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)

The adipocyte-derived hormone leptin maintains energy balance by acting on hypothalamic leptin receptors (Leprs) that act on the signal transducer and activator of transcription 3 (Stat3). Although disruption of Lepr-Stat3 signaling promotes obesity in mice, other features of Lepr function, such as fertility, seem normal, pointing to the involvement of additional regulators. Here we show that the cyclic AMP responsive element-binding protein-1 (Creb1)-regulated transcription coactivator-1 (Crtc1) is required for energy balance and reproduction-Crtc1(-/-) mice are hyperphagic, obese and infertile. Hypothalamic Crtc1 was phosphorylated and inactive in leptin-deficient ob/ob mice, while leptin administration increased amounts of dephosphorylated nuclear Crtc1. Dephosphorylated Crtc1 stimulated expression of the Cartpt and Kiss1 genes, which encode hypothalamic neuropeptides that mediate leptin's effects on satiety and fertility. Crtc1 overexpression in hypothalamic cells increased Cartpt and Kiss1 gene expression, whereas Crtc1 depletion decreased it. Indeed, leptin enhanced Crtc1 activity over the Cartpt and Kiss1 promoters in cells overexpressing Lepr, and these effects were disrupted by expression of a dominant-negative Creb1 polypeptide. As leptin administration increased recruitment of hypothalamic Crtc1 to Cartpt and Kiss1 promoters, our results indicate that the Creb1-Crtc1 pathway mediates the central effects of hormones and nutrients on energy balance and fertility.
 ...
PMID:The Creb1 coactivator Crtc1 is required for energy balance and fertility. 1973 65

Fat cell lipolysis, the cleavage of triglycerides and release of fatty acids and glycerol, evolved to enable survival during prolonged food deprivation but is paradoxically increased in obesity, in which a surfeit of all energy metabolites is found. Essential, previously-unsuspected components have been discovered in the lipolytic machinery, at the protective interface of the lipid droplet surface and in the signaling pathways that control lipolysis. At least two adipocyte lipases are important for controlling lipolysis, hormone-sensitive lipase (HSL) and adipocyte triglyceride lipase (ATGL). Perilipin (PLIN) and possibly other proteins of the lipid droplet surface are master regulators of lipolysis, protecting or exposing the triglyceride core of the droplet to lipases. The prototypes for hormonal lipolytic control are beta adrenergic stimulation and suppression by insulin, both of which affect cyclic AMP levels and hence the protein kinase A-mediated phosphorylation of HSL and PLIN. Newly-recognized mediators of lipolysis include atrial natriuretic peptide, cyclic GMP, the ketone body 3-hydroxybutyrate, AMP kinase and mitogen-activated kinases. Lipolysis must be interpreted in its physiological context since similar rates of basal or stimulated lipolysis occur under different conditions and by different mechanisms. Age, sex, anatomical site, genotype and species differences are each important variables. Manipulation of lipolysis has therapeutic potential in several inborn errors and in the metabolic syndrome that frequently complicates obesity.
 ...
PMID:Lipolysis and the integrated physiology of lipid energy metabolism. 1876 40

Mammalian AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that acts as a sensor of cellular energy status. It is activated by a large variety of cellular stresses that increase cellular AMP and decrease ATP levels and also by physiological stimuli, such as muscle contraction, or by hormones such as leptin and adiponectin. AMPK modulates multiple metabolic pathways. As a result, it has become a target for the development of new drugs for the treatment of type II diabetes, obesity or even cancer. In fact, it has been recently reported that drugs used in the treatment of diabetes, such as metformin and thiazolidinediones (TZDs), exert their beneficial effects through the activation of AMPK. AMPK is a heterotrimeric complex composed of a catalytic subunit (AMPK-alpha) and two regulatory subunits (AMPK-beta and AMPK-gamma). Functional orthologues of this kinase complex are found throughout eukaryotic kingdom, from yeast to humans, indicating that the function of this complex is evolutionarily conserved. This review summarizes the recent studies on the structure and regulation of the AMPK heterotrimeric complex.
 ...
PMID:AMP-activated protein kinase: structure and regulation. 1885 99

The American diet, especially that of adolescents, contains highly palatable foods of high-energy content and large amounts of high-fructose sweeteners. These factors are believed to contribute to the obesity epidemic and insulin resistance. Previous investigations revealed that the central metabolism of glucose suppresses food intake mediated by the hypothalamic AMP-kinase/malonyl-CoA signaling system. Unlike glucose, centrally administered fructose increases food intake. Evidence presented herein indicates that the more rapid initial steps of central fructose metabolism deplete hypothalamic ATP level, whereas the slower regulated steps of glucose metabolism elevate hypothalamic ATP level. Consistent with effects on the [ATP]/[AMP] ratio, fructose increases phosphorylation/activation of hypothalamic AMP kinase causing phosphorylation/inactivation of acetyl-CoA carboxylase, whereas glucose has the inverse effects. The changes provoked by central fructose administration reduce hypothalamic malonyl-CoA level and thereby increase food intake. These findings explain the paradoxical fructose effect on food intake and lend credence to the malonyl-CoA hypothesis.
 ...
PMID:Differential effects of central fructose and glucose on hypothalamic malonyl-CoA and food intake. 1897 29

Obesity is a risk factor for endometrial cancer in pre- and post-menopausal women. Leptin, an adipocyte-derived hormone, in addition to the control weight homeostasis, is implicated in multiple biological actions. A recent study demonstrated that leptin promotes endometrial cancer growth and invasiveness through STAT/MAPK and Akt pathways, but the molecular mechanism involved in such processes still needs to be elucidated. In an attempt to understand the role of leptin in regulating endometrial cancer cells proliferation, we have demonstrated that leptin treatment reduced the numbers of cells in G0/G1-phase while increased cell population in S-phase. This effect is associated with an up-regulation of cyclin D1 together with a down-regulation of cyclin-dependent kinase inhibitor p21(WAF1/Cip1). Mutagenesis studies, eletrophoretic mobility shift, and chromatin immunoprecipitation analysis revealed that signal transducers and activators of transcription 3 (STAT3) and cyclic AMP-responsive element (CRE) binding protein motifs, within cyclin D1 promoter, were required for leptin-induced cyclin D1 expression in Ishikawa endometrial cancer cells. Silencing of STAT3 and CREB gene expression by RNA interference reversed the up-regulatory effect of leptin on cyclin D1 expression and cells proliferation. These results support the hypothesis that STAT3 and CREB play an important role in leptin signaling pathway that leads to the proliferation of Ishikawa cells, thus establishing a direct association between obesity and endometrial tumorogenesis.
 ...
PMID:Evidence that leptin through STAT and CREB signaling enhances cyclin D1 expression and promotes human endometrial cancer proliferation. 1898 90

The AMP-activated protein kinase (AMPK) is an alphabetagamma heterotrimer that plays a pivotal role in regulating cellular and whole-body metabolism. Activation of AMPK reverses many of the metabolic defects associated with obesity and type 2 diabetes, and therefore AMPK is considered a promising target for drugs to treat these diseases. Recently, the thienopyridone A769662 has been reported to directly activate AMPK by an unexpected mechanism. Here we show that A769662 activates AMPK by a mechanism involving the beta subunit carbohydrate-binding module and residues from the gamma subunit but not the AMP-binding sites. Furthermore, A769662 exclusively activates AMPK heterotrimers containing the beta1 subunit. Our findings highlight the regulatory role played by the beta subunit in modulating AMPK activity and the possibility of developing isoform specific therapeutic activators of this important metabolic regulator.
 ...
PMID:Thienopyridone drugs are selective activators of AMP-activated protein kinase beta1-containing complexes. 1902 82

A main function of white adipose tissue is to release fatty acids from stored triacylglycerol for other tissues to use as an energy source. Whereas endocrine regulation of lipolysis has been extensively studied, autocrine and paracrine regulation is not well understood. Here we describe the role of the newly identified major adipocyte phospholipase A(2), AdPLA (encoded by Pla2g16, also called HREV107), in the regulation of lipolysis and adiposity. AdPLA-null mice have a markedly higher rate of lipolysis owing to increased cyclic AMP levels arising from the marked reduction in the amount of adipose prostaglandin E(2) that binds the Galpha(i)-coupled receptor, EP3. AdPLA-null mice have markedly reduced adipose tissue mass and triglyceride content but normal adipogenesis. They also have higher energy expenditure with increased fatty acid oxidation within adipocytes. AdPLA-deficient ob/ob mice remain hyperphagic but lean, with increased energy expenditure, yet have ectopic triglyceride storage and insulin resistance. AdPLA is a major regulator of adipocyte lipolysis and is crucial for the development of obesity.
 ...
PMID:AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. 1913 64

Adiponectin and adiponectin receptors (AdipoRs) have been found to play significant roles in the etiology of obesity-related chronic disease. Their discovery has been a long and complicated path, with many challenges. Developing methods to unravel the molecular secrets has been an informative process in itself. However, with both functional and genetic studies confirming adiponectin as a therapeutic target adipokine, many roles and interactions with certain other biomolecules have been clearly defined. We have found that decreased high molecular weight (HMW) adiponectin plays a crucial and causal role in obesity-linked insulin resistance and metabolic syndrome; that AdipoR1 and AdipoR2 serve as the major AdipoRs in vivo; and that AdipoR1 activates the AMP kinase (AMPK) pathway and AdipoR2, the peroxisome proliferator-activated receptor alpha (PPARalpha) pathway in the liver, to increase insulin sensitivity and decrease inflammation. Further conclusions are that decreased adiponectin action and increased monocyte chemoattractant protein-1 (MCP-1) form a vicious adipokine network causing obesity-linked insulin resistance and metabolic syndrome; PPARgamma upregulates HMW adiponectin and PPARalpha upregulates AdipoRs; that dietary osmotin can serve as a naturally occurring adiponectin receptor agonist; and finally, that under starvation conditions, MMW adiponectin activates AMPK in hypothalamus, and promotes food intake, and at the same time HMW adiponectin activates AMPK in peripheral tissues, such as skeletal muscle, and stimulates fatty-acids combustion. Importantly, under pathophysiological conditions, such as obesity and diabetes, only HMW adiponectin was decreased; therefore, strategies to increase only HMW adiponectin may be a logical approach to provide a novel treatment modality for obesity-linked diseases, such as insulin resistance and type 2 diabetes. It is hoped that these data will be helpful in developing treatments to counteract the destructive, expensive and painful effects of obesity.
 ...
PMID:Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. 1913 82

The Thrifty Gene hypothesis theorizes that during evolution a set of genes has been selected to ensure survival in environments with limited food supply and marked seasonality. Contemporary environments have predictable and unlimited food availability, an attenuated seasonality due to artificial lighting, indoor heating during the winter and air conditioning during the summer, and promote sedentariness and overeating. In this setting the thrifty genes are constantly activated to enhance energy storage. Psychosocial stress and sleep deprivation are other features of modern societies. Stress-induced hypercortisolemia in the setting of unlimited food supply promotes adiposity. Modern man is becoming obese because these ancient mechanisms are efficiently promoting a positive energy balance. We propose that in today's plentifully provisioned societies, where sedentariness and mental stress have become typical traits, chronic activation of the neuroendocrine systems may contribute to the increased prevalence of obesity. We suggest that some of the yet unidentified thrifty genes may be linked to highly conserved energy sensing mechanisms (AMP kinase, mTOR kinase). These hypotheses are testable. Rural societies that are becoming rapidly industrialized and are witnessing a dramatic increase in obesity may provide a historical opportunity to conduct epidemiological studies of the thrifty genotype. In experimental settings, the effects of various forms of psychosocial stress in increasing metabolic efficiency and gene expression can be further tested.
 ...
PMID:The contribution of psychosocial stress to the obesity epidemic: an evolutionary approach. 1915 97

Obesity-associated inflammation causes insulin resistance. Obese adipose tissue displays hypertrophied adipocytes and increased expression of the cannabinoid-1 receptor. Cobalt protoporphyrin (CoPP) increases heme oxygenase-1 (HO-1) activity, increasing adiponectin and reducing inflammatory cytokines. We hypothesize that CoPP administration to Zucker diabetic fat (ZDF) rats would improve insulin sensitivity and remodel adipose tissue. Twelve-week-old Zucker lean and ZDF rats were divided into 4 groups: Zucker lean, Zucker lean-CoPP, ZDF, and ZDF-CoPP. Control groups received vehicle and treatment groups received CoPP (2 mg/kg body weight) once weekly for 6 weeks. Serum insulin levels and glucose response to insulin injection were measured. At 18 weeks of age, rats were euthanized, and aorta, kidney, and subcutaneous and visceral adipose tissues were harvested. HO-1 expression was measured by Western blot analysis and HO-1 activity by serum carbon monoxide content. Adipocyte size and cannabinoid-1 expression were measured. Adipose tissue volumes were determined using MRI. CoPP significantly increased HO-1 activity, phosphorylated AKT and phosphorylated AMP kinase, and serum adiponectin in ZDF rats. HO-1 induction improved hyperinsulinemia and insulin sensitivity in ZDF rats. Subcutaneous and visceral adipose tissue volumes were significantly decreased in ZDF rats. Adipocyte size and cannabinoid-1 expression were both significantly reduced in ZDF-CoPP rats in subcutaneous and visceral adipose tissues. This study demonstrates that HO-1 induction improves insulin sensitivity, downregulates the peripheral endocannabinoid system, reduces adipose tissue volume, and causes adipose tissue remodeling in a model of obesity-induced insulin resistance. These findings suggest HO-1 as a potential therapeutic target for obesity and its associated health risks.
 ...
PMID:Heme oxygenase-1 induction remodels adipose tissue and improves insulin sensitivity in obesity-induced diabetic rats. 1917 94


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