Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin is produced in adipose tissue and acts in the hypothalamus to regulate food intake. However, recent evidence also indicates a potential for direct roles for leptin in peripheral tissues, including those of the immune system. In this study, we provide direct evidence that macrophages are a target tissue for leptin. We found that J774.2 macrophages express the functional long form of the leptin receptor (ObRb) and that this becomes tyrosine-phosphorylated after stimulation with low doses of leptin. Leptin also stimulates both phosphoinositide 3-kinase (PI 3-kinase) activity and tyrosine phosphorylation of JAK2 and STAT3 in these cells. We investigated the effects of leptin on hormone-sensitive lipase (HSL), which acts as a neutral cholesterol esterase in macrophages and is a rate-limiting step in cholesterol ester breakdown. Leptin significantly increased HSL activity in J774.2 macrophages, and these effects were additive with the effects of cAMP and were blocked by PI 3-kinase inhibitors. Conversely, insulin inhibited HSL in macrophages, but unlike adipocytes, this effect did not require PI 3-kinase. These results indicate that leptin and insulin regulate cholesterol-ester homeostasis in macrophages and, therefore, defects in this process caused by leptin and/or insulin resistance could contribute to the increased incidence of atherosclerosis found associated with obesity and type 2 diabetes.
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PMID:Insulin and leptin acutely regulate cholesterol ester metabolism in macrophages by novel signaling pathways. 1133 38

I review evidence that leptin is a liporegulatory hormone that controls lipid homeostasis in nonadipose tissues during periods of overnutrition. When adipocytes store excess calories as triacylglycerol (TG), leptin secretion rises so as to prevent accumulation of lipids in nonadipose tissues, which are not adapted for TG storage. Whenever leptin action is lacking, whether through leptin deficiency or leptin resistance, overnutrition causes disease of nonadipose tissues with generalized steatosis, lipotoxicity, and lipoapoptosis. Examples of such disorders of liporegulation include generalized lipodystrophies, mutations of leptin and leptin receptor genes, and diet-induced obesity. Lipotoxicity of pancreatic beta-cells, myocardium, and skeletal muscle leads, respectively, to type 2 diabetes, cardiomyopathy, and insulin resistance. In humans this constellation of abnormalities is referred to as the metabolic syndrome, a major health problem in the United States. When lipids overaccumulate in nonadipose tissues during overnutrition, fatty acids enter deleterious pathways such as ceramide production, which, through increased nitric oxide formation, causes apoptosis of lipid-laden cells, such as beta-cells and cardiomyocytes. Lipoapoptosis can be prevented by caloric restriction, by thiazolidinedione treatment, and by administration of nitric oxide blockers. There is now substantial evidence that complications of human obesity may reflect lipotoxicity similar to that described in rodents.
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PMID:Lipotoxic diseases. 1181 77

Obesity-driven type 2 diabetes (diabesity) involves complex genetic and environmental interactions to trigger disease. Here, we combine variable numbers of known quantitative trait loci (QTL) for obesity and diabetes contributed by New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/Lt) strains in the form of 10 interval-directed recombinant congenic strains (RCS), with NON/Lt as the background strain, to dissect the genetic interactions involved. All 10 RCS gain significantly more weight than the NON parental strain, but none are as obese as the parental, diabetes-prone NZO. Diabetes development in these RCS at F12 ranges between 0 and 100%, depending on genetic constitution. RCS-2, -1, and -10 represent a step-wise increase in numbers of specific diabetogenic QTL, resulting in a step-wise increase in diabetes incidence. RCS-10 recreates the 100% incidence seen in (NZOxNON)F1 males, but with less weight gain. Similarly, RCS-6, -7, -8, and -9 represent diabetes-prone strains with different combinations of diabetogenic QTL. RCS-3, -4, and -5 represent obese strains that do not transit to diabetes. Because these obesity and diabetes syndromes reflect different collections of QTL, rather than null mutations in the leptin or leptin receptor genes, they are extremely relevant as models for the polygenic obesity/diabesity syndromes in humans.
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PMID:Deconstructing and reconstructing obesity-induced diabetes (diabesity) in mice. 1187 87

Great progress has been made in identifying several genes and in understanding the molecular pathogenesis of inherited syndromes of obesity and diabetes mellitus (DM). In humans, mutations in leptin, leptin receptor, proopiomelanocortin (POMC), melanocortin-4 receptor (MC4R) and prohormone convertase 1 (PC1) have been described in patients with severe obesity. Most of these obesity disorders, with the exception of the MC4R mutations, exhibit recessive inheritance and a distinct phenotype with varying degrees of hypothalamic dysfunction, and they unravel the critical role of the central leptin and melanocortin pathways in human appetite control and energy homeostasis. Maturity onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of type 2 DM with early onset autosomal dominant inheritance and a primary defect in insulin secretion. To date, six MODY genes have been identified, the glucokinase gene and five beta cell-specific transcription factor genes, hepatocyte nuclear factor-1alpha (HNF-1alpha), HNF-1beta, HNF-4alpha, insulin promoter factor-1 (IPF-1) and NeuroD1/BETA2. Mitochondrial DNA mutations cause another form of DM with an insulin secretory defect that is commonly associated with neurosensory hearing impairment, and has strict maternal inheritance. At the other end of the spectrum are the inherited syndromes of insulin resistance that are caused by mutations in the insulin receptor gene and in the adipocyte-specific transcription factor PPARgamma. The advances in our knowledge of the phenotypic manifestations and underlying molecular mechanisms of genetic syndromes of obesity and DM raise expectations for molecular diagnosis, as well as for more etiological therapies and better prevention of the continuously increasing prevalence of obesity and DM in our modern societies.
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PMID:Monogenic forms of obesity and diabetes mellitus. 1192 26

The prevalence of obesity is rising at an alarming rate worldwide, with consequent increases in type 2 diabetes, hypertension and cardiovascular morbidity and mortality. Central neural mechanisms, via the activation of the sympathetic nervous system may contribute to obesity-related cardiovascular diseases through the promotion of hypertension, dysrhythmia and atherosclerosis. However, the mechanisms responsible for this sympatho activation have not been identified. Leptin is an adipocyte-derived hormone that promotes weight loss by reducing appetite and by increasing energy expenditure through sympathetic stimulation to thermogenic tissue. Leptin also produces sympathoactivation to kidneys, hindlimb and adrenal glands, suggesting that the obesity-associated increase in sympathetic nerve activity could be due in part to these sympathetic effects of leptin. However, most human obesity appears to be associated with leptin resistance. Recent studies indicate that leptin resistance may be selective, with preservation of adverse sympathetic effects despite the loss of the metabolic actions of leptin. The leptin receptor is expressed in several hypothalamic nuclei including the arcuate nucleus. The melanocortin system, neuropeptide Y and corticotrophin-releasing factor have emerged as principal neuropeptide mediators of leptin action in the arcuate nucleus. These neuropeptides exert varying effects by different pathways. Several other candidate hypothalamic pathways that can mediate the effects of leptin have been identified. The understanding of neuronal signaling pathways involved in leptin signaling and energy balance has opened new research possibilities for the treatment of obesity.
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PMID:Leptin and the central neural mechanisms of obesity hypertension. 1258 70

Infant macrosomia is a classic feature of a gestational diabetes mellitus (GDM) pregnancy and is associated with increased risk of adult obesity and type II diabetes mellitus, however mechanisms linking GDM and later disease remain poorly understood. The heterozygous leptin receptor-deficient (Lepr(db/+)) mouse develops spontaneous GDM and the fetuses display characteristics similar to infants of GDM mothers. We examined the effects of GDM on maternal insulin resistance, fetal growth, and postnatal development of hepatic insulin resistance. Fetal body weight on d 18 of gestation was 6.5% greater (p < 0.05) in pups from ad libitum-fed db/+ mothers compared with wild-type (WT) controls. Pair-feeding db/+ mothers to the intake of WT mothers normalized fetal weight despite less than normal maternal insulin sensitivity. More stringent caloric restriction reduced insulin and glucose levels below WT controls and resulted in fetal intrauterine growth restriction. The level of hepatic insulin receptor protein was decreased by 28% to 31% in both intrauterine growth restriction and fetuses from ad libitum-fed GDM mothers compared with offspring from WT mothers. In 24-wk-old adult offspring from GDM mothers, body weight was similar to WT offspring, however, the females from GDM mothers were fatter and hyperinsulinemic compared with offspring from WT mothers. Insulin-stimulated phosphorylation of Akt, a key intermediate in insulin signaling, was severely decreased in the livers of adult GDM offspring. Hepatic glucose-6-phosphatase activity was also inappropriately increased in the adult offspring from GDM mothers. These results suggest that spontaneous GDM in the pregnant Lepr(db/+) mouse is triggered by overfeeding, and this effect results in obesity and insulin resistance in the livers of the adult offspring. The specific decrease in Akt phosphorylation in livers of adult offspring suggests that this may be a mechanism for reduced insulin-dependent physiologic events, such as suppression of hepatic glucose production, a defect associated with susceptibility to type II diabetes mellitus.
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PMID:Effect of spontaneous gestational diabetes on fetal and postnatal hepatic insulin resistance in Lepr(db/+) mice. 1259 88

Recent data suggest that plasma leptin may represent a cardiovascular risk factor in diabetic patients. To gain further insight into the role of leptin in atherogenesis associated with diabetes, we investigated in the present study the role of this hormone in the regulation of macrophage lipoprotein lipase (LPL), a proatherogenic cytokine overexpressed in patients with type 2 diabetes. Treatment of human macrophages with leptin (1-10 nmol/l) increased LPL expression, at both the mRNA and protein levels. Pretreatment of these cells with anti-leptin receptor (Ob-R) antibody, protein kinase C (PKC) inhibitors, calphostin C, and GF109203X, or the antioxidant N-acetylcysteine (NAC) blocked the effects of leptin. Similar results were observed in leptin-treated J774 macrophages. In these cells, leptin increased the membrane expression of conventional PKC isoforms and downregulation of endogenous PKC expression abolished the effects of leptin on macrophage LPL expression. In leptin-treated J774 cells, enhanced LPL synthetic rate and increased binding of nuclear proteins to the activated protein-1 (AP-1) consensus sequence of the LPL gene promoter were also observed. This latter effect was abrogated by GF109203X. Overall, these data demonstrate that binding of leptin at the macrophage cell surface increases, through oxidative stress- and PKC-dependent pathways, LPL expression. This effect appears to be exerted at the transcriptional level and to involve AP-1 activation.
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PMID:Leptin increases lipoprotein lipase secretion by macrophages: involvement of oxidative stress and protein kinase C. 1288 31

Although recent evidence suggests that leptin can directly regulate a wide spectrum of peripheral functions, including fat metabolism, genetic examples are still needed to illustrate the physiological significance of direct actions of leptin in a given peripheral tissue. To this end, we used a technical knock-out approach to reduce the expression of leptin receptors specifically in white adipose tissue. The evaluation of leptin receptor reduction in adipocytes was based on real time PCR analysis of the mRNA levels, Western blot analysis of the proteins, and biochemical analysis of leptin signaling capability. Despite a normal level of leptin receptors in the hypothalamus and normal food intake, mutant mice developed increased adiposity, decreased body temperature, hyperinsulinemia, hypertriglyceridemia, impaired glucose tolerance and insulin sensitivity, as well as elevated hepatic and skeletal muscle triglyceride levels. In addition, a variety of genes involved in regulating fat and glucose metabolism were dysregulated in white adipose tissue. These include tumor necrosis factor-alpha, adiponectin, leptin, fatty acid synthase, sterol regulatory element-binding protein 1, glycerol kinase, and beta3-adrenergic receptor. Furthermore, the mutant mice are significantly more sensitive to high fat feeding with regard to developing obesity and severe insulin resistance. Thus, we provide a genetic model demonstrating the physiological importance of a peripheral effect of leptin in vivo. Importantly, this suggests the possibility that leptin resistance at the adipocyte level might be a molecular link between obesity and type 2 diabetes.
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PMID:Adipocyte-selective reduction of the leptin receptors induced by antisense RNA leads to increased adiposity, dyslipidemia, and insulin resistance. 1292 33

Growing evidence suggests that positive associations between fat mass (FM) and bone mineral density (BMD) are mediated by not only biomechanical but also biochemical factors. Adiponectin is a novel adipocyte-derived hormone that regulates energy homeostasis and has anti-inflammatory and anti-atherogenic effects. Unlike other adipokines such as leptin, adiponectin levels decrease in obesity and type 2 diabetes. The purpose of our study was to investigate associations of serum adiponectin with BMD (DXA and QCT), FM (DXA and QCT), and serum leptin and soluble leptin receptor levels in 38 women and 42 men (age 39-81, BMI 17-55, 86% with type 2 diabetes). After adjusting for age, gender, race, smoking, and diabetes status, serum adiponectin was inversely associated with areal BMD (r = -0.20 to -0.3, all P < 0.01), volumetric BMD (r = -0.35 to -0.44, all P < 0.01), and visceral fat volume (r = -0.30, P < 0.01). These associations remained significant after adjusting for whole body fat mass. The associations of adiponectin with subcutaneous fat volume, whole body FM, and serum leptin level were not significant (all P > 0.1). These data suggest that adiponectin may play a role in the protective effects of visceral fat on BMD.
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PMID:Adiponectin as a novel determinant of bone mineral density and visceral fat. 1512 Oct 26

The hormone leptin is secreted from white adipocytes, and serum levels of leptin correlate with adipose tissue mass. Leptin was first described to act on the satiety center in the hypothalamus through specific receptors (leptin receptor [ObR]) to restrict food intake and enhance energy expenditure. Important peripheral actions of leptin involve inhibition of insulin biosynthesis and secretion in pancreatic beta-cells. In turn, insulin stimulates leptin secretion from adipose tissue, establishing a hormonal regulatory feedback loop-the so-called "adipo-insular axis." Multiple signal transduction pathways are involved in leptin signaling in pancreatic beta-cells. We have identified the proinsulin gene and protein phosphatase 1 gene as leptin repressed genes and the gene for the suppressor of cytokine signaling 3 protein as a leptin-induced gene in pancreatic beta-cells. The molecular effects of leptin culminate to restrict insulin secretion and biosynthesis to adapt glucose homeostasis to the amount of body fat. In most overweight individuals, however, physiological regulation of body weight by leptin seems to be disturbed, representing "leptin resistance." This leptin resistance at the level of the pancreatic beta-cell may contribute to dysregulation of the adipo-insular axis and promote the development of hyperinsulinemia and manifest type 2 diabetes in overweight patients.
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PMID:Leptin effects on pancreatic beta-cell gene expression and function. 1474 81


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