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

Mutation of the Ob gene, which encodes for leptin, or mutation of the leptin receptor leads to obesity in mice. Humans, for the most part, have a positive correlation of leptin with body fat mass suggesting possible defects in leptin effector mechanisms that may contribute to obesity. As patients on hemodialysis have difficulty with appetite, we investigated whether leptin is cleared by the kidney and is elevated in hemodialysis patients. In patients with intact renal function there was a net renal uptake of 12% of circulating leptin, whereas in patients with renal insufficiency there was no renal uptake of leptin. In a separate cohort of 36 patients with end-stage renal disease (ESRD), peripheral leptin levels factored for body mass index was increased by fourfold as compared to a group of healthy controls (N = 338). The leptin receptor exists in a long and short form, with the long form primarily expressed in the hypothalamus but also in the lungs and kidneys of the mouse. Further studies are necessary to clarify the role of leptin in regulating appetite in patients with ESRD and the role of leptin in directly affecting kidney function via its receptors.
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PMID:The Ob protein (leptin) and the kidney. 1021 65

We analyzed the inheritance of body fat, leptin levels, plasma lipoprotein levels, insulin levels, and related traits in an intercross between inbred mouse strains CAST/Ei and C57BL/6J. CAST/Ei mice are unusually lean, with only approximately 8% of body weight as fat, whereas C57BL/6J mice have approximately 18% body fat. Quantitative trait locus analysis using > 200 F2 mice revealed highly significant loci (lod scores > 4.3) on chromosomes 2 (three separate loci) and 9 that contribute to mouse fat-pad mass for mice on a high-fat diet. Some loci also influenced plasma lipoprotein levels and insulin levels either on chow or high-fat diets. Two loci for body fat and lipoprotein levels (on central and distal chromosome 2) coincided with a locus having strong effects on hepatic lipase activity, an activity associated with visceral obesity and lipoprotein levels in humans. A locus contributing to plasma leptin levels (lod score 5.3) but not obesity was identified on chromosome 4, near the leptin receptor gene. These data identify candidate regions and candidate genes for studies of human obesity and diabetes, and suggest obesity is highly complex in terms of the number of genetic factors involved. Finally, they support the existence of specific genetic interactions between body fat, insulin metabolism, and lipoprotein metabolism.
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PMID:Genetic loci controlling body fat, lipoprotein metabolism, and insulin levels in a multifactorial mouse model. 961 20

The application of molecular and genetic techniques to the study of body weight regulation have produced exciting new insights into the physiological systems governing energy expenditure, appetite, and metabolic signaling. A number of new peptides have been identified that play important roles in these regulatory systems. These include the hormone leptin, the short and long forms of the leptin receptor, uncoupling proteins, agouti protein, melanocortin receptor isoforms, melanin-concentrating hormone, and the proteins responsible for tub and fat, two monogenic mouse models of obesity. This article reviews some of the new insights gained from studies of these peptides. Although much of this new knowledge has come from studies of obesity, there may be implications for the clinical syndromes associated with weight loss. As more is learned about these systems, potential new targets for therapeutic intervention will likely become evident. These interventions may develop first as obesity treatments, but investigators and clinicians involved in the care of cachectic patients should follow these scientific developments as well.
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PMID:Recently identified peptides involved in the regulation of body weight. 962 80

Systemic administration of the neurocytokine ciliary neurotrophic factor (CNTF) normalizes the obese phenotype of ob/ob and db/db mice. CNTF exerts its multiple effects through a receptor complex whose sequence, localization in hypothalamic nuclei and mode of signal transduction share remarkable similarities with the leptin receptor. In the human CNTF gene, a mutation in the first intron creates a new splice acceptor site, with the resulting mRNA coding for an aberrant protein (Takahashi et al., 1994). Given the potential of CNTF to influence energy homeostasis, this study was undertaken to determine whether variability in the CNTF gene is associated with human obesity. The previously described mutation was found in 30.3% of obese children and adolescents, 7 of which were homozygous (allele frequency 0.163). 29.5% of lean subjects carried the mutation, none of which were homozygous (allele frequency 0.148; corrected p = 1 compared to obese). No further mutations were detected by single strand conformational polymorphism (SSCP) analysis. In conclusion, variants in the CNTF gene are unlikely to be associated with the development of early-onset obesity.
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PMID:Screening for variability in the ciliary neurotrophic factor (CNTF) gene: no evidence for association with human obesity. 962 40

Leptin affects food intake and body weight by actions on the hypothalamus. Although leptin resistance is common in obesity, mechanisms have not been identified. We examined the effect of leptin on expression of the suppressors-of-cytokine-signaling (SOCS) family of proteins. Peripheral leptin administration to ob/ob, but not db/db mice, rapidly induced SOCS-3 mRNA in hypothalamus, but had no effect on CIS, SOCS-1, or SOCS-2. A leptin-dependent increase of SOCS-3 mRNA was seen in areas of hypothalamus expressing high levels of the leptin receptor long form. In mammalian cell lines, SOCS-3, but not CIS or SOCS-2, blocked leptin-induced signal transduction. Expression of SOCS-3 mRNA in the arcuate and dorsomedial hypothalamic nuclei is increased in Ay/a mice, a model of leptin-resistant murine obesity. In conclusion, SOCS-3 is a leptin-inducible inhibitor of leptin signaling, and a potential mediator of leptin resistance in obesity.
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PMID:Identification of SOCS-3 as a potential mediator of central leptin resistance. 966 Sep 46

Obesity causes its complications through functional and morphologic damage to remotely situated tissues via undetermined mechanisms. In one rodent model of obesity, the Zucker diabetic fatty fa/fa rat, overaccumulation of triglycerides in the pancreatic islets may be responsible for a gradual depletion of beta cells, leading to the most common complication of obesity, non-insulin-dependent diabetes mellitus. At the onset of non-insulin-dependent diabetes mellitus, the islets from fa/fa rats contain up to 100 times the fat content of islets from normal lean rats. Ultimately, about 75% of the beta cells disappear from these fat-laden islets as a consequence of apoptosis induced by long-chain fatty acids (FA). Here we quantify Bcl-2, the anti-apoptosis factor in these islets, and find that Bcl-2 mRNA and protein are, respectively, 85% and 70% below controls. In normal islets cultured in 1 mM FA, Bcl-2 mRNA declined by 68% and completely disappeared in fa/fa islets cultured in FA. In both groups, suppression was completely blocked by the fatty acyl-CoA synthetase inhibitor, triacsin C, evidence of its mediation by fatty acyl-CoA. To determine whether leptin action blocked FA-induced apoptosis, we cultured normal and fa/fa islets in 1 mM FA with or without leptin. Leptin completely blocked FA-induced Bcl-2 suppression in normal islets but had no effect on islets from fa/fa rats, which are unresponsive to leptin because of a mutation in their leptin receptors (OB-R). However, when wild-type OB-R is overexpressed in fa/fa islets, leptin completely prevented FA-induced Bcl-2 suppression and DNA fragmentation.
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PMID:Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression. 968 19

Leptin is a fat cell-derived satiety factor that regulates food intake and energy expenditure. Its effects are mediated by interactions with the leptin receptor (Ob-R) that is alternatively spliced to encode at least five isoforms(a-e), which are distributed in a wide range of tissues including the hypothalamus. Ob-R is a member of cytokine receptors and involves the JAK-STAT signal transduction system. We found Ob-R mutations in Zucker fatty rats and obese Koletsky rats and demonstrated that Ob-R dysfunction brings around hyperphagia and obesity. However we and others have not found any Ob-R mutation in human obese subjects.
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PMID:[Leptin Receptor]. 970 77

We used mouse genetics to model how polygenic thresholds for the transition from impaired glucose tolerance (IGT) to NIDDM are reached. NON/Lt and NZO/Hl are inbred mouse strains selected for IGT and polygenic obesity, respectively. Their F1 male progeny consistently developed NIDDM. Genetic analysis of F2 males from both cross directions identified an NON-derived diabetogenic locus, Nidd 1, on chromosome (Chr) 4 near the leptin receptor. This locus was associated with reduced plasma insulin, increased non-fasted blood glucose, and lower body weight. Another NON-derived diabetogenic locus on Chr 18 (Nidd2) that controls blood glucose was identified. An NZO-derived diabetogenic region on Chr 11 (Nidd3), possibly comprising two separate loci, reduced ability to sustain elevated plasma insulin and significantly reduced weight gain over time. Thus, the diabetogenic synergism between genetic loci from strains separately exhibiting subthreshold defects perturbing glucose homeostasis underscores the likely complexity of the inheritance of obesity-associated forms of NIDDM in humans.
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PMID:NIDDM genes in mice: deleterious synergism by both parental genomes contributes to diabetogenic thresholds. 970 30

Obesity is at present one of the most important health risk factors in developed countries. Several studies show significant involvement of genetic factors. A gene called ob is active in the adipose tissue and its product leptin is secreted from adipocytes. Fully functional leptin receptors (encoded by the ob/R gene, also db) have been found in highest numbers in the hypothalamus and therefore it was suggested that it is the leptin plasma level which in forms the brain about total body fat mass and calories intake. Using this pathway it can directly influence a balance between food intake and energy expenditure. The phenotype of ob/ob mutant mice is characterized by severe obesity, NIDDM (non insulin dependent diabetes mellitus), diminished fertility and hypothermia. Db/db mutant mice show a similar phenotype, here the defect lies in the block of leptin receptor downstream signalling. After leptin administration, it was possible to correct the defect only in the ob/ob, but not db/db mice. There is a positive correlation between body mass index and leptin plasma level in humans and no obese patients have been found defective in leptin production or producing or producing ineffective leptin. Human obesity might be connected to a defect of leptin receptor or to its altered signal transduction. Leptin administration is therefore not important in human obesity treatment.
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PMID:[Leptin--the key to obesity?]. 972 70

Mutations of the leptin receptor have been found to cause obesity in rodents. The fa mutation that is responsible for obesity in Zucker rats is a missense mutation (269 gln-->pro) in the extracellular domain of the leptin receptor. We have characterized the effects of this mutation on the two major isoforms of the leptin receptor, Ob-Rb and Ob-Ra, by studying cell-surface expression, leptin binding affinity, signaling capacity, and receptor-mediated internalization and degradation of leptin in transfected mammalian cell lines. Both Ob-Rb(269 gln-->pro) and Ob-Ra(269 gln-->pro) have decreased cell-surface expression and decreased leptin binding affinity. Ob-Rb(269 gln-->pro) was shown to have defective signaling to the JAK-STAT pathway and markedly diminished ability to activate transcription of the egr-1 promoter. Constitutive ligand-independent activation of Ob-Rb(269 gln-->pro) was observed for activation of egr-1-luc but only under conditions when JAK2 was coexpressed with Ob-Rb(269 gln-->pro), Finally, Ob-Ra(269 gln-->pro) has an increased ability to internalize leptin but is less efficient at degrading leptin, as compared with Ob-Ra. In conclusion, both Ob-Ra(269 gln-->pro) and Ob-Rb(269 gln-->pro) have multiple functional defects.
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PMID:Functional properties of leptin receptor isoforms containing the gln-->pro extracellular domain mutation of the fatty rat. 972 17


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