Cymbopogon schoenanthus (L) extract ameliorates high fat diet-induced obesity and dyslipidemia via reducing expression of lipogenic and thermogenic proteins.

Globally, obesity has become one of the major health problems. This study was conducted to evaluate the anti-obesity potential of Cymbopogon schoenanthus methanolic extract (CS) in rats. Fifty male Wistar rats of six to eight weeks old, 100-120 g body weight (BW) were randomly assigned into 5 groups (n = 10): The control group was fed a basal diet. CS-group was supplied with basal diet and orally given CS (200 mg/kg BW) for 12 weeks. HFD-group was fed a high-fat diet (HFD) for 18 weeks. HFD + CS-group was fed on HFD and CS HFD then CS-group was fed HFD for 12 weeks then shifted to basal diet and CS for another 6 weeks. Phytochemical analysis of CS indicated the presence of various terpenes and flavonoid compounds. Among the compounds characterized are quercetin, apigenin, luteolin, orientin, eudesmene, cymbopogonol, caffeic acid, coumaric acid, and linolenic acid. Supplementation of HFD significantly increased the body weight, levels of serum triacylglycerol, total cholesterol, very low-density lipoprotein, low-density lipo-protein (HDL), glucose, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. In addition, HFD up-regulated the protein expression of uncoupling protein (UCP)-1 in both brown and white adipose tissue; and the expression of hepatic mRNA of sterol regulatory element-binding protein (SREBP)-1c and SREBP-2. However, it decreased the serum level of HDL, and protein expression level of UCP-1 in both brown and white adipose tissue. Treatment of HFD-fed animals with CS extract either concurrently (HFD + CS-group), or after obesity induction (HFD then CS-group) significantly reversed all HFD-induced alterations in body weight; food intake; serum biochemical profile (including hyperglycemia, dyslipidemia); and tissue gene expressions. These results indicate that CS methanolic extract ameliorated HFD-induced obesity, serum biochemical, hepatic, and adipose tissue gene expression alterations. CS extract accomplished these effects mostly through its various identified bioactive compounds which have been proven to have anti-obesity and anti-diabetic activities.

Screening of Platycodonis Radix Fractions for Antiobesity Activities and Elucidation of Its Molecular Mechanisms in High-Fat Diet-Fed C57BL/6 Mice.

Obesity is a threat to public health and effective new medications are required. Platycodonis Radix (PR) is a traditional medicinal/dietary plant with activities against obesity. Using mice given a diet rich in fat, the antiobesity components of PR were identified and their molecular mechanisms were clarified further in this investigation. Initially, the impacts of PR fractions on liver histology and biochemical markers were assessed. Subsequently, the degrees of lipogenic and lipolytic gene and protein expressions were determined. Oral administration of PR polysaccharides (PG) (0.80 g/kg body weight) improved liver function (alanine aminotransferase and aspartate aminotransferase) and its antioxidant activities (total superoxide dismutase, glutathione peroxidase, and malondialdehyde), as well as alleviated blood lipid (total cholesterol, total triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol) values, inflammatory systemic (TNF-α and IL-1ß), and histological abnormalities within the liver. Furthermore, PG administration downregulated the expression for lipogenic genes (ACC and FAS) and upregulated the expression for the lipolytic gene (PPARα, LPL, CPT1, and HSL). Importantly, PG raised AMPK phosphorylation and decreased SREBP-1c protein synthesis. Thus, it is possible that PG stimulates the AMPK-LPL/HSL path (lipolytic route) plus the AMPK-ACC/PPARα-CPT1 path (associated to ß-oxidation of fatty acids), while inhibiting the AMPK/(SREBP-1c)-ACC/FAS path (lipogenic route). In summary, PG has the ability to regulate lipid metabolism, and it may be useful to pharmacologically activate AMPK with PG to prevent and cure obesity.

Differential Influence of Soluble Dietary Fibres on Intestinal and Hepatic Carbohydrate Response.

Refined foods are commonly depleted in certain bioactive components that are abundant in 'natural' (plant) foods. Identification and addition of these 'missing' bioactives in the diet is, therefore, necessary to counteract the deleterious impact of convenience food. In this study, multiomics approaches were employed to assess the addition of the popular supplementary soluble dietary fibers inulin and psyllium, both in isolation and in combination with a refined animal feed. A 16S rRNA sequencing and 1H NMR metabolomic investigation revealed that, whilst inulin mediated an increase in Bifidobacteria, psyllium elicited a broader microbial shift, with Parasutterella and Akkermansia being increased and Enterorhabdus and Odoribacter decreased. Interestingly, the combination diet benefited from both inulin and psyllium related microbial changes. Psyllium mediated microbial changes correlated with a reduction of glucose (R -0.67, -0.73, respectively, p < 0.05) and type 2 diabetes associated metabolites: 3-methyl-2-oxovaleric acid (R -0.72, -0.78, respectively, p < 0.05), and citrulline (R -0.77, -0.71, respectively, p < 0.05). This was in line with intestinal and hepatic carbohydrate response (e.g., Slc2a2, Slc2a5, Khk and Fbp1) and hepatic lipogenesis (e.g., Srebf1 and Fasn), which were significantly reduced under psyllium addition. Although established in the liver, the intestinal response associated with psyllium was absent in the combination diet, placing greater significance upon the established microbial, and subsequent metabolomic, shift. Our results therefore highlight the heterogeneity that exists between distinct dietary fibers in the context of carbohydrate uptake and metabolism, and supports psyllium containing combination diets, for their ability to negate the impact of a refined diet.

Raphani Semen (Raphanus sativus L.) Ameliorates Alcoholic Fatty Liver Disease by Regulating De Novo Lipogenesis.

In this study, we investigated the pharmacological effect of a water extract of Raphani Semen (RSWE) on alcoholic fatty liver disease (AFLD) using ethanol-induced AFLD mice (the NIAAA model) and palmitic acid (PA)-induced steatosis HepG2 cells. An RSWE supplement improved serum and hepatic triglyceride (TG) levels of AFLD mice, as well as their liver histological structure. To explore the molecular action of RSWE in the improvement of AFLD, we investigated the effect of RSWE on four major pathways for lipid homeostasis in the liver: free fatty acid transport, lipogenesis, lipolysis, and ß-oxidation. Importantly, RSWE decreased the mRNA expression of de novo lipogenesis-related genes, such as Srebf1, Cebpa, Pparg, and Lpin1, as well as the protein levels of these factors, in the liver of AFLD mice. That these actions of RSWE affect lipogenesis was confirmed using PA-induced steatosis HepG2 cells. Overall, our findings suggest that RSWE has the potential for improvement of AFLD by inhibiting de novo lipogenesis.

Pharmacological Approaches to Attenuate Inflammation and Obesity with Natural Products Formulations by Regulating the Associated Promoting Molecular Signaling Pathways.

Obesity is a public health problem characterized by increased body weight due to abnormal adipose tissue expansion. Bioactive compound consumption from the diet or intake of dietary supplements is one of the possible ways to control obesity. Natural products with adipogenesis-regulating potential act as obesity treatments. We evaluated the synergistic antiangiogenesis, antiadipogenic and antilipogenic efficacy of standardized rebaudioside A, sativoside, and theasaponin E1 formulations (RASE1) in vitro in human umbilical vein endothelial cells (HUVECs), 3T3-L1 preadipocytes respectively, and in vivo using a high-fat and carbohydrate diet-induced obesity mouse model. Orlistat was used as a positive control, while untreated cells and animals were normal controls (NCs). Adipose tissue, liver, and blood were analyzed after dissection. Extracted stevia compounds and green tea seed saponin E1 exhibited pronounced antiobesity effects when combined. RASE1 inhibited HUVEC proliferation and tube formation by suppressing VEGFR2, NF-κB, PIK3, and-catenin beta-1 expression levels. RASE1 inhibited 3T3-L1 adipocyte differentiation and lipid accumulation by downregulating adipogenesis- and lipogenesis-promoting genes. RASE1 oral administration reduced mouse body and body fat pad weight and blood cholesterol, TG, ALT, AST, glucose, insulin, and adipokine levels. RASE1 suppressed adipogenic and lipid metabolism gene expression in mouse adipose and liver tissues and enhanced AMP-activated protein kinase levels in liver and adipose tissues and in serum adiponectin. RASE1 suppressed the NF-κB pathway and proinflammatory cytokines IL-10, IL-6, and TNF-α levels in mice which involve inflammation and progression of obesity. The overall results indicate RASE1 is a potential therapeutic formulation and functional food for treating or preventing obesity and inflammation.

Red Quinoa Bran Extract Prevented Alcoholic Fatty Liver Disease via Increasing Antioxidative System and Repressing Fatty Acid Synthesis Factors in Mice Fed Alcohol Liquid Diet.

Alcohol is metabolized in liver. Chronic alcohol abuse results in alcohol-induced fatty liver and liver injury. Red quinoa (Chenopodium formosanum) was a traditional staple food for Taiwanese aborigines. Red quinoa bran (RQB) included strong anti-oxidative and anti-inflammatory polyphenolic compounds, but it was usually regarded as the agricultural waste. Therefore, this study is to investigate the effect of water and ethanol extraction products of RQB on the prevention of liquid alcoholic diet-induced acute liver injury in mice. The mice were given whole grain powder of red quinoa (RQ-P), RQB ethanol extract (RQB-E), RQB water extract (RQB-W), and rutin orally for 6 weeks, respectively. The results indicated that RQB-E, RQB-W, and rutin decreased alcoholic diet-induced activities of aspartate aminotransferase and alanine aminotransferase, and the levels of serum triglyceride, total cholesterol, and hepatic triglyceride. Hematoxylin and eosin staining of liver tissues showed that RQB-E and RQB-W reduced lipid droplet accumulation and liver injury. However, ethanol extraction process can gain high rutin and antioxidative agents contents from red quinoa, that showed strong effects in preventing alcoholic fatty liver disease and liver injury via increasing superoxide dismutase/catalase antioxidative system and repressing the expressions of fatty acid synthesis enzyme acetyl-CoA carboxylase.

Chondroitin Sulfate Alleviates Diabetic Osteoporosis and Repairs Bone Microstructure via Anti-Oxidation, Anti-Inflammation, and Regulating Bone Metabolism.

Diabetic osteoporosis (DOP) belongs to secondary osteoporosis caused by diabetes; it has the characteristics of high morbidity and high disability. In the present study, we constructed a type 1 diabetic rat model and administered chondroitin sulfate (200 mg/kg) for 10 weeks to observe the preventive effect of chondroitin sulfate on the bone loss of diabetic rats. The results showed that chondroitin sulfate can reduce blood glucose and relieve symptoms of diabetic rats; in addition, it can significantly increase the bone mineral density, improve bone microstructure, and reduce bone marrow adipocyte number in diabetic rats; after 10 weeks of chondroitin sulfate administration, the SOD activity level was upregulated, as well as CAT levels, indicating that chondroitin sulfate can alleviate oxidative stress in diabetic rats. Chondroitin sulfate was also found to reduce the level of serum inflammatory cytokines (TNF-α, IL-1, IL-6, and MCP-1) and alleviate the inflammation in diabetic rats; bone metabolism marker detection results showed that chondroitin sulfate can reduce bone turnover in diabetic rats (decreased RANKL, CTX-1, ALP, and TRACP 5b levels were observed after 10 weeks of chondroitin sulfate administration). At the same time, the bone OPG and RUNX 2 expression levels were higher after chondroitin sulfate treatment, the bone RANKL expression was lowered, and the OPG/RANKL ratio was upregulated. All of the above indicated that chondroitin sulfate could prevent STZ-induced DOP and repair bone microstructure; the main mechanism was through anti-oxidation, anti-inflammatory, and regulating bone metabolism. Chondroitin sulfate could be used to develop anti-DOP functional foods and diet interventions for diabetes.

Grape pomace reduces the severity of non-alcoholic hepatic steatosis and the development of steatohepatitis by improving insulin sensitivity and reducing ectopic fat deposition in mice.

While non-alcoholic fatty liver disease (NAFLD) represents the common cause of chronic liver disease, specific therapies are currently unavailable. The wine industry produces millions of tons of residue (pomace), which contains high levels of bioactive phytochemicals. The aim of this study was to clarify the potential benefits of grape pomace for the treatment of NAFLD at different levels of severity, and to clarify the mechanism of action. C57Bl/6 mice were given high fat diet (HFD) or western diet (WD) as models of obesity and hepatic steatosis or steatohepatitis, respectively, with or without pomace supplementation (50-250 mg/day). Pomace inhibited food intake, and reduced serum leptin and body weight gain. Ectopic fat deposition was reduced, while white adipose tissue mass was preserved. In addition, pomace improved glucose tolerance and insulin sensitivity, prevented the development of adipose tissue inflammation, and reduced hepatic steatosis. Higher expression of genes involved in fatty acids transport and oxidation was observed in adipose tissue, while lipogenic genes were attenuated in the liver of pomace-treated mice. In WD-fed mice, pomace reduced the severity of hepatic steatosis and inflammation and improved blood lipid profile, but was ineffective in reversing hepatic damage of advanced NASH. In conclusion, pomace improved insulin sensitivity and reduced ectopic fat deposition, leading to a healthier metabolic profile. Pomace may hold the potential as a supplement with beneficial health outcomes for the prevention and treatment of hepatic steatosis and other obesity-related pathologies.

Molecular mechanism of DLBS3733, a bioactive fraction of Lagerstroemia speciosa (L.) Pers., on ameliorating hepatic lipid accumulation in HepG2 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Lagerstroemia speciosa (L.) Pers., commonly known as banaba and locally known as bungur, is widely used in Indonesia and other countries as a folk remedy for various chronic diseases such as diabetes mellitus and hypertension. L. speciosa (L.) Pers. has been used and evaluated on conditions associated to liver diseases by altering cholesterol absorption, lipid metabolism, as well as the related gene expressions. AIM OF THE STUDY: The aim of this study is to evaluate the effect of DLBS3733, a standardized bioactive fraction of Lagerstroemia speciosa (L.) Pers. leaves, on ameliorating hepatic steatosis induced by oleic acid, and elucidate its mechanism of action to ameliorate lipid accumulation in HepG2 cells. MATERIALS AND METHODS: Effects of DLBS3733 on expression of genes and proteins associated with lipid metabolism were evaluated in HepG2 cells in this study. Genes associated with lipid metabolism were evaluated using PCR, while the protein levels were revealed using western blot and ELISA. Cellular lipid accumulations and triglyceride (TG) synthesis were measured using ELISA, and antioxidant assay was conducted using DPPH assay. RESULTS: DLBS3733 significantly reduced lipid accumulation and TG synthesis by 51% and 32% (p < 0.01), respectively, through the significant increment of adiponectin expression by 58% (p < 0.01). Subsequently, adiponectin enhanced PPARα expression and AMPK phosphorylation which further regulate the downstream signaling pathway of lipogenesis and lipolysis. Moreover, 2.5 µg/mL DLBS3733 was found to significantly downregulate the expression of HMGCR, ACC and SREBP by 66%, 61% and 36%, respectively (p < 0.01), as well as significantly upregulate CPT-1 by 300% at the protein level (P < 0.05). DLBS3733 was also found to possess high antioxidant activity, where the highest concentration exhibited DPPH inhibition activity by up to 93% (P < 0.01). CONCLUSIONS: We propose that DLBS3733 may provide a prevention on hepatic steatosis through its activity as anti-lipogenesis, anti-cholesterologenesis and pro-lipolysis in HepG2 cells. This is the first report that revealed the molecular mechanism of L. speciosa (L.) Pers. as a potential treatment of hepatic steatosis-related diseases.

Polyphenols from blue honeysuckle (Lonicera caerulea var. edulis) berry inhibit lipid accumulation in adipocytes by suppressing lipogenesis.

ETHNOPHARMACOLOGICAL RELEVANCE: Blue honeysuckle (Lonicera caerulea var. edulis) berry has been used in folk medicine for the treatment of bacterial infections, gastrointestinal disorders, and metabolic diseases. There is evidence to support its pharmacological effects in improving diabetes, fatty liver, and obesity. AIM OF STUDY: To investigate the effect of blue honeysuckle berry extract (BHBE) on lipid accumulation in adipocytes and the underlying mechanism. MATERIALS AND METHODS: High-performance liquid chromatography (HPLC) coupled with mass spectrometry (MS) was applied to analyze the polyphenolic compounds in BHBE. 3T3-L1 cells were used to induce into adipocytes. Oil Red O staining combined with triglyceride (TG) content determination were carried out to evaluate intracellular lipid accumulation. Western blot was used to determine the expression of lipogenic enzymes and transcription factors. Real-time PCR was used to determine the expression of lipolytic enzymes and adipocyte markers. RESULTS: The primary polyphenols in BHBE are flavonoids (mainly flavonols and anthocyanins). BHBE dose-dependently inhibited lipid accumulation in adipocytes by reducing the expression of fatty acid synthase (FAS) and increasing the phosphorylation level of acetyl-CoA carboxylase (ACC). Moreover, BHBE was found to promote the phosphorylation of AMP-activated protein kinase (AMPK) and further reduce the expression of lipogenic transcription factors (PPARγ, C/EBPα, and SREBP-1c), while the selective AMPK inhibitor attenuated the suppressive effect of BHBE on lipogenesis. In addition, BHBE increased the expression of beige adipocyte markers (Cd137 and Tmem26) and uncoupling protein 1 (UCP1) without affecting the expression of brown adipocyte markers (Ebf3 and Eva1). CONCLUSION: BHBE inhibits lipid accumulation in adipocytes by suppressing lipogenesis via AMPK activation as well as by promoting beiging of adipocytes, which supports the anti-obesity potential of blue honeysuckle berry.

Repurposing New Use for Old Drug Chloroquine against Metabolic Syndrome: A Review on Animal and Human Evidence.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are traditional anti-malarial drugs that have been repurposed for new therapeutic uses in many diseases due to their simple usage and cost-effectiveness. The pleiotropic effects of CQ and HCQ in regulating blood pressure, glucose homeostasis, lipid, and carbohydrate metabolism have been previously described in vivo and in humans, thus suggesting their role in metabolic syndrome (MetS) prevention. The anti-hyperglycaemic, anti-hyperlipidaemic, cardioprotective, anti-hypertensive, and anti-obesity effects of CQ and HCQ might be elicited through reduction of inflammatory response and oxidative stress, improvement of endothelial function, activation of insulin signalling pathway, inhibition of lipogenesis and autophagy, as well as regulation of adipokines and apoptosis. In conclusion, the current state of knowledge supported the repurposing of CQ and HCQ usage in the management of MetS.

Peripheral Insulin Regulates a Broad Network of Gene Expression in Hypothalamus, Hippocampus, and Nucleus Accumbens.

The brain is now recognized as an insulin-sensitive tissue; however, the role of changing insulin concentrations in the peripheral circulation in gene expression in the brain is largely unknown. Here, we performed a hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice for 3 h. We show that, in comparison with results in saline-infused controls, increases in peripheral insulin within the physiological range regulate expression of a broad network of genes in the brain. Insulin regulates distinct pathways in the hypothalamus (HTM), hippocampus, and nucleus accumbens. Insulin shows its most robust effect in the HTM and regulates multiple genes involved in neurotransmission, including upregulating expression of multiple subunits of GABA-A receptors, Na+ and K+ channels, and SNARE proteins; differentially modulating glutamate receptors; and suppressing multiple neuropeptides. Insulin also strongly modulates metabolic genes in the HTM, suppressing genes in the glycolysis and pentose phosphate pathways, while increasing expression of genes regulating pyruvate dehydrogenase and long-chain fatty acyl-CoA and cholesterol biosynthesis, thereby rerouting of carbon substrates from glucose metabolism to lipid metabolism required for the biogenesis of membranes for neuronal and glial function and synaptic remodeling. Furthermore, based on the transcriptional signatures, these changes in gene expression involve neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells. Thus, peripheral insulin acutely and potently regulates expression of a broad network of genes involved in neurotransmission and brain metabolism. Dysregulation of these pathways could have dramatic effects in normal physiology and diabetes.

Sodium Butyrate Supplementation Inhibits Hepatic Steatosis by Stimulating Liver Kinase B1 and Insulin-Induced Gene.

BACKGROUND AND AIMS: Butyric acid is an intestinal microbiota-produced short-chain fatty acid, which exerts salutary effects on alleviating nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism of butyrate on regulating hepatic lipid metabolism is largely unexplored. METHODS: A mouse model of NAFLD was induced with high-fat diet feeding, and sodium butyrate (NaB) intervention was initiated at the eighth week and lasted for 8 weeks. Hepatic steatosis was evaluated and metabolic pathways concerning lipid homeostasis were analyzed. RESULTS: Here, we report that administration of NaB by gavage once daily for 8 weeks causes an augmentation of insulin-induced gene (Insig) activity and inhibition of lipogenic gene in mice fed with high-fat diet. Mechanistically, NaB is sufficient to enhance the interaction between Insig and its upstream kinase AMP-activated protein kinase (AMPK). The stimulatory effects of NaB on Insig-1 activity are abolished in AMPKα1/α2 double knockout (AMPK-/-) mouse primary hepatocytes. Moreover, AMPK activation by NaB is mediated by LKB1, as evidenced by the observations showing NaB-mediated induction of phosphorylation of AMPK, and its downstream target acetyl-CoA carboxylase is diminished in LKB1-/- mouse embryonic fibroblasts. CONCLUSIONS: These studies indicate that NaB serves as a negative regulator of hepatic lipogenesis in NAFLD and that NaB attenuates hepatic steatosis and improves lipid profile and liver function largely through the activation of LKB1-AMPK-Insig signaling pathway. Therefore, NaB has therapeutic potential for treating NAFLD and related metabolic diseases.

Annona muricata leaf extract attenuates hepatic lipogenesis and adipogenesis.

Annona muricata (graviola) is a medicinal plant that can be used to alleviate chronic human diseases by providing antioxidants and inducing immunomodulation. In this study, we found that treatment of AML12 hepatocytes with steam (SGE) and ethanol (EGE) extracts of graviola leaf downregulated the expression of fatty acid (FA) oxidation genes, including ACOX1, CPT1, and PPARα, with no change in the expression of FA synthesis genes. However, whereas EGE inhibited the differentiation and lipid accumulation of 3T3-L1 adipocytes and downregulated FA synthesis genes, no similar changes were observed in response to treatment with SGE. In an in vivo experiment using mice fed a high-fat diet (HFD), body weight was reduced in response to treatment with EGE, which also dose-dependently alleviated liver hepatocyte ballooning induced by the consumption of a HFD. However, genes involved in FA oxidation and the secretion of very low density lipoprotein (VLDL) were downregulated. We also found that the size of adipocytes was reduced in response to EGE treatment, and that there was a downregulated expression of genes involved in adipogenesis and FA synthesis. Furthermore, we detected increases in the levels of cholesterol in the plasma, whereas ALT activity was reduced. Collectively, these results indicates that EGE inhibits lipid influx into the liver and adipogenesis in adipose tissues. These bioactive properties of EGE indicate its potential as a natural ingredient that can be used to prevent obesity.

Safflower seed oil improves steroidogenesis and spermatogenesis in rats with type II diabetes mellitus by modulating the genes expression involved in steroidogenesis, inflammation and oxidative stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes mellitus (DM), as a multiorgan syndrome, is an endocrine and metabolic disorder that is associated with male reproductive system dysfunction and infertility. Safflower (Carthamus tinctorius L.) as an herbal remedy improves DM and infertility-related disorders. The anti-hypercholesterolemic, anti-inflammatory, and antioxidative properties of this herb have been well documented, but its role in testosterone production, male reproductive system and zinc homeostasis has not been fully illustrated. AIM OF THE STUDY: This study aimed to investigate the preventive and therapeutic properties of different doses of safflower seed oil against reproductive damage caused by type II DM by investigating zinc element homeostasis, inflammation and oxidative damage in testis tissue and their relationship with testosterone production and sperm parameters. MATERIALS AND METHODS: Eighty adult male Sprague-Dawley rats were randomly divided into eight groups and treated daily for 12 and 24 weeks in protective and therapeutic studies, respectively. Type II DM was induced by a High Fat Diet (HFD) in normoglycemic rats for three months. At the end of each study, serum level of glucose, testosterone, gonadotropins, TNF-α, insulin, and leptin were measured. Moreover, antioxidant enzymes activity, lipid peroxidation, zinc and testosterone along with the expression of Nrf-2, NF-κB, TNF-α, StAR, P450scc, and 17ßHSD3 genes in the testis were detected. RESULTS: After the intervention, the activity of antioxidant enzymes and the level of testosterone and gonadotropins significantly decreased in the rats with DM in comparison to the others. However, lipid peroxidation and serum level of insulin, leptin and TNF-α increased and the testicular level of zinc significantly changed in the rats with DM compared to the control groups (p < 0.05). The gene expression of NF-κB and TNF-α were also significantly increased and the gene expression of Nrf2, StAR, P450scc and 17ßHSD3 were decreased in the testis of diabetic rats (p < 0.05). The results showed that pretreatment and treatment with safflower seed oil could improve these parameters in diabetic rats compared with untreated diabetic rats (p < 0.05). CONCLUSION: HFD could impair the production of testosterone and sperm, and reduce gonadotropin by increasing the serum level of leptin and inducing insulin resistance, oxidative stress and inflammation. However, safflower oil in a dose-dependent manner could improve testosterone level and sperm parameters by improving the level of leptin, zinc and insulin resistance, and the genes expression involved in testosterone synthesis, inflammation and oxidative stress.

Fat regulatory mechanisms of pine nut oil based on protein interaction network analysis.

BACKGROUND: Pine nut oil (PNO), a standardized and well-defined extract of Pinus koraiensis (Korean pine), has beneficial effects on wound healing, inflammatory diseases, and cancer. However, the explanation for the mechanism by which PNO reduces body fat remains uncertain. We performed a protein-protein interaction network (PPIN) analysis to explore the genes associated with pinolenic acid using the MEDILINE database from PubChem and PubMed. It was concluded through the PPIN analysis that PNO was involved in a neutral lipid biosynthetic process. PURPOSE: This study evaluated the effects of PNO predicted by the network analysis of fat accumulation in chronic obesity mouse models established by feeding a high fat diet (HFD) to C57BL/6J mice and explored potential mechanisms. METHODS: HFD mice were fed only HFD or HFD with PNO at 822 and 1644 mg/kg. After an oral administration of 7 weeks, several body weight and body fat-related parameters were examined, including the following: adipose weight, adipocyte size, serum lipid profiles, adipocyte expression of PPAR-γ, sterol regulatory element binding protein (SREBP)-1c, lipoprotein lipase (LPL) and leptin. RESULTS: We showed that oral administration of PNO to HFD mice reduces body fat weight, fat in tissue, white adipose tissue weight, and adipocyte size. The serum cholesterol was improved in the HFD mice treated with PNO. Additionally, PNO has significantly attenuated the HFD-induced changes in the adipose tissue expression of PPAR-γ, SREBP-1c, LPL, and leptin. CONCLUSIONS: The findings from this study based on the PPIN analysis suggest that PNO has potential as drug to reduce body fat through fat regulatory mechanisms by PPAR-γ and SREBP-1c.

Carnosic Acid and Carnosol Activate AMPK, Suppress Expressions of Gluconeogenic and Lipogenic Genes, and Inhibit Proliferation of HepG2 Cells.

Carnosic acid (CA), carnosol (CL) and rosmarinic acid (RA), components of the herb rosemary, reportedly exert favorable metabolic actions. This study showed that both CA and CL, but not RA, induce significant phosphorylation of AMP-dependent kinase (AMPK) and its downstream acetyl-CoA carboxylase 1 (ACC1) in HepG2 hepatoma cells. Glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1), rate-limiting enzymes of hepatic gluconeogenesis, are upregulated by forskolin stimulation, and this upregulation was suppressed when incubated with CA or CL. Similarly, a forskolin-induced increase in CRE transcriptional activity involved in G6PC and PCK1 regulations was also stymied when incubated with CA or CL. In addition, mRNA levels of ACC1, fatty acid synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP-1c) were significantly reduced when incubated with CA or CL. Finally, it was shown that CA and CL suppressed cell proliferation and reduced cell viability, possibly as a result of AMPK activation. These findings raise the possibility that CA and CL exert a protective effect against diabetes and fatty liver disease, as well as subsequent cases of hepatoma.

Protective Effect of Cudrania tricuspidata Extract against High-Fat Diet Induced Nonalcoholic Fatty Liver Disease through Nrf-2/HO-1 Pathway.

Nonalcoholic fatty liver disease is the most common chronic disease affecting a wide range of the world's population and associated with obesity-induced metabolic syndrome. It is possibly emerging as a leading cause of life-threatening liver diseases for which a drug with a specific therapeutic target has not been developed yet. Previously, there have been reports on the benefits of Cudrania tricuspidata (CT) for treating obesity and diabetes via regulation of metabolic processes, such as lipogenesis, lipolysis, and inflammation. In this study, we investigated the ameliorative effect of orally administered 0.25% and 0.5% (w/w) CT mixed with high-fat diet (HFD) to C57BL/6J mice for 7 weeks. It was found that body weight, fat mass, hepatic mass, serum glucose level, and liver cholesterol levels were significantly reduced after CT treatment. In CT-treated HFD-fed mice, the mRNA expression levels of hepatic lipogenic and inflammatory cytokine-related genes were markedly reduced, whereas the expression level of epididymal lipogenic genes was increased. The mRNA expression level of beta-oxidation and Nrf-2/HO-1 genes significantly increased in CT-treated obese mice livers. We propose that CT alleviates hepatic steatosis by reducing oxidative stress and inflammation.

Discovery of a Vitamin D Receptor-Silent Vitamin D Derivative That Impairs Sterol Regulatory Element-Binding Protein In Vivo.

Vitamin D3 metabolites inhibit the expression of lipogenic genes by impairing sterol regulatory element-binding protein (SREBP), a master transcription factor of lipogenesis, independent of their canonical activity through a vitamin D receptor (VDR). Herein, we designed and synthesized a series of vitamin D derivatives to search for a drug-like small molecule that suppresses the SREBP-induced lipogenesis without affecting the VDR-controlled calcium homeostasis in vivo. Evaluation of the derivatives in cultured cells and mice led to the discovery of VDR-silent SREBP inhibitors and to the development of KK-052 (50), the first vitamin D-based SREBP inhibitor that has been demonstrated to mitigate hepatic lipid accumulation without calcemic action in mice. KK-052 maintained the ability of 25-hydroxyvitamin D3 to induce the degradation of SREBP but lacked in the VDR-mediated activity. KK-052 serves as a valuable compound for interrogating SREBP/SCAP in vivo and may represent an unprecedented translational opportunity of synthetic vitamin D analogues.