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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that acts as an intracellular energy sensor maintaining the energy balance within the cell. This pivotal role of AMPK places it in an ideal position for regulating whole-body energy metabolism, and AMPK might play a part in protecting the body from metabolic diseases such as type 2 diabetes and obesity. Mutations in AMPK cause cardiac hypertrophy and arrhythmia. Recent findings have identified LKB1--a protein kinase that is mutated in a hereditary form of cancer--as a candidate for the upstream kinase in the AMPK cascade. AMPK could provide a link in human diseases of which the underlying cause is due to defects in energy metabolism.
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PMID:The AMP-activated protein kinase cascade--a unifying system for energy control. 1472 28

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that acts as an intracellular energy sensor maintaining the energy balance within the cell. The finding that leptin and adiponectin activate AMPK to alter metabolic pathways in muscle and liver provides direct evidence for this role in peripheral tissues. The hypothalamus is a key regulator of food intake and energy balance, coordinating body adiposity and nutritional state in response to peripheral hormones, such as leptin, peptide YY-(3-36), and ghrelin. To date the hormonal regulation of AMPK in the hypothalamus, or its potential role in the control of food intake, have not been reported. Here we demonstrate that counter-regulatory hormones involved in appetite control regulate AMPK activity and that pharmacological activation of AMPK in the hypothalamus increases food intake. In vivo administration of leptin, which leads to a reduction in food intake, decreases hypothalamic AMPK activity. By contrast, injection of ghrelin in vivo, which increases food intake, stimulates AMPK activity in the hypothalamus. Consistent with the effect of ghrelin, injection of 5-amino-4-imidazole carboxamide riboside, a pharmacological activator of AMPK, into either the third cerebral ventricle or directly into the paraventricular nucleus of the hypothalamus significantly increased food intake. These results suggest that AMPK is regulated in the hypothalamus by hormones which regulate food intake. Furthermore, direct pharmacological activation of AMPK in the hypothalamus is sufficient to increase food intake. These findings demonstrate that AMPK plays a role in the regulation of feeding and identify AMPK as a novel target for anti-obesity drugs.
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PMID:AMP-activated protein kinase plays a role in the control of food intake. 1474 38

Dietary energy restriction (DER) has long been known to strikingly inhibit carcinogenesis in many animal models. The animal data has been corroborated by recent and ongoing epidemiological studies demonstrating the importance of energy balance, physical exercise and obesity in human cancer. Dr. Edward Bresnick provided key insights into this important area of research and pivotal direction for the author's research while he served as Director of the Eppley Institute for Research in Cancer, Omaha, NE. These insights moved this research toward demonstrating that DER reduced the expression of key protein kinase C isoforms in mouse skin. More recent studies have uncovered downstream events that are inhibited by DER including blockage of tumor promoter activation of Raf-1, ERK 1,2 and AP-1 expression. Parallel studies have demonstrated the DER inhibition of these key cellular signaling events in mouse skin carcinogenesis are dependent upon an intact adrenal gland because adrenalectomized mice fed DER diet did not have reduced tumor burden or inhibited signaling and blocked AP-1 activation as was observed in DER mice with intact adrenal glands. In addition, the DER inhibition of tumorigenesis and AP-1 signaling was restored in adrenalectomized mice that were given corticosterone in the drinking water. This showed that in mice in the chemical carcinogenesis protocol glucocorticoid hormone plays a major role in mediating DER prevention of cancer. Studies are ongoing to further assess the mechanism of DER modulation of skin cancer by assessing impacts on transcriptional regulation and expression of genes that are critical in skin carcinogenesis.
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PMID:Identification of molecular targets for dietary energy restriction prevention of skin carcinogenesis: an idea cultivated by Edward Bresnick. 1474 86

Leptin modulates glucose homeostasis by acting as an insulin-sensitizing factor in most insulin target tissues. Nevertheless, insulin-dependent glucose uptake in white adipose tissue decreases after in vivo treatment with leptin. Moreover, elevated leptin concentrations inhibit insulin metabolic effects in adipocytes. Here we studied both, direct and centrally mediated effects of leptin on insulin signaling in rat adipocytes. Adipocyte incubation with low leptin concentrations did not modify the insulin stimulation of mitogen-activated protein kinase (MAPK). However, at elevated concentrations, leptin impaired insulin-stimulated MAPK activity, glycogen synthase kinase (GSK)3beta phosphorylation, and insulin receptor tyrosine phosphorylation without altering vanadate stimulation. An increase of suppressor of cytokine signaling-3 protein was also observed. Central administration of leptin decreased insulin effects on adipocyte MAPK and GSK3beta phosphorylation. In insulin-resistant aged rats with hyperleptinemia and central leptin resistance, insulin poorly stimulated MAPK and central leptin infusion did not further deteriorate adipocyte insulin responsiveness. Food restriction increased MAPK stimulation by insulin and restored the ability of centrally infused leptin to attenuate adipocyte insulin signaling in aged rats. We conclude that leptin can modulate, in an inhibitory manner, adipocyte insulin signaling by two different ways: as an autocrine signal and, indirectly, through neuroendocrine pathways. These mechanisms may be of relevance in situations of hyperleptinemia, such as aging and/or obesity.
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PMID:Leptin impairs insulin signaling in rat adipocytes. 1474 84

The adipose renin-angiotensin system (RAS) has been assigned to participate in the control of adipose tissue development and in the pathogenesis of obesity-related hypertension. In adipose cells, the biological responses to beta-adrenergic stimulation are mediated by an increase in intracellular cAMP. Because cAMP is known to promote adipogenesis and because an association exists between body fat mass, hypertension, and increased sympathetic stimulation, we examined the influence of cAMP on angiotensinogen (ATG) expression and secretion in rat adipose tissue. Exposure of primary cultured differentiated preadipocytes to the cAMP analog 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) or cAMP-stimulating agents (forskolin and IBMX) results in a significant increase in ATG mRNA levels. In adipose tissue fragments, 8-BrcAMP also increases ATG mRNA levels and protein secretion, but not in the presence of the protein kinase A inhibitor H89. The addition of isoproterenol, known to stimulate the synthesis of intracellular cAMP via beta-adrenoreceptors, had the same stimulatory effect on ATG expression and secretion. These results indicate that cAMP in vitro upregulates ATG expression and secretion in rat adipose tissue via the protein kinase A-dependent pathway. Further studies are required to determine whether this regulatory pathway is activated in human obesity, where increased sympathetic tone is frequently observed, and to elucidate the importance of adipose ATG to the elevated blood pressure observed in this pathological state.
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PMID:cAMP-positive regulation of angiotensinogen gene expression and protein secretion in rat adipose tissue. 1476 74

The association between obesity and diabetes supports an endocrine role for the adipocyte in maintaining glucose homeostasis. Here we report that mice lacking the adipocyte hormone resistin exhibit low blood glucose levels after fasting, due to reduced hepatic glucose production. This is partly mediated by activation of adenosine monophosphate-activated protein kinase and decreased expression of gluconeogenic enzymes in the liver. The data thus support a physiological function for resistin in the maintenance of blood glucose during fasting. Remarkably, lack of resistin diminishes the increase in post-fast blood glucose normally associated with increased weight, suggesting a role for resistin in mediating hyperglycemia associated with obesity.
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PMID:Regulation of fasted blood glucose by resistin. 1497 16

The perilipins are highly phosphorylated adipocyte proteins that are localized at the surface of the lipid droplet. With activation by protein kinase A, perilipins translocate away from the lipid droplet and allow hormone-sensitive lipase to hydrolyze the adipocyte triglycerides to release nonesterified fatty acids (NEFA). Because of the potential importance of adipocyte lipolysis to obesity and insulin resistance, we measured perilipin protein and mRNA levels in nondiabetic subjects with varying degrees of insulin resistance. By Northern and Western blotting, we could detect perilipin A, but not perilipin B. Perilipin A protein and mRNA levels were quantitated and were highly correlated with each other. There was a significant positive relationship between perilipin expression and obesity (r = 0.55; P < 0.01, perilipin mRNA vs. percent body fat). However, there was no significant relationship between perilipin expression and blood NEFA, nor was there a significant relationship between perilipin expression and insulin resistance, using the insulin sensitivity index derived from the iv glucose tolerance test with minimal modeling. In addition, there was no significant relationship between perilipin and adipocyte or systemic inflammatory markers, such as TNFalpha, IL-6, and adiponectin. Thus, perilipin was elevated in obese subjects, perhaps as a compensatory mechanism to limit basal lipolysis. However, there was no relationship between perilipin and insulin resistance.
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PMID:Perilipin expression in human adipose tissue is elevated with obesity. 1500 33

Mice with a fat-specific insulin receptor knock-out (FIRKO) have reduced adipose tissue mass, are protected against obesity, and have an extended life span. White adipose tissue of FIRKO mice is also characterized by a polarization into two major populations of adipocytes, one small (<50 microm) and one large (>100 microm), which differ with regard to basal triglyceride synthesis and lipolysis, as well as in the expression of fatty acid synthase, sterol regulatory element-binding protein 1c, and CCAAT/enhancer-binding protein alpha (C/EBP-alpha). Gene expression analysis using RNA isolated from large and small adipocytes of FIRKO and control (IR lox/lox) mice was performed on oligonucleotide microarrays. Of the 12,488 genes/expressed sequence tags represented, 111 genes were expressed differentially in the four populations of adipocytes at the p < 0.001 level. These alterations exhibited 10 defined patterns and occurred in response to two distinct regulatory effects. 63 genes were identified as changed in expression depending primarily upon adipocyte size, including C/EBP-alpha, C/EBP-delta, superoxide dismutase 3, and the platelet-derived growth factor receptor. 48 genes were regulated primarily by impairment of insulin signaling, including transforming growth factor beta, interferon gamma, insulin-like growth factor I receptor, activating transcription factor 3, aldehyde dehydrogenase 2, and protein kinase Cdelta. These data suggest an intrinsic heterogeneity of adipocytes with differences in gene expression related to adipocyte size and insulin signaling.
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PMID:Intrinsic heterogeneity in adipose tissue of fat-specific insulin receptor knock-out mice is associated with differences in patterns of gene expression. 1513 Nov 19

Mice lacking the RII beta regulatory subunit of protein kinase A exhibit a 50% reduction in white adipose tissue stores compared with wild-type littermates and are resistant to diet-induced obesity. RII beta(-/-) mice also have an increase in resting oxygen consumption along with a 4-fold increase in the brown adipose-specific mitochondrial uncoupling protein 1 (UCP1). In this study, we examined the basis for UCP1 induction and tested the hypothesis that the induced levels of UCP1 in RII beta null mice are essential for the lean phenotype. The induction of UCP1 occurred at the protein but not the mRNA level and correlated with an increase in mitochondria in brown adipose tissue. Mice lacking both RII beta and UCP1 (RII beta(-/-)/Ucp1(-/-)) were created, and the key parameters of metabolism and body composition were studied. We discovered that RII beta(-/-) mice exhibit nocturnal hyperactivity in addition to the increased oxygen consumption at rest. Disruption of UCP1 in RII beta(-/-) mice reduced basal oxygen consumption but did not prevent the nocturnal hyperactivity. The double knockout animals also retained the lean phenotype of the RII beta null mice, demonstrating that induction of UCP1 and increased resting oxygen consumption is not the cause of leanness in the RII beta mutant mice.
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PMID:The role of uncoupling protein 1 in the metabolism and adiposity of RII beta-protein kinase A-deficient mice. 1519 81

FOXC2 is a winged helix/forkhead transcription factor involved in PKA signaling. Overexpression of FOXC2 in the adipose tissue of transgenic mice protected against diet-induced obesity and insulin resistance. We examined the expression of FOXC2 in fat and muscle of nondiabetic humans with varying obesity and insulin sensitivity. There was no relation between body mass index (BMI) and FOXC2 mRNA in either adipose or muscle. There was a strong inverse relation between adipose FOXC2 mRNA and insulin sensitivity, using the frequently sampled intravenous glucose tolerance test (r = -0.78, P < 0.001). However, there was no relationship between muscle FOXC2 and any measure of insulin sensitivity. To separate insulin resistance from obesity, we examined FOXC2 expression in pairs of subjects who were matched for BMI but who were discordant for insulin sensitivity. Compared with insulin-sensitive subjects, insulin-resistant subjects had threefold higher levels of adipose FOXC2 mRNA (P = 0.03). In contrast, muscle FOXC2 mRNA expression was no different between insulin-resistant and insulin-sensitive subjects. There was no association of adipose or muscle FOXC2 mRNA with either circulating or adipose-secreted TNF-alpha, IL-6, leptin, adiponectin, or non-esterified fatty acids. Thus adipose FOXC2 is more highly expressed in insulin-resistant subjects, and this effect is independent of obesity. This association between FOXC2 and insulin resistance may be related to the role of FOXC2 in PKA signaling.
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PMID:Expression of FOXC2 in adipose and muscle and its association with whole body insulin sensitivity. 1519 34


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