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)

AMPK is a potential target of metabolic diseases including obesity and type 2 diabetes. The activation of AMPK can lead to an increase of glucose uptake into muscle, decreased gluconeogenesis in liver, increased fatty acid oxidation in muscle and liver, decreased fatty acid synthesis in liver and adipose tissue, and increase mitochondrial biogenesis. Until now, many efforts from industrial and academia have been focused on searching novel agents that activate AMPK directly or indirectly. This review will discuss recent advances in the search for novel therapeutic agents that mediate their activity via AMPK activation.
 ...
PMID:AMPK activators as novel therapeutics for type 2 diabetes. 2018 Jul 61

Energy homeostasis and stress resistance are closely linked on aging and longevity. AMPK (AMP-activated protein kinase) is a sensor of cellular energy status activated by metabolic stress that accelerates AMP/ATP ratio, regulating cell polarity, metabolic homeostasis and sensitivity to stress resistance. AMPK could be therapeutic targets for cancer, diabetic mellitus and obesity, providing a possible link to metabolic syndrome. However, little is known how functional deficiency of AMPK affects longevity and stress resistance in vivo due to its redundancy and lethality in null-mutant. SNF1A/dAMPKalpha (CG3051) is a single orthologue for its mammalian counterparts in Drosophila melanogaster. Using time- and tissue-specific RNAi system in D. melanogaster, we found that adult-onset inhibition of dAMPKalpha especially in muscle shortens lifespan. In addition, inhibition of dAMPKalpha in muscle enhances sensitivity to paraquat and starvation stress. Real-time PCR analysis showed that inhibition of dAMPKalpha in muscle affected the transcriptional regulation of various genes in response to starvation. These results raise the possibility that muscle is one of major tissues in which AMPK plays a critical role on longevity and stress resistance and the intervention to activate AMPK in muscle could be a prominent treatment strategy for longevity.
 ...
PMID:A critical role of SNF1A/dAMPKalpha (Drosophila AMP-activated protein kinase alpha) in muscle on longevity and stress resistance in Drosophila melanogaster. 2018 62

The molecular mechanisms responsible for the association of obesity with adverse colon cancer outcomes are poorly understood. We investigated the effects of a high-energy diet on growth of an in vivo colon cancer model. Seventeen days following the injection of 5x10(5) MC38 colon carcinoma cells, tumors from mice on the high-energy diet were approximately twice the volume of those of mice on the control diet. These findings were correlated with the observation that the high-energy diet led to elevated insulin levels, phosphorylated AKT, and increased expression of fatty acid synthase (FASN) by the tumor cells. Metformin, an antidiabetic drug, leads to the activation of AMPK and is currently under investigation for its antineoplastic activity. We observed that metformin blocked the effect of the high-energy diet on tumor growth, reduced insulin levels, and attenuated the effect of diet on phosphorylation of AKT and expression of FASN. Furthermore, the administration of metformin led to the activation of AMPK, the inhibitory phosphorylation of acetyl-CoA carboxylase, the upregulation of BNIP3 and increased apoptosis as estimated by poly (ADP-ribose) polymerase (PARP) cleavage. Prior work showed that activating mutations of PI3K are associated with increased AKT activation and adverse outcome in colon cancer; our results demonstrate that the aggressive tumor behavior associated with a high-energy diet has similar effects on this signaling pathway. Furthermore, metformin is demonstrated to reverse the effects of the high-energy diet, thus suggesting a potential role for this agent in the management of a metabolically defined subset of colon cancers.
 ...
PMID:Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. 2022 37

Deficiency of adiponectin (APN), an adipocyte-derived vascular protective molecule, contributes to diabetic vascular injury. The current study determined whether obesity/hyperlipidemia may alter the vascular response to APN, and investigated the involved mechanisms and pathologic significance. Adult male Sprague-Dawley rats were fed a regular or high-fat diet (HF) for 4-16 weeks. Circulating APN levels, aortic pAMPK/AMPK, peNOS/eNOS, and APN receptor expression levels were determined. Compared to time-matched animals fed control diet, plasma APN levels in HF-diet animals were significantly increased at 8 weeks, and rapidly declined thereafter. Despite unchanged or elevated circulating APN levels, phosphorylated AMPK and eNOS in vascular tissue were significantly reduced at all observed time points. Recombinant full-length APN (rAPN)-induced AMPK/eNOS phosphorylation and vasodilatation were significantly reduced in 16-week obese/hyperlipidemic aortic segments. Vascular APN receptor 1 (AdipoR1) and receptor 2 (AdipoR2) expression were significantly reduced 16 weeks after HF-diet. Pre-incubation of rAPN with obese/hyperlipidemic plasma, but not with normal plasma, significantly reduced its AMPK and eNOS activation effect, and blunted its protective effect against TNFalpha-induced HUVEC apoptosis. This study demonstrated for the first time that obesity/hyperlipidemia reduces vascular responsiveness to APN. Modification/inactivation of APN by unidentified factors present in obese/hyperlipidemic plasma, decreased vascular AdipoR1/R2 expression, and reduced circulating APN levels contribute to reduced vascular responsiveness to APN at different stages of the obese condition. Reduced APN bioactivity allows unmitigated TNFalpha pro-apoptotic and pro-inflammatory actions, contributing to vascular injury in obesity/hyperlipidemia.
 ...
PMID:Reduced vascular responsiveness to adiponectin in hyperlipidemic rats--mechanisms and significance. 2030 76

Adiponectin is an anti-diabetic adipokine. Its receptors possess a seven-transmembrane topology with the amino terminus located intracellularly, which is the opposite of G-protein-coupled receptors. Here we provide evidence that adiponectin induces extracellular Ca(2+) influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular Ca(2+) concentration, and decreased the activation of CaMKK, AMPK and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC-1alpha expression and deacetylation, decreased mitochondrial content and enzymes, decreased oxidative type I myofibres, and decreased oxidative stress-detoxifying enzymes in skeletal muscle, which were associated with insulin resistance and decreased exercise endurance. Decreased levels of adiponectin and AdipoR1 in obesity may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetes.
 ...
PMID:Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. 2051 15

The molecular mechanisms of obesity-associated insulin resistance are becoming increasingly clear, and the effects of various lipid molecules, such as diacylglycerol and ceramide, on the insulin signal are being actively explored. To better understand the divergent response to lipid exposure between lean and obese, we incubated primary human muscle cells from lean [body mass index (BMI) <25 kg/m(2)] and morbidly obese (BMI >40 kg/m(2)) subjects with the saturated fatty acid palmitate. Additionally, given that AMPK-activating drugs are widely prescribed for their insulin-sensitizing effects, we sought to determine whether 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR)-stimulated AMPK activation could prevent or reverse the deleterious effects of lipid on insulin signaling. We found that a 1-h palmitate incubation in lean myotubes reduced (P < 0.05) insulin-stimulated phosphoprotein kinase B (Akt), Akt substrate 160 (AS160), and inhibitory factor kappaBalpha (IkappaBalpha) mass, all of which were prevented with AICAR inclusion. With a longer incubation, we observed that myotubes from morbidly obese individuals appear to be largely resistant to the detrimental effects of 16 h lipid exposure as was evident, in contrast to the lean, by the absence of a reduction in insulin-stimulated insulin receptor substrate (IRS)-1 Tyr phosphorylation, phospho-Akt, and phospho-AS160 (P < 0.05). Furthermore, 16 h lipid exposure significantly reduced IkappaBalpha levels and increased phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and IRS1-Ser(312) in lean myotubes only (P < 0.05). Despite a divergent response to lipid between lean and obese myotubes, AICAR inclusion improved insulin signaling in all myotubes. These findings suggest an important role for regular exercise in addition to offering a potential mechanism of action for oral AMPK-activating agents, such as thiazolidinediones and metformin.
 ...
PMID:Lipid-induced insulin resistance is prevented in lean and obese myotubes by AICAR treatment. 2039 62

The yeast Saccharomyces cerevisiae attains energy homeostasis through complex regulatory events that are predominantly controlled by the Snf1 kinase. This master regulator senses the stress and energy starvation and activates the metabolic processes to produce ATP and inhibits biosynthesis. In doing so, Snf1 controls the switch between catabolism and anabolism accordingly, and regulates the cellular growth and development in coordination with other signaling pathways. Since its mammalian ortholog AMPK, a drug target for obesity and type II diabetes, also exerts analogous control of metabolism, there has been extensive interest recently to understand the chemical and biological aspects of Snf1 activation and regulation in yeast to expedite human disease studies as well as fundamental understanding of yeast. This review will focus on how Snf1 regulates lipid metabolism based on the cellular energy status in yeast and drawing parallels with the mammalian system.
 ...
PMID:Systems biology of energy homeostasis in yeast. 2043 64

Mitochondrial fatty acid oxidation provides an important energy source for cellular metabolism, and decreased mitochondrial fatty acid oxidation has been implicated in the pathogenesis of type 2 diabetes. Paradoxically, mice with an inherited deficiency of the mitochondrial fatty acid oxidation enzyme, very long-chain acyl-CoA dehydrogenase (VLCAD), were protected from high-fat diet-induced obesity and liver and muscle insulin resistance. This was associated with reduced intracellular diacylglycerol content and decreased activity of liver protein kinase Cvarepsilon and muscle protein kinase Ctheta. The increased insulin sensitivity in the VLCAD(-/-) mice were protected from diet-induced obesity and insulin resistance due to chronic activation of AMPK and PPARalpha, resulting in increased fatty acid oxidation and decreased intramyocellular and hepatocellular diacylglycerol content.
 ...
PMID:Resistance to high-fat diet-induced obesity and insulin resistance in mice with very long-chain acyl-CoA dehydrogenase deficiency. 2044 20

Adenine monophosphate (AMP) activated protein kinase (AMPK) is an important regulator of obesity. The objective of the present work was to study and compare AMPK protein expression in visceral vs. subcutaneous adipose tissue of morbid obese subjects and to correlate it with adipose tissue characteristics. We selected a total population of 17 extreme obese (BMI>or=40 kg/m2) aged 42.8+/-10.2 years were included in this study. We measured anthropometric and body composition parameters. Adiponectin expression by qRT-PCR, isoproterenol-stimulated lipolytic rates, and AMPK alpha subunits expression by Western blot in adipose tissue explants were determined. Finally plasma concentrations of glucose, triacylglycerols, total cholesterol, HDL-c, LDL-c and insulin were also measured. Our results showed that AMPK alpha expression was higher in subcutaneous than in visceral tissue. A positive correlation between AMPK expression and adiponectin expression in human subcutaneous adipose tissue was observed. Furthermore, a positive correlation between AMPK expression and isoproterenol evoked upregulation of lipolysis rate was also observed. In conclusion, AMPK alpha expression differed according to adipose tissue location. The positive correlation between subcutaneous adipose tissue AMPK and adiponectin or the evoked lipolysis rate could indicate a protective role of AMPK in this tissue, counteracting insulin resistance in morbid obese patients.
 ...
PMID:Differences in AMPK expression between subcutaneous and visceral adipose tissue in morbid obesity. 2046 11

Excess energy intake via a palatable low-fat diet (cafeteria diet) is known to induce obesity and glucose intolerance in rats. However, the molecular mechanisms behind this adaptation are not known, and it is also not known whether exercise training can reverse it. Male Wistar rats were assigned to 12-wk intervention groups: chow-fed controls (CON), cafeteria diet (CAF), and cafeteria diet plus swimming exercise during the last 4 wk (CAF(TR)). CAF feeding led to increased body weight (16%, P < 0.01) and increased plasma glucose (P < 0.05) and insulin levels (P < 0.01) during an IVGTT, which was counteracted by training. In the perfused hindlimb, insulin-stimulated glucose transport in red gastrocnemius muscle was completely abolished in CAF and rescued by exercise training. Apart from a tendency toward an approximately 20% reduction in both basal and insulin-stimulated Akt Ser(473) phosphorylation (P = 0.051) in the CAF group, there were no differences in insulin signaling (IR Tyr(1150/1151), PI 3-kinase activity, Akt Thr(308), TBC1D4 Thr(642), GSK3-alpha/beta Ser(21/9)) or changes in AMPKalpha1 or -alpha2, GLUT4, Munc18c, or syntaxin 4 protein expression or in phosphorylation of AMPK Thr(172) among the groups. In conclusion, surplus energy intake of a palatable but low-fat cafeteria diet resulted in obesity and insulin resistance that was rescued by exercise training. Interestingly, insulin resistance was not accompanied by major defects in the insulin-signaling cascade or in altered AMPK expression or phosphorylation. Thus, compared with previous studies of high-fat feeding, where insulin signaling is significantly impaired, the mechanism by which CAF diet induces insulin resistance seems different.
 ...
PMID:Cafeteria diet-induced insulin resistance is not associated with decreased insulin signaling or AMPK activity and is alleviated by physical training in rats. 2048 11


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