Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melanocortins play a central role in autonomic modulation of metabolism by acting through a family of highly homologous G protein-coupled receptors. Studies with gene knockout mice have implicated neural melanocortin receptors, MC3R and MC4R, in the etiology of obesity, insulin resistance, and salt-sensitive hypertension. In an attempt to better understand the mechanisms of function of these receptors, we expressed MC3R and MC4R in neuronal cells and demonstrated their co-localization to several membrane regions. We now show that in cultured neuronal cells, MC3R localizes to lipid rafts and undergoes endocytic internalization upon activation by gamma-MSH through a protein kinase-sensitive pathway. The appearance of the internalized receptor in lysosomes suggests that it is subsequently degraded. The expression of protein kinase A regulatory subunits and of c-Jun and c-Fos was analyzed by either immunoblotting or real-time PCR. No discernable changes were observed in the expression levels of these protein kinase A and protein kinase C responsive genes. Immunohistochemical studies showed a robust expression of MC3R protein in brain nuclei with relevance to cardiovascular function and fluid homeostasis further supporting the notion that the physiological effects of melanocortins on the cardiovascular system arise from effects on the central nervous system.
 ...
PMID:Activation and endocytic internalization of melanocortin 3 receptor in neuronal cells. 1740 38

Obesity increases the risk of colon cancer. Hyperleptinemia is characteristic of obesity and leptin has been reported to be a colonic growth factor. We have examined the involvement of the cyclo-oxygenase (COX) pathways in the proliferation and anti-apoptotic effects of leptin. Leptin stimulated proliferation in HT-29 colon cancer cells: this was unaffected by inhibition of COX-1, COX-2, protein kinase C, or the epidermal growth factor receptor. Leptin did not increase COX-2 mRNA or COX-derived prostaglandin E2 production. Celecoxib induced apoptosis in a COX-independent manner. Leptin reduced both serum starvation- and celecoxib-induced apoptosis. Inhibition of ERK, p38 MAP kinase, and nuclear factor (NF)-kappaB abolished the growth-promoting and anti-apoptotic effects of leptin. Treatment of HT-29 cells with leptin stimulated phosphorylation of ERK and p38 MAP kinase and nuclear translocation of active NF-kappaB. We conclude that leptin stimulates colon cancer proliferation via COX-independent pathways and reduces celecoxib-induced apoptosis via ERK, p38 MAP kinase, and NF-kappaB pathways.
 ...
PMID:Cyclo-oxygenase-independent inhibition of apoptosis and stimulation of proliferation by leptin in human colon cancer cells. 1740 16

Obesity, the metabolic syndrome, and type 2 diabetes mellitus (T2DM) are major global health problems. Insulin resistance is frequently present in these disorders, but the causes and effects of such resistance are unknown. Here, we generated mice with muscle-specific knockout of the major murine atypical PKC (aPKC), PKC-lambda, a postulated mediator for insulin-stimulated glucose transport. Glucose transport and translocation of glucose transporter 4 (GLUT4) to the plasma membrane were diminished in muscles of both homozygous and heterozygous PKC-lambda knockout mice and were accompanied by systemic insulin resistance; impaired glucose tolerance or diabetes; islet beta cell hyperplasia; abdominal adiposity; hepatosteatosis; elevated serum triglycerides, FFAs, and LDL-cholesterol; and diminished HDL-cholesterol. In contrast to the defective activation of muscle aPKC, insulin signaling and actions were intact in muscle, liver, and adipocytes. These findings demonstrate the importance of aPKC in insulin-stimulated glucose transport in muscles of intact mice and show that insulin resistance and resultant hyperinsulinemia owing to a specific defect in muscle aPKC is sufficient to induce abdominal obesity and other lipid abnormalities of the metabolic syndrome and T2DM. These findings are particularly relevant because humans who have obesity, impaired glucose tolerance, and T2DM reportedly have defective activation and/or diminished levels of muscle aPKC.
 ...
PMID:Muscle-specific knockout of PKC-lambda impairs glucose transport and induces metabolic and diabetic syndromes. 1764 77

Numerous reports on the molecular mechanism of atherogenesis indicate an increase in oxidative stress, formation of advanced glycoxidation end products (AGEs), chronic inflammation, and activated cellular response particularly in diabetic patients. To elucidate the initiating and early accelerating events this review will focus on the molecular causes of the induction of these stress factors, their interactions, and their contribution to atherogenesis. Metabolic factors such as elevated free fatty acids, high glucose levels or AGEs induce reactive oxygen species (ROS) in vascular cells leading to ongoing AGE formation and to gene induction of proinflammatory cytokines. Vice versa, numerous cytokines found elevated in obesity and diabetes may also induce oxidative stress thus a circulus vitious may be initiated and accelerated. Increased production of ROS, mainly from mitochondria and NAD(P)H oxidase, stimulates signaling cascades including protein kinase C and mitogen-activated protein kinase pathway leading to nuclear translocation of transcription factors such as nuclear factor-kappaB (NF-kappaB), activator protein 1, and specificity protein 1. Subsequently, the expression of numerous genes including cytokines is rapidly induced, which, in turn, may act on vascular cells promoting the deleterious effects. From animal models of accelerated atherosclerosis a causal role of NAD(P)H oxidase and the AGE/RAGE/NF-kappaB axis to atherogenesis is suggested. Because all factors involved form a highly interwoven network of interactions, the blockade of ROS or AGE formation at different sites may interrupt the vicious cycle. Promising candidate agents are, currently on trial. Most important to clinical practice, a number of drugs commonly used in the treatment of diabetes, hypertension, or cardiovascular disease, such as angiotensin-converting enzyme inhibitors, AT(1) receptor blockers, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins), and thiazolidindiones have shown promising 'preventive' intracellular antioxidant activity in addition to their primary pharmacological actions.
 ...
PMID:Oxidative stress, AGE, and atherosclerosis. 1765 6

Adipose tissue secretes a wide range of hormones named adipokines, and these may play a role in obesity-related inflammation. Adiponectin is an exceptional adipokine because low plasma concentrations are associated with obesity, type 2 diabetes, and cardiovascular diseases. It has been observed that plasma adiponectin concentrations are elevated during inflammatory conditions like preeclampsia and arthritis. Nuclear factor-kappaB (NF-kappaB) is an essential transcription factor for expression of inflammation-related proteins. We have used U937 cells stably transfected to express luciferase under the control of NF-kappaB to examine if adiponectin may modulate NF-kappaB activity. Physiological concentrations of native adiponectin induced NF-kappaB activity. This effect was relatively strong compared with proinflammatory adipokines like leptin, resistin, and IL-6. The enhanced NF-kappaB activity was attributed to the high molecular weight adiponectin isoforms. NF-kappaB was not activated by mutated adiponectin that is unable to form high molecular weight complexes. Furthermore, the C-terminal fragment, globular adiponectin, markedly increased NF-kappaB reporter activity, cytokine release, and mRNA expression of inflammation marker genes, at higher levels than stimulation with TNF-alpha and lipopolysaccharide. NF-kappaB activation by globular adiponectin was not affected by antibody inhibition of toll-like receptor 4 or TNF receptors 1 and 2 but was attenuated by inhibitors of p38 MAPK, phosphatidylinositol 3-kinase, and protein kinase C. Analyses of the p65 subunit of NF-kappaB in different leukocyte cell lines showed activation of two monocytic cell lines (U937 and THP-1) by native and globular adiponectin. Our results indicate that adiponectin has proinflammatory properties in monocytic cells.
 ...
PMID:Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin. 1770 46

Intramyocellular triglyceride (imcTG) content in skeletal muscle is abnormally high in lipid oversupply models in obesity, type 2 diabetes (T2D) and other metabolically diseased conditions. The imcTG abnormality was also found to be significantly correlated with muscle insulin resistance (MIR). As skeletal muscle is the main site for insulin-mediated glucose utilization, the research on this topic has been active since. However, to date the pathways responsible for the imcTG excess and the mechanisms underlying the imcTG-MIR correlation have not been identified. A current view is focused on a backward mechanism that fatty acid oxidation by muscle is impaired causing imcTG to accumulate and, therefore, an enlarged imcTG pool is merely a marker of MIR. However, based on kinetic studies, it is more likely that imcTG is a source of MIR. On one hand, an enlarged and fast turning over imcTG pool interferes with insulin signaling by producing excess amounts of signaling molecules that activate PKC pathways. On the other hand, it may promote mitochondrial beta-oxidation that suppresses glucose metabolism via substrate competition. Therefore, it is hypothesized that imcTG is a source of MIR.
 ...
PMID:Intramyocellular lipids: maker vs. marker of insulin resistance. 1776 54

Resistin, an adipocyte-derived hormone, is thought to represent a link between obesity and insulin-resistant diabetes. The potential role of resistin as a cardioprotective agent has not been explored. Our hypothesis is that resistin has a cardioprotective effect that is mediated by the resistin receptor-coupled activation of PI3K/Akt/PKC/K(ATP) dependent pathways. Our studies demonstrated that pretreatment of mouse hearts with 10 nM resistin for 5 min protected the heart against I/R injury in a mouse heart perfusion model. When mouse hearts were subjected to 60 min of LAD ligation followed by 4 h of reperfusion, resistin pretreatment (33 microg/kg) for 30 min or 24 h before ligation was able to significantly reduce the infarct size/risk area. The protective effect of resistin was abolished by wortmannin, as well as by an Akt inhibitor, triciribine. Resistin's protective effect was absent in Akt kinase-deficient mutant mice. The protective effect was also blocked by chelerythrine, a PKC inhibitor, and epsilonV1-2, a PKCepsilon inhibitor. Finally, the protective effect was blocked by 5-hydroxydecanoate, which blocks the opening of mitoK(ATP) channels. Resistin-induced Akt phosphorylation in HL-1 cells was inhibited by wortmannin and triciribine. Resistin also induced PKCepsilon phosphorylation, which was blocked by triciribine. These studies demonstrate that resistin's cardioprotective effect is mediated by PI3K/Akt/PKC dependent pathways. In addition to cardiomyocytes, resistin also induced Akt phosphorylation in endothelial cells and smooth muscle cells, suggesting that resistin receptors are present in these cells. The effect of resistin on apoptosis was assessed in hearts subjected to 30 min of ischemia and 3 h of reperfusion. There were significantly fewer in situ oligo ligation-positive myocyte nuclei in mice treated with resistin. Our results show that resistin can dramatically reduce apoptosis and infarct size, thus protecting the heart against I/R injury.
 ...
PMID:Resistin, an adipocytokine, offers protection against acute myocardial infarction. 1790 55

Acetyl-CoA carboxylase 2 (ACC)2 is a key regulator of mitochondrial fat oxidation. To examine the impact of ACC2 deletion on whole-body energy metabolism, we measured changes in substrate oxidation and total energy expenditure in Acc2(-/-) and WT control mice fed either regular or high-fat diets. To determine insulin action in vivo, we also measured whole-body insulin-stimulated liver and muscle glucose metabolism during a hyperinsulinemic-euglycemic clamp in Acc2(-/-) and WT control mice fed a high-fat diet. Contrary to previous studies that have suggested that increased fat oxidation might result in lower glucose oxidation, both fat and carbohydrate oxidation were simultaneously increased in Acc2(-/-) mice. This increase in both fat and carbohydrate oxidation resulted in an increase in total energy expenditure, reductions in fat and lean body mass and prevention from diet-induced obesity. Furthermore, Acc2(-/-) mice were protected from fat-induced peripheral and hepatic insulin resistance. These improvements in insulin-stimulated glucose metabolism were associated with reduced diacylglycerol content in muscle and liver, decreased PKC activity in muscle and PKCepsilon activity in liver, and increased insulin-stimulated Akt2 activity in these tissues. Taken together with previous work demonstrating that Acc2(-/-) mice have a normal lifespan, these data suggest that Acc2 inhibition is a viable therapeutic option for the treatment of obesity and type 2 diabetes.
 ...
PMID:Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. 1792 73

Elevations in branched-chain amino acids (BCAAs) in human obesity were first reported in the 1960s. Such reports are of interest because of the emerging role of BCAAs as potential regulators of satiety, leptin, glucose, cell signaling, adiposity, and body weight (mTOR and PKC). To explore loss of catabolic capacity as a potential contributor to the obesity-related rises in BCAAs, we assessed the first two enzymatic steps, catalyzed by mitochondrial branched chain amino acid aminotransferase (BCATm) or the branched chain alpha-keto acid dehydrogenase (BCKD E1alpha subunit) complex, in two rodent models of obesity (ob/ob mice and Zucker rats) and after surgical weight loss intervention in humans. Obese rodents exhibited hyperaminoacidemia including BCAAs. Whereas no obesity-related changes were observed in rodent skeletal muscle BCATm, pS293, or total BCKD E1alpha or BCKD kinase, in liver BCKD E1alpha was either unaltered or diminished by obesity, and pS293 (associated with the inactive state of BCKD) increased, along with BCKD kinase. In epididymal fat, obesity-related declines were observed in BCATm and BCKD E1alpha. Plasma BCAAs were diminished by an overnight fast coinciding with dissipation of the changes in adipose tissue but not in liver. BCAAs also were reduced by surgical weight loss intervention (Roux-en-Y gastric bypass) in human subjects studied longitudinally. These changes coincided with increased BCATm and BCKD E1alpha in omental and subcutaneous fat. Our results are consistent with the idea that tissue-specific alterations in BCAA metabolism, in liver and adipose tissue but not in muscle, may contribute to the rise in plasma BCAAs in obesity.
 ...
PMID:Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. 1792 55

Leptin enhances agonist-induced platelet aggregation, and human platelets have been reported to express the leptin receptor. However, the pathways and mediators lying downstream of leptin binding to platelets remain, with few exceptions, unknown. In the present study, we sought to gain further insight into the possible role of leptin as a platelet agonist. Stimulation of platelets with leptin promoted thromboxane generation and activation of alpha(IIb)beta(3), as demonstrated by PAC-1 binding. Furthermore, it increased the adhesion to immobilised fibrinogen (p<0.001) and induced cytoskeletal rearrangement of both platelets and Meg01 cells. Leptin time- and dose-dependently phosphorylated the intracellular signalling molecules JAK2 and STAT3, although the importance of STAT3 for leptin-induced platelet activation remains to be determined. Important intracellular mediators and pathways activated by leptin downstream of JAK2 were found to include phosphatidylinositol-3 kinase, phospholipase Cgamma2 and protein kinase C, as well as the p38 MAP kinase-phospholipase A(2) axis. Accordingly, incubation with the specific inhibitors AG490, Ly294002, U73122, and SB203580 prevented leptin-mediated platelet activation. These results help delineate biologically relevant leptin signalling pathways in platelets and may improve our understanding of the mechanisms linking hyperleptinaemia to the increased thrombosis risk in human obesity.
 ...
PMID:Leptin signalling and leptin-mediated activation of human platelets: importance of JAK2 and the phospholipases Cgamma2 and A2. 1800 Jun 12


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>