Silencing of hypothalamic FGF11 prevents diet-induced obesity.

Fibroblast growth factor 11 (FGF11) is a member of the intracellular fibroblast growth factor family. Here, we report the central role of FGF11 in the regulation of metabolism. Lentiviral injection of Fgf11 shRNA into the arcuate nucleus of the mouse hypothalamus decreased weight gain and fat mass, increased brown adipose tissue thermogenesis, and improved glucose and insulin intolerances under high-fat diet conditions. Fgf11 was expressed in the NPY-expressing neurons, and Fgf11 knockdown considerably decreased Npy expression and projection, leading to increased expression of tyrosine hydroxylase in the paraventricular nucleus. Mechanistically, FGF11 regulated Npy gene expression through the glycogen synthase kinase 3-cAMP response element-binding protein pathway. Our study defines the physiological significance of hypothalamic FGF11 in the regulation of metabolism in response to overnutrition such as high-fat diet.

Palmitate reduces starvation-induced ER stress by inhibiting ER-phagy in hypothalamic cells.

Palmitate is a saturated fatty acid that is well known to induce endoplasmic reticulum (ER) stress and autophagy. A high-fat diet increases the palmitate level in the hypothalamus, the main region of the brain regulating energy metabolism. Interestingly, hypothalamic palmitate level is also increased under starvation, urging the study to distinguish the effects of elevated hypothalamic palmitate level under different nutrient conditions. Herein, we show that ER-phagy (ER-targeted selective autophagy) is required for progress of ER stress and that palmitate decreases ER stress by inhibiting ER-phagy in hypothalamic cells under starvation. Palmitate inhibited starvation-induced ER-phagy by increasing the level of B-cell lymphoma 2 (Bcl-2) protein, which inhibits autophagy initiation. These findings suggest that, unlike the induction of ER stress under nutrient-rich conditions, palmitate protects hypothalamic cells from starvation-induced stress by inhibiting ER-phagy.

Tanycytic TSPO inhibition induces lipophagy to regulate lipid metabolism and improve energy balance.

Hypothalamic glial cells named tanycytes, which line the 3rd ventricle (3V), are components of the hypothalamic network that regulates a diverse array of metabolic functions for energy homeostasis. Herein, we report that TSPO (translocator protein), an outer mitochondrial protein, is highly enriched in tanycytes and regulates homeostatic responses to nutrient excess as a potential target for an effective intervention in obesity. Administration of a TSPO ligand, PK11195, into the 3V, and tanycyte-specific deletion of Tspo reduced food intake and elevated energy expenditure, leading to negative energy balance in a high-fat diet challenge. Ablation of tanycytic Tspo elicited AMPK-dependent lipophagy, breaking down lipid droplets into free fatty acids, thereby elevating ATP in a lipid stimulus. Our findings suggest that tanycytic TSPO affects systemic energy balance through macroautophagy/autophagy-regulated lipid metabolism, and highlight the physiological significance of TSPO in hypothalamic lipid sensing and bioenergetics in response to overnutrition. ABBREVIATIONS: 3V: 3rd ventricle; ACAC: acetyl-Coenzyme A carboxylase; AGRP: agouti related neuropeptide; AIF1/IBA1: allograft inflammatory factor 1; AMPK: AMP-activated protein kinase; ARC: arcuate nucleus; Atg: autophagy related; Bafilo: bafilomycin A1; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2, beta; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CNS: central nervous system; COX4I1: cytochrome c oxidase subunit 4I1; FFA: free fatty acid; GFAP: glial fibrillary acidic protein; HFD: high-fat diet; ICV: intracerebroventricular; LAMP2: lysosomal-associated membrane protein 2; LD: lipid droplet; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MBH: mediobasal hypothalamus; ME: median eminence; MEF: mouse embryonic fibroblast; NCD: normal chow diet; NEFM/NFM: neurofilament medium; NPY: neuropeptide Y; OL: oleic acid; POMC: pro-opiomelanocortin-alpha; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; Rax: retina and anterior neural fold homeobox; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; RER: respiratory exchange ratio; siRNA: small interfering RNA; SQSTM1: sequestosome 1; TG: triglyceride; TSPO: translocator protein; ULK1: unc-51 like kinase 1; VCO2: carbon dioxide production; VMH: ventromedial hypothalamus; VO2: oxygen consumption.

Hypothalamic AMP-activated Protein Kinase as a Regulator of Food Intake and Energy Balance.

The maintenance of appetite at proper levels, depending on the energy status, is important; otherwise abnormal appetite may cause a series of disorders, such as anorexia, hyperphagia, obesity, and its complications (diabetes mellitus, hypertension, cardiovascular disease, and fatty liver disease). Hypothalamic AMPactivated protein kinase (AMPK) integrates diverse hormonal and nutritional signals to regulate food intake and energy metabolism. Recent evidence suggests that different hormones, nutrients and synthetic chemicals can modulate AMPK activity in the hypothalamus, thereby regulating food intake and body weight, through neuropeptide expressions. In order to elucidate the mechanisms that control hypothalamic AMPK activity, a variety of studies have focused on finding upstream and downstream modulators of hypothalamic AMPK for the regulation of food intake and energy balance. This review highlights the current evidence for understanding how hypothalamic AMPK regulates food intake and energy balance, and will help in the development of effective interventions for the treatment of food intake-related disorders. In the future, it is hoped that new pharmaceutical developments targeting hypothalamic AMPK, in combination with careful clinical trials, will lead to improved and effective therapeutic strategies for complications caused by abnormal appetite and energy balance.

Hypothalamic AMPK-induced autophagy increases food intake by regulating NPY and POMC expression.

Hypothalamic AMP-activated protein kinase (AMPK) plays important roles in the regulation of food intake by altering the expression of orexigenic or anorexigenic neuropeptides. However, little is known about the mechanisms of this regulation. Here, we report that hypothalamic AMPK modulates the expression of NPY (neuropeptide Y), an orexigenic neuropeptide, and POMC (pro-opiomelanocortin-α), an anorexigenic neuropeptide, by regulating autophagic activity in vitro and in vivo. In hypothalamic cell lines subjected to low glucose availability such as 2-deoxy-d-glucose (2DG)-induced glucoprivation or glucose deprivation, autophagy was induced via the activation of AMPK, which regulates ULK1 and MTOR complex 1 followed by increased Npy and decreased Pomc expression. Pharmacological or genetic inhibition of autophagy diminished the effect of AMPK on neuropeptide expression in hypothalamic cell lines. Moreover, AMPK knockdown in the arcuate nucleus of the hypothalamus decreased autophagic activity and changed Npy and Pomc expression, leading to a reduction in food intake and body weight. AMPK knockdown abolished the orexigenic effects of intraperitoneal 2DG injection by decreasing autophagy and changing Npy and Pomc expression in mice fed a high-fat diet. We suggest that the induction of autophagy is a possible mechanism of AMPK-mediated regulation of neuropeptide expression and control of feeding in response to low glucose availability.

Wnt3a upregulates brain-derived insulin by increasing NeuroD1 via Wnt/ß-catenin signaling in the hypothalamus.

BACKGROUND: Insulin plays diverse roles in the brain. Although insulin produced by pancreatic ß-cells that crosses the blood-brain barrier is a major source of brain insulin, recent studies suggest that insulin is also produced locally within the brain. However, the mechanisms underlying the production of brain-derived insulin (BDI) are not yet known. RESULTS: Here, we examined the effect of Wnt3a on BDI production in a hypothalamic cell line and hypothalamic tissue. In N39 hypothalamic cells, Wnt3a treatment significantly increased the expression of the Ins2 gene, which encodes the insulin isoform predominant in the mouse brain, by activating Wnt/ß-catenin signaling. The concentration of insulin was higher in culture medium of Wnt3a-treated cells than in that of untreated cells. Interestingly, neurogenic differentiation 1 (NeuroD1), a target of Wnt/ß-catenin signaling and one of transcription factors for insulin, was also induced by Wnt3a treatment in a time- and dose-dependent manner. In addition, the treatment of BIO, a GSK3 inhibitor, also increased the expression of Ins2 and NeuroD1. Knockdown of NeuroD1 by lentiviral shRNAs reduced the basal expression of Ins2 and suppressed Wnt3a-induced Ins2 expression. To confirm the Wnt3a-induced increase in Ins2 expression in vivo, Wnt3a was injected into the hypothalamus of mice. Wnt3a increased the expression of NeuroD1 and Ins2 in the hypothalamus in a manner similar to that observed in vitro. CONCLUSION: Taken together, these results suggest that BDI production is regulated by the Wnt/ß-catenin/NeuroD1 pathway in the hypothalamus. Our findings will help to unravel the regulation of BDI production in the hypothalamus.

Extracts from Dendropanax morbifera Leaves Have Modulatory Effects on Neuroinflammation in Microglia.

Dendropanax morbifera (D. morbifera), a species endemic to Korea, is largely distributed throughout the southern part of the country. Its leaves, stems, roots, and seeds have been used as a form of alternative medicine for various diseases and neurological disorders including paralysis, stroke, and migraine. However, the molecular mechanisms that underlie the remedial effects of D. morbifera remain largely unknown. In this paper, extracts from D. morbifera leaves were prepared using ethyl acetate as a solvent (abbreviated as DMLE). The modulatory effects of DMLE on neuroinflammation were studied in a lipopolysaccharide (LPS)-stimulated BV2 murine microglial cell line. Production of pro-inflammatory cytokines, activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-[Formula: see text]B), and different M1/M2 activation states of microglia were examined. DMLE treatment suppressed the production of pro-inflammatory cytokines including tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]), interleukin-6 (IL-6), and nitric oxide (NO) in LPS-stimulated BV2 cells. DMLE treatment also attenuated the activation of MAPKs and NF-[Formula: see text]B. In a novel discovery, we found that DMLE up-regulated the marker genes representing an alternative, anti-inflammatory M2 polarization, while suppressing the expression of the classical, pro-inflammatory M1 activation state genes. Here, we uncovered the cellular mechanisms underlying the beneficial effects of D. morbifera against neuroinflammation using BV2 microglia cells. These results strongly suggest that DMLE was able to counter the effects of LPS on BV2 cells via control of microglia polarization states. Additionally, study results indicated that DMLE may have therapeutic potential as a neuroinflammation-suppressing treatment for neurodegenerative diseases.

D-chiro-inositol glycan reduces food intake by regulating hypothalamic neuropeptide expression via AKT-FoxO1 pathway.

The regulation of food intake is important for body energy homeostasis. Hypothalamic insulin signaling decreases food intake by upregulating the expression of anorexigenic neuropeptides and downregulating the expression of orexigenic neuropeptides. INS-2, a Mn(2+) chelate of 4-O-(2-amino-2-deoxy-ß-D-galactopyranosyl)-3-O-methyl-D-chiro-inositol, acts as an insulin mimetic and sensitizer. We found that intracerebroventricular injection of INS-2 decreased body weight and food intake in mice. In hypothalamic neuronal cell lines, INS-2 downregulated the expression of neuropeptide Y (NPY), an orexigenic neuropeptide, but upregulated the expression of proopiomelanocortin (POMC), an anorexigenic neuropeptide, via modulation of the AKT-forkhead box-containing protein-O1 (FoxO1) pathway. Pretreatment of these cells with INS-2 enhanced the action of insulin on downstream signaling, leading to a further decrease in NPY expression and increase in POMC expression. These data indicate that INS-2 reduces food intake by regulating the expression of the hypothalamic neuropeptide genes through the AKT-FoxO1 pathway downstream of insulin.

Effects of high-dose atorvastatin pretreatment in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a cardiac magnetic resonance study.

It is uncertain that atorvastatin pretreatment can reduce myocardial damage in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). The aim of this study was to investigate the effects of atorvastatin pretreatment on infarct size measured by contrast-enhanced magnetic resonance imaging (CE-MRI) in STEMI patients. Patients undergoing primary PCI for STEMI within 12 hr after symptom onset were randomized to an atorvastatin group (n=30, 80 mg before PCI and for 5 days after PCI) or a control group (n=37, 10 mg daily after PCI). The primary end point was infarct size evaluated as the volume of delayed hyperenhancement by CE-MRI within 14 days after the index event. The median infarct size was 19% (IQR 11.1%-31.4%) in the atorvastatin group vs. 16.3% (7.2%-27.2%) in the control group (P=0.27). The myocardial salvage index (37.1% [26.9%-58.7%] vs. 46.9% [39.9-52.4], P=0.46) and area of microvascular obstruction (1.1% [0%-2.0%] vs. 0.7% [0%-1.8%], P=0.37) did not differ significantly between the groups. Frequency of the hemorrhagic and transmural infarctions was not significantly different in the 2 groups. Pretreatment with a high-dose atorvastatin followed by further treatment for 5 days in STEMI patients undergoing primary PCI failed to reduce the extent of myocardial damage or improve myocardial salvage.

Increasing fatty acid oxidation remodels the hypothalamic neurometabolome to mitigate stress and inflammation.

Modification of hypothalamic fatty acid (FA) metabolism can improve energy homeostasis and prevent hyperphagia and excessive weight gain in diet-induced obesity (DIO) from a diet high in saturated fatty acids. We have shown previously that C75, a stimulator of carnitine palmitoyl transferase-1 (CPT-1) and fatty acid oxidation (FAOx), exerts at least some of its hypophagic effects via neuronal mechanisms in the hypothalamus. In the present work, we characterized the effects of C75 and another anorexigenic compound, the glycerol-3-phosphate acyltransferase (GPAT) inhibitor FSG67, on FA metabolism, metabolomics profiles, and metabolic stress responses in cultured hypothalamic neurons and hypothalamic neuronal cell lines during lipid excess with palmitate. Both compounds enhanced palmitate oxidation, increased ATP, and inactivated AMP-activated protein kinase (AMPK) in hypothalamic neurons in vitro. Lipidomics and untargeted metabolomics revealed that enhanced catabolism of FA decreased palmitate availability and prevented the production of fatty acylglycerols, ceramides, and cholesterol esters, lipids that are associated with lipotoxicity-provoked metabolic stress. This improved metabolic signature was accompanied by increased levels of reactive oxygen species (ROS), and yet favorable changes in oxidative stress, overt ER stress, and inflammation. We propose that enhancing FAOx in hypothalamic neurons exposed to excess lipids promotes metabolic remodeling that reduces local inflammatory and cell stress responses. This shift would restore mitochondrial function such that increased FAOx can produce hypothalamic neuronal ATP and lead to decreased food intake and body weight to improve systemic metabolism.

Therapeutic phytogenic compounds for obesity and diabetes.

Natural compounds have been used to develop drugs for many decades. Vast diversities and minimum side effects make natural compounds a good source for drug development. However, the composition and concentrations of natural compounds can vary. Despite this inconsistency, half of the Food and Drug Administration (FDA)-approved pharmaceuticals are natural compounds or their derivatives. Therefore, it is essential to continuously investigate natural compounds as sources of new pharmaceuticals. This review provides comprehensive information and analysis on natural compounds from plants (phytogenic compounds) that may serve as anti-obesity and/or anti-diabetes therapeutics. Our growing understanding and further exploration of the mechanisms of action of the phytogenic compounds may afford opportunities for development of therapeutic interventions in metabolic diseases.

Epigallocatechin-3-gallate ameliorates both obesity and autoinflammatory arthritis aggravated by obesity by altering the balance among CD4+ T-cell subsets.

Epigallocatechin-3-gallate (EGCG) is the most biologically active catechin in green tea. EGCG has been shown to have therapeutic effects in autoinflammatory diseases and obesity. Obesity is currently regarded-partly-as an inflammatory condition because of the inflammatory cytokines and higher Th1 cell differentiation detected in obese animal models and human cohort studies. In this work, the effects of EGCG on diet-induced obesity (DIO) mice and obese collagen-induced arthritis (CIA) mice were investigated. EGCG reduced the body weight and fat infiltration in liver tissue while improving serum lipid profiles in DIO mice. EGCG also induced a higher Treg/Th17 cell ratio in CD4(+) T-cell differentiation by decreasing the ratio of STAT3/STAT5 expression in DIO mice. EGCG was also effective in obese CIA mice. Reducing Th17 cells and increasing regulatory T (Treg) cells by affecting the STAT protein ratio were important effects of EGCG that might result in improved arthritic scores and levels of several inflammatory indicators. Thus, EGCG has an anti-inflammatory effect by suppressing STAT3 proteins and Th17-cell differentiation. EGCG thus shows promise for treating autoimmune conditions related to STAT3 or Th17 cells, such as metabolic syndrome, inflammatory arthritis, and some neoplastic diseases.

Supplementation of pyruvate prevents palmitate-induced impairment of glucose uptake in C2 myotubes.

Elevated fatty acid levels have been thought to contribute to insulin resistance. Repression of the glucose transporter 4 (GLUT4) gene as well as impaired GLUT4 translocation may be a mediator for fatty acid-induced insulin resistance. This study was initiated to determine whether palmitate treatment repressed GLUT4 expression, whether glucose/fatty acid metabolism influenced palmitate-induced GLUT4 gene repression (PIGR), and whether attempts to prevent PIGR restored palmitate-induced impairment of glucose uptake (PIIGU) in C2 myotubes. Not only stimulators of fatty acid oxidation, such as bezafibrate, AICAR, and TOFA, but also TCA cycle substrates, such as pyruvate, leucine/glutamine, and α-ketoisocaproate/monomethyl succinate, significantly prevented PIGR. In particular, supplementing with pyruvate through methyl pyruvate resulted in nearly complete prevention of PIIGU, whereas palmitate treatment reduced the intracellular pyruvate level. These results suggest that pyruvate depletion plays a critical role in PIGR and PIIGU; thus, pyruvate supplementation may help prevent obesity-induced insulin resistance in muscle cells.

[Esophageal sinus formation due to cyanoacrylate injection for esophageal variceal ligation-induced ulcer bleeding in a cirrhotic patient].

Intravariceal injection of N-butyl-2-cyanoacrylate is widely used for the hemostasis of bleeding gastric varices, but not routinely for esophageal variceal hemorrhage because of various complications such as pyrexia, bacteremia, deep ulceration, and pulmonary embolization. We report a rare case of esophageal sinus formation after cyanoacrylate obliteration therapy for uncontrolled bleeding from post-endoscopic variceal ligation (EVL) ulcer. A 50-year-old man with alcoholic liver cirrhosis presented with hematemesis. Emergent esophagogastroscopy revealed bleeding from large esophageal varices with ruptured erosion, and bleeding was initially controlled by EVL, but rebleeding from the post-EVL ulcer occurred at 17th day later. Although we tried again EVL and the injections of 5% ethanolamine oleate at paraesophageal varices, bleeding was not controlled. Therefore, we administered 1 mL cyanoacrylate diluted with lipiodol and bleeding was controlled. Three months after the endoscopic therapy, follow-up endoscopy showed medium to large-sized esophageal varices and sinus at lower esophagus. Barium esophagography revealed an outpouching in esophageal wall and endoscopic ultrasonography demonstrated an ostium with sinus. It is noteworthy that esophageal sinus can be developed as a rare late complication of endoscopic cyanoacrylate obliteration therapy.

Intake of brown rice lees reduces waist circumference and improves metabolic parameters in type 2 diabetes.

Intake of whole grains has been associated with lower risks of type 2 diabetes and cardiovascular disease. Brown rice is unrefined whole grain and is produced by removing the outermost layers containing the germ and bran, which are rich in nutrients including dietary fiber, vitamins, minerals, and other unmeasured dietary constituents. The lees of brown rice (LB) are by-products of its fermentation in the process of manufacturing takju, a Korean turbid rice wine. In this study, we hypothesized that intake of LB would reduce waist circumference, a strong risk factor for cardiovascular disease in type 2 diabetic patients. A randomized, double-blind, placebo-controlled study was scheduled for 12 weeks. Thirty subjects were randomly assigned to receive a supplement prepared from the LB or from a mixed-grain dietary product (MG). Body weight, waist circumference, body composition, lipid profiles, and other laboratory parameters were measured. The LB group showed greater reduction in waist circumference (LB: 87.9 ± 8.8 to 85.1 ± 9.0 cm; MG: 86.9 ± 8.8 to 86.0 ± 9.3 cm; P = .032). In addition, the consumption of LB resulted in a significantly greater decrease in the level of aspartate transaminase (LB: 25.4 ± 8.5 to 21.0 ± 5.1 IU/mL; MG: 22.5 ± 5.3 to 22.4 ± 5.7 IU/mL; P = .044) and alanine transaminase (LB: 28.6 ± 11.3 to 21.9 ± 8.2 IU/mL; MG: 24.4 ± 7.5 to 24.5 ± 9.9 IU/mL; P = .038). Consumption of the LB was associated with a decreased waist circumference in type 2 diabetic patients. Further study is required to evaluate the metabolic effect of the extract of the LB in type 2 diabetes.

Pinoresinol-4,4'-di-O-beta-D-glucoside from Valeriana officinalis root stimulates calcium mobilization and chemotactic migration of mouse embryo fibroblasts.

Lignans are major constituents of plant extracts and have important pharmacological effects on mammalian cells. Here we showed that pinoresinol-4,4'-di-O-beta-D-glucoside (PDG) from Valeriana officinalis induced calcium mobilization and cell migration through the activation of lysophosphatidic acid (LPA) receptor subtypes. Stimulation of mouse embryo fibroblast (MEF) cells with 10 microM PDG resulted in strong stimulation of MEF cell migration and the EC(50) was about 2 microM. Pretreatment with pertussis toxin (PTX), an inhibitor of G(i) protein, completely blocked PDG-induced cell migration demonstrating that PDG evokes MEF cell migration through the activation of the G(i)-coupled receptor. Furthermore, pretreatment of MEF cells with Ki16425 (10 microM), which is a selective antagonist for LPA(1) and LPA(3) receptors, completely blocked PDG-induced cell migration. Likewise, PDG strongly induced calcium mobilization, which was also blocked by Ki16425 in a dose-dependent manner. Prior occupation of the LPA receptor with LPA itself completely blocked PDG-induced calcium mobilization. Finally, PDG-induced MEF cell migration was attenuated by pretreatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor such as LY294002. Cells lacking downstream mediator of PI3K such as Akt1 and Akt2 (DKO cells) showed loss of PDG-induced migration. Re-expression of Akt1 (but not Akt2) completely restored PDG-induced DKO cell migration. Given these results, we conclude that PDG is a strong inducer of cell migration. We suggest that the pharmacological action of PDG may occur through the activation of an LPA receptor whereby activation of PI3K/Akt signaling pathway mediates PDG-induced MEF cell migration.

Lithospermi radix extract inhibits histamine release and production of inflammatory cytokine in mast cells.

Lithospermi radix (LR, Borraginaceae, the root of Lithospermum erythrorhizon Siebold. et Zuccarinii) is used in herbal medicine to treat such conditions as eczema, skin burns and frostbite. This study investigates the effects of LR on the anti-allergy mechanism. LR inhibited the release of histamine from rat peritoneal mast cells by compound 48/80 in a dose-dependent manner. LR orally administered at 6.59 mg/100 g also inhibited the anti-DNP IgE-induced passive cutaneous anaphylaxis reaction. LR inhibited the PMA plus A23187-induced increase in IL-6, IL-8, and TNF-alpha expression in HMC-1 cells. In addition, LR also inhibited nuclear factor-kappa B (NF-kappaB) activation and I kappaB-alpha degradation. These results show that LR had an inhibitory effect on the atopic allergic reaction. Furthermore, the in vivo and in vitro anti-allergic effect of LR suggests possible therapeutic applications of this agent for inflammatory allergic diseases.

Fatty acid synthase gene regulation in primary hypothalamic neurons.

Understanding the mechanisms that regulate feeding is critical to the development of therapeutic interventions for obesity. Many studies indicate that enzymes within fatty acid metabolic pathways may serve as targets for pharmacological tools to treat this epidemic. We, and others have previously demonstrated that C75, a fatty acid synthase (FAS) inhibitor, induced significant anorexia and weight loss by both central and peripheral mechanisms. Because the hypothalamus is important in the regulation of homeostatic processes for feeding control, we have identified pathways that alter the gene expression of FAS in primary hypothalamic neuronal cultures. Insulin, glucose and AICAR (an activator of AMP-activated protein kinase) affected changes in hypothalamic FAS mRNA, which may be regulated via the SREBP1c dependent or independent pathway.

Protective effects of Cuscutae semen against dimethylnitrosamine-induced acute liver injury in Sprague-Dawley rats.

We investigated the protective effect of Cuscutae semen (CS) on acute liver injury induced by dimethylnitrosamine (DMN) in Sprague-Dawley rats. CS is an important traditional herbal medicine widely used as a tonic and aphrodisiac to nourish the liver and kidney and to treat impotence and seminal emission. Rats were given a single intraperitoneal injection of DMN (40 mg/kg), and were then treated with CS daily by oral gavage for 4 d. Immunohistochemical studies for alpha-smooth muscle actin (alpha-SMA) and proliferating cell nuclear antigen (PCNA) were performed, along with hydroxyproline and biological assay. Liver injury caused by DMN-injection was significantly inhibited in the CS-treated group compared to the silymarin-treated group. The results of blood biological assay were significantly protected by CS in serum total protein (T-protein), T-bilirubin (T-bili), D-bilirubin (D-bili), GOT, GPT, and ALP. The hydroxyproline content and amount of active alpha-SMA and PCNA were significantly decreased in the CS-treated group than in the silymarin-treated group. CS exhibited an in vivo hepatoprotective effect and anti-fibrogenic effects against DMN-induced acute liver injury and inhibited the formation of hydroxyproline, which suggests that CS may be useful in preventing fibrogenesis after liver injury.

C75 alters central and peripheral gene expression to reduce food intake and increase energy expenditure.

C75, a synthetic inhibitor of fatty acid synthase (FAS), causes anorexia and profound weight loss in lean and genetically obese mice. C75 also acts as a stimulator of carnitine palmitoyltransferase-1 to induce fatty acid oxidation. To approximate human obesity, we used a 2-wk C75 treatment model for diet-induced obese (DIO) mice to investigate the central and peripheral effects of C75 on gene expression. C75 treatment decreased food intake, increased energy expenditure, and reduced body weight more effectively in DIO than in lean mice. Analysis of the gene expression changes in hypothalamus demonstrated that the reduced food intake in C75-treated DIO mice might be mediated by inhibition of orexigenic neuropeptide expression and induction of anorexigenic neuropeptide expression. Gene expression changes in peripheral tissues indicated that C75 increased energy expenditure by the induction of genes involved in fatty acid oxidation. C75 also inhibited the expression of genes in peripheral tissues responsible for fatty acid synthesis and accumulation. The patterns of the changes in central and peripheral gene expression that occur with C75 treatment provide mechanisms to explain the reduced food intake and increased energy expenditure observed with C75.