndrome. Transcriptional modulation of metabolic networks has become a focus of current drug discovery research into the prevention and treatment of metabolic disorders associated with energy surplus and obesity. Tang-Nai-Kang (TNK), a mixture of five herbal plant extracts, has been shown to improve abnormal glucose metabolism in patients with pre-diabetes. Here, we report the metabolic phenotype of SHR.Cg-Leprcp/NDmcr (SHR/cp) rats treated with TNK. Pre-diabetic SHR/cp rats were randomly divided into control, TNK low-dose (1.67 g/kg) and TNK high-dose (3.24 g/kg) groups. After high-dose treatment for 2 weeks, the serum triglycerides and free fatty acids in SHR/cp rats were markedly reduced compared to controls. After 3 weeks of administration, the high dose of TNK significantly reduced the body weight and fat mass of SHR/cp rats without affecting food consumption. Serum fasting glucose and insulin levels in the TNK-treated groups decreased after 6 weeks of treatment. Furthermore, TNK-treated rats exhibited obvious improvements in glucose intolerance and insulin resistance. The improved glucose metabolism may be caused by the substantial reduction in serum lipids and body weight observed in SHR/cp rats starting at 3 weeks of TNK treatment. The mRNA expression of NAD+-dependent deacetylase sirtuin 1 (SIRT1) and genes related to fatty acid oxidation was markedly up-regulated in the muscle, liver and adipose tissue after TNK treatment. Furthermore, TNK promoted the deacetylation of two well-established SIRT1 targets, PPARγ coactivator 1α (PGC1α) and forkhead transcription factor 1 (FOXO1), and induced the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in different tissues. These observations suggested that TNK may be an alternative treatment for pre-diabetes and metabolic syndrome by inducing a gene expression switch toward fat oxidation through the activation of SIRT1 and AMPK signaling.

The contributions of oxidative stress, oxidised lipoproteins and AMPK towards exercise-associated PPARγ signalling within human monocytic cells.

Peroxisome proliferator-activated receptor gamma (PPARγ) is known to be activated via exercise-associated transient increases in oxidative stress. However, the precise mechanism(s) triggering PPARγ activation in monocytes during/following exercise remain to be confirmed. Here, two cohorts of five healthy male individuals undertook exercise bouts (cycling; 70% VO2max; 45 min) in the presence/absence of dietary antioxidant supplementation (vitamins C (1000 mg/day) and E (400IU/day) for four weeks before exercise); monocytic 5' adenosine monophosphate-activated protein kinase (AMPK)/PPARγ co-activator-1alpha (PGC-1α)/PPARγ signalling was investigated in samples obtained before exercise and up to 24 h after exercise, while THP-1 cells were cultured as an in vitro monocyte model. In THP-1 cells, AMPKα1 was phosphorylated within 1h of menadione (15 µM)-triggered increases in [reactive oxygen species (ROS)]cyto, an effect which was followed by upregulation of PPARγ and several of its target genes (PGC-1α, liver X receptor alpha [LXRα] and ATP-binding cassette subfamily A, member 1 [ABCA1]; 24-72 h), with these effects being blunted by co-administration of vitamin C (62.5 µM). Conversely, treatment with oxidised low-density lipoprotein (oxLDL) (1 µg/mL; 24-72 h), but not non-oxidised LDL, upregulated the above PPARγ-regulated genes without affecting AMPKα1 phosphorylation. In vivo, dietary antioxidant supplementation (which is known to prevent exercise-triggered increases in oxLDL levels) blunted exercise-associated upregulation of the above PPARγ-regulated genes, but had no effect on exercise-associated transient [ROS]cyto increases, or on AMPK phosphorylation. These data suggest that exercise-associated PPARγ signalling effects appear, at least in monocytes, to be mediated by increased generation of PPARγ ligands via oxidation of lipoproteins (following exercise-associated transient increases in oxidative stress), rather than via [ROS]cyto-mediated AMPK activation. These findings may be of clinical relevance, as PPARγ activation in monocytes is associated with beneficial effects related to type-2 diabetes and its cardiovascular complications.