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)

To explore the pathophysiological significance of the obese (ob) gene product, leptin, in ventromedial hypothalamus (VMH)-lesioned rats, we examined the synthesis and secretion of leptin and its satiety effect in VMH-lesioned rats compared with those in sham-operated rats. Northern blot analysis revealed that ob gene expression is markedly augmented in the mesenteric and sc white adipose tissue, but remained unchanged in the epididymal white adipose tissue during the development of obesity in VMH-lesioned rats. Plasma leptin levels were relatively constant in sham-operated rats, but were elevated during the development of obesity in VMH-lesioned rats. In sham-operated rats, a single i.v. (1.0 mg/rat) or intracerebroventricular (2.0 micrograms/rat) injection of recombinant human leptin reduced food intake and body weight gain in sham-operated rats. By contrast, no significant effect on food intake or body weight gain was observed in VMH-lesioned rats. The present study provides evidence that VMH-lesioned rats overproduce leptin and increase its release but cannot respond to it and suggests that the loss of its satiety effect contributes to the development of obesity and the obesity-related phenotypes in VMH-lesioned rats.
 ...
PMID:Pathophysiological significance of the obese gene product, leptin, in ventromedial hypothalamus (VMH)-lesioned rats: evidence for loss of its satiety effect in VMH-lesioned rats. 904 94

Obesity is a major predisposing factor for the development of several chronic diseases including non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD). Leptin is a serum protein which is secreted by adipocytes and thought to play a role in the regulation of body fat. Leptin levels in humans have been found to be highly correlated with an individual's total adiposity. We performed a genome-wide scan and conducted multipoint linkage analysis using a general pedigree-based variance component approach to identify genes with measurable effects on quantitative variation in leptin levels in Mexican Americans. A microsatellite polymorphism, D2S1788, mapped to chromosome 2p21 (approximately 74 cM from the tip of the short arm) and showed strong evidence of linkage with serum leptin levels with a lod score of 4.95 (P = 9 x 10(-7)). This locus accounted for 47% of the variation in serum leptin levels, with a residual additive genetic component contributing an additional 24%. This region contains several potential candidate genes for obesity, including glucokinase regulatory protein (GCKR) and pro-opiomelanocortin (POMC). Our results show strong evidence of linkage of this region of chromosome 2 with serum leptin levels and indicate that this region could contain an important human obesity gene.
 ...
PMID:A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. 905 40

The ob gene product, leptin, has been shown in several studies to be involved in weight control and recombinant leptin recently has entered clinical trials to treat obesity. The leptin receptor (OB-R/B219) is expressed in a variety of protein isoforms not only in the central nervous system, but also in reproductive, and hematopoietic tissues. We reported recently that the OB-R/B219 was associated with a variety of hematopoietic lineages as well as the small fraction of cells containing the long-term reconstituting hematopoietic stem cells. Herein we report that leptin significantly stimulates the proliferation and differentiation of yolk sac cells and fetal liver cells and stimulates directly hematopoietic precursors. Leptin alone can increase the number of macrophage and granulocyte colonies, and leptin plus erythropoietin act synergistically to increase erythroid development. These data show that leptin has a significant, direct effect on early hematopoietic development and can stimulate the differentiation of lineage-restricted precursors of the erythrocytic and myelopoietic lineages. These observations along with a recent report strongly support our previous hypothesis that leptin has an unanticipated important role in hematopoietic and immune system development.
 ...
PMID:Leptin stimulates fetal and adult erythroid and myeloid development. 937 66

Our knowledge of the role of the recently cloned ob-protein (leptin) in the regulation of body fat stores is largely derived from experiments performed in mice. Different mouse models exhibit abnormalities in ob-gene expression, with extreme overexpression in mice which lack bioactive ob-protein, have nonfunctional ob-receptors or hypothalamic lesions, and undetectable expression in mice with suggested defects in regulatory elements. The aim of this study is to examine if defects, corresponding to those in mice, exist in human obesity. Adipose tissue was obtained from 94 adult obese subjects and from six children who had developed obesity after surgery in the hypothalamic region. Total RNA was isolated and ob-gene expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and Northern blot. The coding region of the ob-gene was sequenced in both directions in the 94 obese adults. No mutations were detected in the coding region of the ob-gene and ob-gene expression was detectable in all subjects and none of the subjects had an extreme overexpression. There was no systematic increase in ob-expression in obese children with hypothalamic disease compared to their healthy brothers and sisters. These results show that severe abnormalities involving the ob-gene, analogous to those described in mouse models, are rare in human obesity. We therefore conclude that the cloning and subsequent analysis of the ob-gene has not provided information that can, by itself, explain the genetic component in the development of human obesity.
 ...
PMID:Obese (ob) gene defects are rare in human obesity. 906 13

Plasma leptin concentration is directly related to the degree of obesity and is higher in women than in men of the same body mass index (BMI). We hypothesized that fasting plasma leptin concentrations and the response of leptin to weight loss would differ in older men and women of a similar fat mass. Plasma leptin concentrations (radioimmunoassay) and fat mass (DXA) were measured in 47 older, obese (BMI = 30 +/- 4 kg/m2) women and 23 older, obese (BMI = 31 +/- 3 kg/m2) men after a 2 to 4 week period of weight and dietary stabilization, and then in 22 of the women and 18 of the men after a 6-month weight loss intervention (250-350 kcal/d deficit). Leptin correlated with fat mass in men and women (r = 0.75 and r = 0.77, respectively; p values < 0.0001), but women had 3-fold higher leptin levels for a given fat mass than men (p = 0.01). In response to the 6-month hypocaloric diet, men and women lost a similar percentage of fat mass (-13% and -16%, respectively), but the relative decline in circulating leptin was greater in women than men (-45% and -21%, respectively; p < 0.0001). In addition, when leptin was normalized for fat mass using the ratio method, the decrease in leptin per kilogram of fat mass was greater in women than men (-0.37 +/- 0.34 vs. -0.04 +/- 0.06 ng/mL/kg; p < 0.01). After weight loss, the change in leptin concentrations correlated positively with the change in fat mass in men (r = 0.60; p < 0.01), but not in women (r = 0.31; p = 0.17). Furthermore, the loss in fat mass correlated negatively with baseline leptin levels in women (r = -0.47; p < 0.05), but not in men (r = 0.03, p = NS). These results indicate that the decline in leptin concentration with weight loss correlates with the loss in fat mass in men; but, in women, other factors affect the decrease in leptin concentration. This suggests that the role of leptin in the regulation of obesity is gender-specific and may account for gender differences in response to hypocaloric treatment and maintenance of lost weight.
 ...
PMID:Gender differences in the response of plasma leptin concentrations to weight loss in obese older individuals. 906 17

To explore the pathophysiologic roles of the obese (ob) gene product, leptin, in the development of obesity and hypertension, we examined ob gene expression and leptin secretion in obese spontaneously hypertensive rats (obese SHR or Koletsky rats) at the stage of established obesity and hypertension. Expression of the ob gene was augmented in the epididymal, mesenteric, subcutaneous, and retroperitoneal white adipose tissue (WAT) from 20-week-old male obese SHR compared to their lean littermates (lean SHR). Using a radioimmunoassay for rat leptin, we also measured plasma leptin levels in 20-week-old lean and obese SHR. Plasma leptin levels in obese SHR (292.5 +/- 37.1 ng/ml) were more than 100-fold higher than those in lean SHR (2.8 +/- 1.0 ng/ml). The present study demonstrates that ob gene expression and leptin secretion are markedly augmented in obese SHR.
 ...
PMID:Augmentation of obese (ob) gene expression and leptin secretion in obese spontaneously hypertensive rats (obese SHR or Koletsky rats). 907 Aug 50

The product of the ob gene, leptin, is a hormone secreted by adipose tissue that acts in the hypothalamus to regulate the size of the body fat depot. Its central administration has been shown to decrease food intake and body weight, while favoring energy dissipation. As glucocorticoids are known to play a permissive role in the establishment and maintenance of obesity syndromes in rodents, it was hypothesized that they do so by restraining the effect of leptin. Leptin injected intracerebroventricularly as a bolus of 3 microg in normal rats induced modest reductions in body weight and food intake. In marked contrast, the same dose of leptin had very potent and long-lasting effects in decreasing both body weight and food intake when administered to adrenalectomized rats. Further, glucocorticoid supplementation of adrenalectomized rats dose-dependently inhibited these potent effects of leptin. These data suggest that glucocorticoids play a key inhibitory role in the action of leptin. Under normal conditions, this inhibitory influence of glucocorticoids may prevent lasting hypophagia. In obesity with degrees of hypercorticism, it may contribute to "leptin resistance," whose etiology is still little understood.
 ...
PMID:Glucocorticoids as counterregulatory hormones of leptin: toward an understanding of leptin resistance. 907 17

Thirty-five years ago, Lois and Theodore Zucker reported the discovery of a genetic mutation in the rat that resulted in juvenile-onset obesity, increased food intake, decreased energy expenditure, and insulin resistance. The mutation was called fatty (fa). The fatty gene is passed on to successive generations by an autosomal recessive mode of inheritance. In the intervening years, much work has been done to characterize the many abnormalities of this animal model of obesity. Nearly 10 years ago, we reviewed the evidence for a central nervous system mechanism in the etiology of obesity in the fatty Zucker rat. Since that time, the discovery of novel peptides and genes has revolutionized the study of the etiology of genetically linked obesities. In this review, we update the evidence for a central nervous system mechanism of obesity in Zucker rats by focusing on the possible role of neuropeptide Y (NPY) and leptin in the etiology of obesity. We also discuss the role of glucocorticoids and insulin in the regulation of NPY.
 ...
PMID:Evidence for a central mechanism of obesity in the Zucker rat: role of neuropeptide Y and leptin. 908 55

Leptin is the protein product of the obesity (OB) gene in humans. To date, no study has correlated serum leptin levels with ethnicity, cigarette smoking, or other cardiovascular risk factors. In this study, serum leptin levels were measured in 100 Mexican Americans and 50 non-Hispanic whites who participated in the San Antonio Heart Study. Mexican Americans had higher levels of serum leptin than age- and sex-matched non-Hispanic whites (21 vs. 16 ng/mL). However, the leptin levels were similar in the two groups after controlling for body mass index (BMI). Women had higher levels of serum leptin than did men (24 vs. 9 ng/mL; P < .0001). There was a strong association between leptin levels and BMI (r = 0.91 in non-Hispanic white men; r = 0.77 in non-Hispanic women; r = 0.81 in Mexican American men; and r = 0.78 in Mexican American women). A model containing age, sex, and BMI explained 79% of the variance in serum leptin levels. After adjustment for age, sex, and BMI, current cigarette smokers had significantly lower leptin levels than never-smokers (p < 0.05). The results suggested that human obesity was associated with leptin-resistance rather than leptin-deficiency. Leptin levels were positively associated with BMI in this cross-sectional analysis. Cigarette smoking may increase sensitivity to leptin, since cigarette smokers had lower leptin levels than did nonsmokers with the same BMI.
 ...
PMID:Serum leptin levels in Mexican Americans and non-Hispanic whites: association with body mass index and cigarette smoking. 909 94

Leptin is an adipocyte hormone involved in the regulation of energy homeostasis. Generally accepted biological effects of leptin are inhibition of food intake and stimulation of metabolic rate in ob/ob mice that are defective in the leptin gene. In contrast to these centrally mediated effects of leptin, we are reporting here on leptin effects on isolated rat adipocytes. Leptin impairs several metabolic actions of insulin, i.e. stimulation of glucose transport, glycogen synthase, lipogenesis, inhibition of isoproterenol-induced lipolysis, and protein kinase A activation, as well as stimulation of protein synthesis. Insulin effects were reduced by leptin (2 nM) with a half-life of about 8 h. At low leptin concentrations (<1 nM), the insulin sensitivity was reduced leading to a shift to the right in the dose-response curve. At higher concentrations the responsiveness was diminished, resulting in nearly complete inhibition of insulin effects at >30 nM leptin. The IC50 value of leptin was 3.1 +/- 1 nM after 15 h of preincubation of adipocytes in primary culture. The natural splice variant des-Gln49-leptin exhibited a significantly lower potency. Adipocytes regained full insulin sensitivity within a few hours after leptin removal. The stimulation of glucose transport by vanadate was not affected by leptin. These data show specific and potent impairment of insulin action by leptin in the physiological concentration range of both leptin and insulin, which may be related to the pathophysiology of insulin resistance in both non-insulin-dependent diabetes mellitus and obesity.
 ...
PMID:Leptin impairs metabolic actions of insulin in isolated rat adipocytes. 909 5


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