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

OB protein (also known as leptin), a previously unknown protein signal, is secreted from adipose tissue, circulates in the blood, probably bound to a family of binding proteins, and acts on central neural networks that regulate ingestive behavior and energy balance. OB protein provides a communication link from fat tissue and the brain. Rapidly accumulating evidence suggests that OB protein appears to play a major role in the control of body fat stores through coordinated regulation of feeding behavior, metabolism, autonomic nervous system and body energy balance in rodents, primates and humans. The field has rapidly moved from cloning of the ob gene to demonstration of complex regulation of ob gene expression in adipose tissue in rats and humans, and then the demonstration of potent biological activity of OB protein in ob/ob, diet-induced, and lean mice as well as obese and lean rats but not in db/db obese mice. A significant milestone was our demonstration that central administration of OB protein lead to reductions in food intake, body weight and alterations in metabolism consistent with activation of the autonomic nervous system. These findings were followed by the identification of a central binding site for labelled OB protein in the choroid plexus in ob/ob, db/db and lean mice as well as lean and obese Zucker rats. The expression cloning of a central receptor, OB-R, from the mouse choroid plexus soon followed. The OB-R receptor was found to be expressed in the choroid plexus, the hypothalamus as well as several peripheral tissues. OB-R exists in multiple forms; the two major forms are a short form (with a truncated intracellular domain) and long form (with the complete intracellular domain). The long form is thought to be the form that signals and mediates the biological effects of OB protein. Initial in situ hybridization studies have demonstrated the mRNA for the long form OB-R receptor to be localized to the hypothalamus as well as peripheral sites. Recently, it was demonstrated that the db gene encodes the OB-R receptor. Evidence has been provided for a specific transport system for OB protein to cross the blood-brain-barrier and enter the brain of mice, rats and humans. The rate of transport can be decreased by high plasma concentrations of OB protein. Thus, reduced entry of OB protein to the brain may be one of the mechanisms of reduced sensitivity of the OB protein pathway in obese individuals. OB protein appears to also play a role in the important neuroendocrine adaptive responses to fasting and in the control of reproduction. Therapeutic approaches to the treatment of obesity based on OB protein ranging from OB protein by injection to OB-R receptor agonists and to upregulation of OB signalling pathways are under intense investigation.
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PMID:The OB protein (leptin) pathway--a link between adipose tissue mass and central neural networks. 901 31

Over the years, the work of research laboratories in Baton Rouge (USA), Seattle (USA) and Geneva (Switzerland) have reached analogous conclusions regarding the main etiology of obesity as studied in animals: it largely lies within the brain, notably within the hypothalamus. The hypothalamus is indeed known to modulate food intake and energy partitioning, while the periphery has also been proposed to feed-back on the central nervous system (CNS) to provide information on the state of body energy stores, the two together constituting a loop system connecting the brain to the periphery (1,2,3). This etiologic viewpoint of a pivotal role of the hypothalamus in obesity syndromes has been strengthened by the discovery of one hypothalamic neuropeptide and one peripheral (adipose tissue) hormone, respectively neuropeptide Y (4), and quite particularly, leptin (5). As neuropeptide Y produces hyperphagia (6, 7) and as leptin produces hypophagia in normal animals (8,9,10), the loop system just mentioned was thought to comprise functional relationships, at least between these two factors. Other evidence also suggested that such a loop system was altered in obese animals.
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PMID:The loop system between neuropeptide Y and leptin in normal and obese rodents. 901 34

The protein encoded by the obese (ob) gene, leptin, is secreted from adipose tissue and is proposed to act in the brain as an important regulator of food intake and body weight. To investigate the direct effects of leptin within the CNS, we injected 3.5 microg of either mouse or human leptin into the third ventricle (ICV) of lean Long-Evans rats or obese (fa/fa) Zucker rats, in which obesity results from a mutation in the leptin receptor gene. ICV administration of leptin reduced 4-h food intake in both deprived and non-deprived lean rats. In addition, repeated ICV administration produced a long-lasting reduction in body weight while peripheral administration of the same dose had no effect. ICV administration of the same dose of leptin into the third ventricle of obese Zucker rats did not reduce food intake. These results are consistent with the hypothesis that leptin has direct actions in the CNS as an afferent signal related to the state of energy stores in adipose tissue. Furthermore, insensitivity to these central effects of leptin may be an important determinant of obesity.
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PMID:Intraventricular leptin reduces food intake and body weight of lean rats but not obese Zucker rats. 901 38

NON mice exhibit a polygenic syndrome of mild obesity which is less pronounced than that of the ob and db strains. Here, we have shown that the syndrome is accompanied by a rise in leptin mRNA levels in adipose tissue, corresponding with the increase in adipose tissue mass. Surprisingly, levels of the leptin protein in adipose tissue and serum were comparable to those of lean control animals (BL57/Ksj-+/+), and markedly lower than those in db/db-mice. The coding regions of the cDNA sequences of both leptin and the leptin receptor from NON mice were identical with those of the wild-type sequences. We suggested that low levels of leptin in adipose tissue and serum contribute to the obesity of NON mice.
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PMID:Evidence that reduced leptin levels, but not an aberrant sequence of leptin or its receptor, contribute to the obesity syndrome in NON mice. 901 39

Plasma leptin levels in normal-weight and spontaneously obese male rhesus monkeys, and the relationships of circulating leptin to beta-cell basal secretion, glucose-stimulated responsiveness and peripheral insulin sensitivity, were determined. Basal leptin in normal lean adult monkeys averaged 6.0 +/- 1.3 ng/ml and in the obese monkeys averaged 22.6 +/- 2.9 ng/ml. In all monkeys, plasma leptin concentration was significantly related to body weight, body fat, fasting plasma insulin, acute insulin response to intravenous glucose, and peripheral insulin sensitivity but not to fasting glucose or glucose tolerance. Body fat and plasma insulin concentration were the best predictors of circulating leptin levels (R2 = 62.6%) independent of peripheral insulin sensitivity. Four of 17 obese monkeys had plasma leptin concentrations in the normal range, a finding that may be related to the heterogeneity of obesity. The close association of plasma leptin to body fat and plasma insulin (both basal and glucose-stimulated) support the possibility of a role of leptin in the link between obesity and beta-cell hypersecretion. However, the potential role of leptin in the development of peripheral insulin resistance, hyperglycemia and type 2 diabetes will require further study.
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PMID:Hyperleptinemia: relationship to adiposity and insulin resistance in the spontaneously obese rhesus monkey. 901 40

Differences in fat cell size and function among adipose tissue depots are well known and may be important in the pathophysiology of the metabolic and cardiovascular complications of obesity. Since the newly discovered adipocyte hormone leptin is thought to be a central factor in the regulation of energy homeostasis, it may be interesting to know if there are regional differences in leptin production. The aim of this study was to compare the level of leptin expression in the omental and subcutaneous abdominal adipose tissue from obese humans. Adipose tissue samples were collected from 25 severely obese adults (mean BMI: 48.9 +/- 9.7 kg/m2) undergoing vertical gastric banding. Semi-quantitative determination of leptin mRNA by the RT-PCR technique showed significantly lower leptin expression in omental compared to subcutaneous abdominal adipose tissue (leptin/Sp1 ratio in omental vs. subcutaneous fat: 1.53 +/- 0.89 vs. 3.02 +/- 1.58, p < 0.01). Identical results were obtained when Northern blotting was applied in a subgroup. Leptin expression increased with age in omental adipose tissue (r = 0.42, p < 0.05), but not in subcutaneous tissue. No correlation was found between BMI or waist/hip ratio (WHR) and leptin expression in omental or subcutaneous adipose tissue. The regional difference in leptin expression was similar in the patients with impaired glucose tolerance/type-2 diabetes and those with normal glucose tolerance. In conclusion, the results of this study indicate that leptin expression is lower in omental than subcutaneous adipose tissue, possibly due to differences in fat cell size and/or sympathetic innervation.
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PMID:Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans. 901 43

Leptin, the product of the obese (ob) gene, is a 16 kilodalton protein secreted from adipose tissue. Restoration of leptin to obese ob/ob mice leads to normalization of body weight. The effect of leptin in larger animals has not been explored, in part because of limited supplies of leptin. To date, the potency and yield of recombinant leptin purified from a variety of eukaryotic sources or from E. coli has been highly variable. While purification of leptin from E. coli inclusion bodies has afforded the greatest yield of protein, its potency is at least an order of magnitude lower than that of leptin secreted from E. coli or eukaryotic cells. The mechanistic basis of this difference in potency is not clear at present. The ability to purify significant quantities of highly active leptin will be crucial for the evaluation of leptin structure, as well as its function in additional animal models of obesity. We now report a facile protocol for the preparation of recombinant leptin using an E. coli expression system. 75-85 milligrams of leptin with a purity of greater than 97 % was prepared from a liter of recombinant E. coil. The procedure can be performed in less than 48 h and requires no chromatography. Intraperitoneal injection of 0.1 mg/kg renatured leptin into ob/ob mice results in a significant reduction in food consumption. The potency of this material is similar to the most potent recombinant leptin described to date. The ability to rapidly prepare large quantities of high specific activity material will hasten the definition of leptin's role in non-rodent models of obesity.
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PMID:Purification of milligram quantities of human leptin from recombinant E. coli. 901 44

Serum leptin concentrations and the levels of ob mRNA in adipocytes in obese humans are elevated. Hyperphagia and obesity are characteristics of hypercortisolism. We have therefore asked whether or not leptin levels were elevated in very obese children, and whether or not dexamethasone would increase leptin levels in obese children. A single dose dexamethasone suppression test was performed in ten obese children (5 girls, 5 boys; age 6 to 16 yrs, mean 12 +/- 1, median 12 yrs) to rule out hypercortisolism. Body mass index (BMI) in the ten children was calculated to be 27-45 kg/m2. Venous blood was sampled before dexamethasone was given in the evening and at 9.00 a.m. the following morning. Endogenous cortisol production was suppressed in all patients. Leptin levels, as measured by a newly developed specific radioimmunoassay, were 31.6 +/- 12.9 microg/l, range 19.2-59.9 microg/l before dexamethasone and 39.9 +/- 16.5 microg/l, range 26.3-80.3 microg/l after dexamethasone in the obese children (ANOVA, p = 0.01). Simple regression analysis revealed that serum levels correlated significantly with body mass index (r = 0.82, p < 0.001). Non-obese children (BMI < 27 kg/m2) had leptin levels between 0.1 and 33.3 microg/l, median 2.2 microg/l (N = 713). Girls (5.5 +/- 4.6 microg/l) (N = 401) had significantly higher leptin levels than boys (1.7 +/- 2.1 microg/l (N = 312) (p < 0.0001). We conclude that 1) high serum leptin concentrations are present in obese children. 2) A single dose of dexamethasone significantly increases the high leptin serum levels in these children. We hypothesize that glucocorticosteroids up-regulate leptin levels in the human.
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PMID:High leptin concentrations in serum of very obese children are further stimulated by dexamethasone. 901 47

Obesity plays a central role in the development of skeletal muscle insulin resistance. The molecular mechanism causing skeletal muscle insulin resistance in obese people is still poorly understood. It has been speculated that circulating factors derived from adipose tissue impair insulin signalling in the skeletal muscle cell. TNF-alpha and leptin, which are overproduced in fat tissue of obese insulin resistant animal models and in obese humans, might mediate such an inhibitory effect on insulin signalling in skeletal muscle. The aim of the present study was to evaluate whether circulating TNF-alpha and leptin correlates to the individual skeletal muscle insulin sensitivity in individuals with different degrees of obesity and insulin resistance. We measured circulating TNF-alpha and leptin values in non diabetic offsprings of NIDDM patients. 36 German and 47 Finnish subjects participated in the study. The GDR of each participant was determined by the euglycemic hyperinsulinemic clamp technique, a range between 1.37 to 14.01 mg/kg LBM x min was observed. Percent of desirable body weight (PDW) covered also a wide range (87.58% to 197.06%). Although linear regression analysis suggested a dependence between TNF-alpha and GDR (Germany group: r = -0.37, p < 0.05, Finnish group: r = -0.32, p < 0.05) and a dependence between TNF and PDW (German group: r = 0.46, p < 0.05, Finnish group: r = 0.38, p < 0.05), in multiple linear regression analysis only the correlation with PDW was significant. Leptin levels were measured from 29 German and 36 Finnish subjects and a strong association was found between leptin and PDW (German group: r = 0.55, p < 0.05, Finnish group: r = 0.73, p < 0.05). In contrast, leptin levels did not correlate with GDR and TNF-alpha. In summary, even though, in a few insulin resistant subjects, higher circulating TNF-alpha or leptin levels with the individual insulin sensitivity can be demonstrated, the data suggest that the circulating pool of TNF-alpha and leptin in blood is unlikely to be a major contributing factor for obesity induced insulin resistance in the vast majority of individuals at high risk to develop NIDDM.
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PMID:Circulating TNF-alpha and leptin levels in offspring of NIDDM patients do not correlate to individual insulin sensitivity. 901 54

The relation between body fat distribution and plasma leptin levels in the human was investigated in 51 obese and 41 non-obese subjects. Plasma levels of leptin showed a positive correlation with body mass index and subcutaneous fat area at the umbilicus level. However, a significant correlation between its plasma levels and visceral fat area was found in neither non-obese nor obese subjects. These results suggest that plasma leptin levels might be attributed mainly to the extent of subcutaneous adiposity in human obesity.
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PMID:Plasma leptin levels and body fat distribution. 901 57


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