dorsomorphin and Obesity

Some adipokines, such as adiponectin (ADPN), other than being implicated in the central regulation of feeding behavior, may influence gastric motor responses, which are a source of peripheral signals that also influence food intake. The present study aims to elucidate the signaling pathways through which ADPN exerts its actions in the mouse gastric fundus. To this purpose, we used a multidisciplinary approach. The mechanical results showed that ADPN caused a decay of the strip basal tension, which was abolished by the nitric oxide (NO) synthesis inhibitor, L-N

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Female; Gastric Fundus; Gastric Mucosa; Mice; Mice, Inbred C57BL; Muscle, Smooth; Obesity; Pyrazoles; Pyrimidines; Receptors, Adiponectin; Signal Transduction

Drug discovery and development is commonly schematized as a "pipeline," and, although appreciated by drug developers to be a useful oversimplification, this cartology may perpetuate inaccurate notions of straightforwardness and is of minimal utility for process engineering to improve efficiency. To create a more granular schema, a group of drug developers, researchers, patient advocates, and regulators developed a crowdsourced atlas of the steps involved in translating basic discoveries into health interventions, annotated with the steps that are particularly prone to difficulty or failure. This Drug Discovery, Development, and Deployment Map (4DM), provides a network view of the process, which will be useful for communication and education to those new to the field, orientation and navigation of individual projects, and prioritization of technology development and re-engineering endeavors to improve efficiency and effectiveness. The 4DM is freely available for utilization, modification, and further development by stakeholders across the translational ecosystem.

Topics: Biomedical Technology; Clinical Trials as Topic; Communication; Drug Development; Drug Discovery; Humans; Intersectoral Collaboration; Learning; Myositis Ossificans; National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division; Neuropeptide Y; Obesity; Polycystic Kidney, Autosomal Dominant; Pyrazoles; Pyrimidines; Research Design; Translational Research, Biomedical; United States; United States Food and Drug Administration

Obesity has become a severe public health problem worldwide. Crocin, a natural product, has been reported to have a number of pharmacological activities, including anti-inflammatory, anti-cancer, neuroprotective, antihypertensive, and cardioprotective action. The aims of the current study were to identify the beneficial effects of crocin on obesity, adipocyte differentiation, and lipolysis and to evaluate the possible role of AMPK. Results indicated that crocin significantly increased AMPK phosphorylation in differentiated adipocytes in vitro and in adipose tissue in db/db mice. Crocin reduced lipid accumulation in differentiated adipocytes. In addition, crocin inhibited the expression of mRNA of important adipogenesis-related regulators, including CEBPα, CEBPβ, PPARγ, aP2, FAS, and CD36, in both differentiated adipocytes and adipose tissue in db/db mice. Crocin increased the expression of mRNA of key lipolysis-associated factors, including PPARα, LPL, and HSL, in both differentiated adipocytes and adipose tissue in db/db mice. In adipocytes, knockdown of AMPK significantly suppressed the crocin-induced inhibition of adipocyte differentiation and increase in lipolysis. BML-275 is an inhibitor of AMPK. In adipose tissue in db/db mice, BML-275 suppressed crocin-induced inhibition of fat formation and alleviation of a metabolic disorder. The current results suggest that crocin alleviates obesity in db/db mice and that it inhibits adipocyte differentiation in preadipocytes. Crocin inhibits adipogenesis and promotes lipolysis via activation of AMPK. Therefore, crocin may have promise as an option for the clinical treatment for obesity and associated metabolic diseases.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adipose Tissue; AMP-Activated Protein Kinases; Animals; Antioxidants; Blood Glucose; Carotenoids; Diabetes Complications; Drug Interactions; Lipid Metabolism; Lipolysis; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Obesity; Phosphorylation; Pyrazoles; Pyrimidines

Fat accumulation in obese individuals worsens the clinical outcomes of cardiovascular disease (CVD). Paradoxically, increased circulating adipocytokines secreted from visceral fat may confer cardioprotective effects. Visfatin, a novel adipocytokine, has anti-diabetic, anti-tumor, and pro-inflammatory properties. However, its effects on cardiomyocytes and the underlying mechanisms remain unknown. This article demonstrated that visfatin counteracted H(2)O(2) -induced apoptotic damage in H9c2 cardiomyocytes in a time-dependent manner. Qualitative immunofluorescence approaches demonstrated that visfatin pretreatment attenuated H(2)O(2) -induced DNA fragmentation (TdT-mediated dUTP-biotin nick end-labeling), phosphatidyl serine exposure (Annexin V/PI staining), and mitochondrial membrane potential (ΔΨm) depolarization (JC-1 staining). Biochemical studies on cardiomyoctes showed improved cell viability and reduced caspase-3 activation caused by visfatin pretreatment. Visfatin did not inhibit the death receptor-dependent apoptotic pathways, as characterized by its absence in both Fas and TNFR1 down-regulation. Instead, visfatin specifically suppressed the mitochondria-dependent apoptotic pathways, as characterized by changed levels of p53 and its downstream Bcl-2 family genes. Visfatin also up-regulated the protein levels of phosphorylated AMPK, and the anti-apoptotic action of visfatin was attenuated by the AMPK-specific inhibitor compound C. These results suggested that visfatin plays a critical role in cardioprotection by suppressing myocardial apoptosis via AMPK activation. These findings may be the missing link between obesity and CVD.

Topics: Adipokines; AMP-Activated Protein Kinases; Animals; Apoptosis; Cardiotonic Agents; Cardiovascular Diseases; Cell Line; Cell Survival; Cytokines; fas Receptor; Hydrogen Peroxide; Myocytes, Cardiac; Nicotinamide Phosphoribosyltransferase; Obesity; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Rats; Receptors, Tumor Necrosis Factor, Type I; RNA, Messenger; Signal Transduction

Since AMP-activated protein kinase (AMPK) activation in skeletal muscle of obese rodents stimulates fatty acid oxidation, it is reasonable to hypothesize that pharmacological activation of AMPK might be of therapeutic benefit in obesity.. To investigate the effects of the traditional Korean anti-obesity drug GGEx18, a mixture of three herbs, Laminaria japonica Aresch (Laminariaceae), Rheum palmatum L. (Polygonaceae), and Ephedra sinica Stapf (Ephedraceae), on obesity and the involvement of AMPK in this process.. After high fat diet-induced obese mice were treated with GGEx18, we studied the effects of GGEx18 on body weight, fat mass, skeletal muscle lipid accumulation, and the expressions of AMPK, peroxisome proliferator-activated receptor ά (PPARα), and PPARα target genes. The effects of GGEx18 and/or the AMPK inhibitor compound C on lipid accumulation and expression of the above genes were measured in C2C12 skeletal muscle cells.. Administration of GGEx18 to obese mice for 9 weeks significantly (p < 0.05) decreased body and adipose tissue weights compared with obese control mice (p < 0.05). Lipid accumulation in skeletal muscle was inhibited by GGEx18. GGEx18 significantly (p < 0.05) increased skeletal muscle mRNA levels of AMPKα1 and AMPKα2 as well as PPARα and its target genes. Consistent with the in vivo data, GGEx18 inhibited lipid accumulation, and similar activation of genes was observed in GGEx18-treated C2C12 cells. However, compound C inhibited these effects in C2C12 cells.. These results suggest that GGEx18 improves obesity through skeletal muscle AMPK and AMPK-stimulated expression of PPARα and its target enzymes for fatty acid oxidation.

Topics: Adiposity; AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; Cell Line; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Ephedra sinica; Gene Expression Regulation; Laminaria; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Plant Extracts; Plant Preparations; Plants, Medicinal; PPAR alpha; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Rheum; RNA, Messenger; Signal Transduction; Time Factors; Weight Loss

We established a new animal model called SPORTS (Spontaneously-Running Tokushima-Shikoku) rats, which show high-epinephrine (Epi) levels. Recent reports show that Epi activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) in adipocytes. Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in fatty acid synthesis, and the enzymatic activity is suppressed when its Ser-79 is phosphorylated by AMPK. The aim of this study was to investigate the in vivo effect of Epi on ACC and abdominal visceral fat accumulation. We divided both 6-week male control and SPORTS rats into two groups, which were fed either normal diet or high fat and sucrose (HFS) diet for 16 weeks. At the end of diet treatment, retroperitoneal fat was collected for western blotting and histological analysis. Food intake was not different among the groups, but SPORTS rats showed significantly lower weight gain than control rats in both diet groups. After 10 weeks of diet treatment, glucose tolerance tests (GTTs) revealed that SPORTS rats had increased insulin sensitivity. Furthermore, SPORTS rats had lower quantities of both abdominal fat and plasma triglyceride (TG). In abdominal fat, elevated ACC Ser-79 phosphorylation was observed in SPORTS rats and suppressed by an antagonist of beta-adrenergic receptor (AR), propranolol, or an inhibitor of AMPK, Compound C. From these results, high level of Epi induced ACC phosphorylation mediated through beta-AR and AMPK signaling pathways in abdominal visceral fat of SPORTS rats, which may contribute to reduce abdominal visceral fat accumulation and increase insulin sensitivity. Our results suggest that beta-AR-regulated ACC activity would be a target for treating lifestyle-related diseases, such as obesity.

Topics: Acetyl-CoA Carboxylase; Adrenergic beta-Antagonists; AMP-Activated Protein Kinases; Analysis of Variance; Animals; Blood Glucose; Blotting, Western; Body Weight; Eating; Enzyme-Linked Immunosorbent Assay; Epinephrine; Glucose Tolerance Test; Insulin; Intra-Abdominal Fat; Male; Obesity; Phosphorylation; Propranolol; Pyrazoles; Pyrimidines; Rats; Receptors, Adrenergic, beta; Up-Regulation

Nonalcoholic fatty liver disease, one of the most common causes of chronic liver disease, is strongly associated with metabolic syndrome. Nordihydroguaiaretic acid (NDGA) has been reported to inhibit lipoprotein lipase; however, the effect of NDGA on hepatic lipid metabolism remains unclear. We evaluated body weight, adiposity, liver histology, and hepatic triglyceride content in high-fat diet (HFD)-fed C57BL/6J mice treated with NDGA. In addition, we characterized the underlying mechanism of NDGA's effects in HepG2 hepatocytes by Western blot and RT-PCR analysis. NDGA (100 or 200mg/kg/day) reduced weight gain, fat pad mass, and hepatic triglyceride accumulation, and improved serum lipid parameters in mice fed a HFD for 8 weeks. NDGA significantly increased AMP-activated protein kinase (AMPK) phosphorylation in the liver and in HepG2 hepatocytes. NDGA downregulated the level of mature SREBP-1 and its target genes (acetyl-CoA carboxylase and fatty acid synthase), but, it upregulated expression of genes involved in fatty acid oxidation, such as peroxisome proliferator-activated receptor (PPAR)α, PPARγ coactivator-1, carnitine palmitoyl transferase-1, and uncoupling protein-2. The specific AMPK inhibitor compound C attenuated the effects of NDGA on expression of lipid metabolism-related proteins in HepG2 hepatocytes. The beneficial effects of NDGA on HFD-induced hepatic triglyceride accumulation are mediated through AMPK signaling pathways, suggesting a potential target for preventing NAFLD.

Topics: Adiposity; AMP-Activated Protein Kinases; Animals; Diet; Dietary Fats; Fatty Liver; Hepatocytes; Insulin; Lipoxygenase Inhibitors; Male; Masoprocol; Mice; Mice, Inbred C57BL; Obesity; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Triglycerides; Weight Gain

Obesity increases the risk of developing several cancers including oesophageal adenocarcinoma (OAC). Obesity is characterised by hyperleptinaemia and hypoadiponectinaemia: we have hypothesised that these hormonal factors may contribute to the progression of OAC. We have examined the effects of leptin and adiponectin on proliferation of OAC cells. Leptin-stimulated proliferation in four different OAC lines (OE33, OE19, BIC-1 and FLO) and this was inhibited by globular but not full length adiponectin. All four OAC lines expressed both adiponectin-receptor isoforms (AdipoR1 and AdipoR2). Globular adiponectin also inhibited leptin-induced proliferation in rat IEC-18 cells which only expressed AdipoR1. Specific inhibitors of 5'-AMP-activated protein kinase (Compound C) and serine/threonine phosphatases (okadaic acid) and a specific siRNA to AdipoR1 blocked the anti-proliferative effects of adiponectin. Adiponectin inhibited leptin-induced Akt phosphorylation; this action was sensitive to okadaic acid but not to Compound C. Adiponectin deficiency may contribute to the promotion of OAC in obesity.

Topics: Adenocarcinoma; Adiponectin; AMP-Activated Protein Kinases; Animals; Cell Line, Tumor; Cell Proliferation; Enzyme Activation; Enzyme Inhibitors; Esophageal Neoplasms; Humans; Leptin; Multienzyme Complexes; Obesity; Okadaic Acid; Protein Isoforms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Rats; Receptors, Adiponectin; RNA Interference

AMP-activated protein kinase (AMPK) serves as an energy sensor and is considered a promising drug target for treatment of type II diabetes and obesity. A previous report has shown that mammalian AMPK alpha1 catalytic subunit including autoinhibitory domain was inactive. To test the hypothesis that small molecules can activate AMPK through antagonizing the autoinhibition in alpha subunits, we screened a chemical library with inactive human alpha1(394) (alpha1, residues 1-394) and found a novel small-molecule activator, PT1, which dose-dependently activated AMPK alpha1(394), alpha1(335), alpha2(398), and even heterotrimer alpha1beta1gamma1. Based on PT1-docked AMPK alpha1 subunit structure model and different mutations, we found PT1 might interact with Glu-96 and Lys-156 residues near the autoinhibitory domain and directly relieve autoinhibition. Further studies using L6 myotubes showed that the phosphorylation of AMPK and its downstream substrate, acetyl-CoA carboxylase, were dose-dependently and time-dependently increased by PT1 with-out an increase in cellular AMP:ATP ratio. Moreover, in HeLa cells deficient in LKB1, PT1 enhanced AMPK phosphorylation, which can be inhibited by the calcium/calmodulin-dependent protein kinase kinases inhibitor STO-609 and AMPK inhibitor compound C. PT1 also lowered hepatic lipid content in a dose-dependent manner through AMPK activation in HepG2 cells, and this effect was diminished by compound C. Taken together, these data indicate that this small-molecule activator may directly activate AMPK via antagonizing the autoinhibition in vitro and in cells. This compound highlights the effort to discover novel AMPK activators and can be a useful tool for elucidating the mechanism responsible for conformational change and autoinhibitory regulation of AMPK.

Topics: Acetyl-CoA Carboxylase; Adenosine Monophosphate; Adenosine Triphosphate; AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Benzimidazoles; Diabetes Mellitus, Type 2; Energy Metabolism; Enzyme Activation; Enzyme Activators; HeLa Cells; Humans; Multienzyme Complexes; Myoblasts; Naphthalimides; Obesity; Phosphorylation; Protein Serine-Threonine Kinases; Protein Structure, Quaternary; Pyrazoles; Pyrimidines; Time Factors