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

Energy balance and body weight are regulated in short, intermediate, and long cycles that are superimposed on each other. We propose that the brain is the primary center of this regulation. The brain has evolved mechanisms for sensing the energy status of the body using neural and metabolic signals such as glucose, insulin, and leptin. It has central processing and storage capacity for handling this afferent information and can change both structurally and functionally in response to its internal and external milieu. The brain regulates energy balance through its control of energy intake on the one hand and expenditure and storage on the other using neurohumoral mechanisms that include the autonomic nervous system. Work in animal models suggests that the brain of obese individuals largely ignores signals of excess adiposity from the periphery, keeping the body weight set point at pathologically high levels. Disordered regulation of neuropeptide Y and monoamine metabolism within the ventromedial hypothalamus is a consistent finding in the brains of obesity-prone and obese rodents. Such dysregulation causes inappropriate neurohumoral control of metabolism and autonomic output to organs such as the pancreas, resulting in increased metabolic efficiency and persistent adiposity. The high recidivism rate in the treatment of obesity suggests that central dysfunction may be due to long-term reorganization of the nervous system in such a way as to perpetuate the abnormally high set point of body weight.
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PMID:Role of the brain in energy balance and obesity. 885 68

Many hormones circulate bound to serum proteins that modulate ligand bioactivity and bioavailability. To understand the biology of leptin action, we investigated the presence of leptin binding proteins in serum. 125I-labeled leptin binds competitively to at least three serum macromolecules with molecular masses of approximately 85, approximately 176, and approximately 240 kDa in rodents and approximately 176 and approximately 240 kDa in humans. The ability to bind appears to involve sulfhydryl/disulfide interactions because it is inhibited under reducing conditions. When serum is added to recombinant 125I-leptin, there is a shift in sedimentation of 125I-leptin as analyzed by sucrose gradient centrifugation from approximately S1.9 to approximately S4.3. This shift is markedly attenuated in serum from obese mice (ob/ob, db/db, brown-fat ablated, gold-thioglucose treated, high-fat fed) compared with that from nonobese controls. The size distribution of endogenous serum leptin as determined by radioimmunoassay (RIA) after sucrose gradient centrifugation is also consistent with saturation of binding in hyperleptinemic obesity. In humans, free leptin increases with BMI. Thus, in lean rodents and humans a large proportion of leptin circulates bound to several serum proteins. Free leptin is increased in serum of obese subjects, which may alter leptin bioactivity, transport, and/or clearance.
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PMID:Evidence for leptin binding to proteins in serum of rodents and humans: modulation with obesity. 886 73

Neuropeptide Y (NPY) neurones in the arcuate nucleus of the rodent hypothalamus may play a key role in responding to reductions in body energy stores with appropriate changes in energy homeostasis, namely an increase in food-seeking behaviour and hyperphagia, together with a reduction in heat production by brown adipose tissue. These adaptive responses are mimicked by the injection of NPY into the main sites of projection of the NPY neurones, and animals that are threatened by energy deficits (e.g. through starvation or insulin-deficient diabetes) show increased activity of these neurones. Genetically obese rodents also show hyperactivity of the NPY neurones, which is inappropriate to their energy needs and may contribute to their hyperphagia, reduced energy expenditure and excessive weight gain. The NPY neurones may be inhibited by insulin and leptin, which may both serve as signals of peripheral fat mass. Ultimately, characterization of the specific "feeding' receptors which mediate NPY's central effects on energy homeostasis may provide opportunities for designing drugs to manipulate and appetite and energy balance in man, notably obesity and the cachexia commonly associated with malignancy and chronic infection.
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PMID:Neuropeptide Y, the hypothalamus and the regulation of energy homeostasis. 887 Nov 82

This article is designed as an introduction to the major theoretical models in the field of regulation of eating behavior, and a selective review of relevant neurobiological data. We first critically consider the paradigm of homeostasis as it relates to body energy content, and argue that additional theoretical constructs will be needed to account for the complexity of eating behavior in both nonhumans and humans. We then summarize some of the methods available to the neuroscientist in this area, and address some of their limitations. We review treatments and potential mechanisms that increase food intake, including deprivation, antimetabolites, norepinephrine, and several peptides including neuropeptide Y. We next review treatments that decrease food intake, including a variety of humoral, gastrointestinal, and pancreatic factors, as well as examine central pathways of satiety. This includes a discussion of leptin and other potential anorectic agents. We conclude with a discussion of human obesity and anorexias, and prospects for pharmacotherapy of eating disorders. We emphasize throughout that most regions of the human brain probably make some contribution to feeding behavior, and so a focus on any one area of transmitter/hormone is an unrealistic approach both in basic and applied areas.
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PMID:The physiology and brain mechanisms of feeding. 887 73

The high prevalence of obesity and its well documented association with the cardiovascular risk factors diabetes mellitus, dyslipidemia and hypertension represents a major problem for the general health status of industrialized societies. Although numerous studies have shown that genetic factors have a major influence on the regulation of energy homeostasis and the susceptibility to obesity, the genes and predisposing mutations involved are insufficiently understood. Among several known rodent models of obesity due to single gene mutations, mice homozygous for the obese (ob) gene exhibit massive early-onset obesity, hyperphagia, non-insulin-dependent diabetes mellitus, defective thermoregulation and infertility. Recently the ob gene was identified by positional cloning and shown to be mutated in ob/ob mice. Leptin, the product of the ob gene, is a 167-amino acid secreted protein that is synthesized exclusively in adipose tissue. With the exception of ob/ob mice, circulating plasma leptin is elevated in obesity. Administration of recombinant leptin to ob/ob mice reduces fat mass, food intake, hyperglycemia and hyperinsulinemia. The various effects of the hormone are mediated by leptin receptors expressed at high levels in the hypothalamus, but also in several other non-neuronal tissues. A mutation in the leptin receptor gene is responsible for the obese phenotype of db/db mice. Plasma leptin in humans is positively correlated with body fat mass, suggesting that leptin resistance rather than leptin deficiency is a common feature of human obesity. This review briefly summarizes the current status of the rapidly growing evidence that leptin plays an important role in the regulation of body weight and fat deposition.
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PMID:Regulation of energy balance by leptin. 888 45

Peptide fragments of the larger 167 amino acid obesity gene related peptide (OBGRP), leptin, were tested for their ability to inhibit feeding in the rat. The C-terminal fragment, OBGRP 116-167 exerted only minimal inhibition of feeding when administered into the lateral cerebroventricle. No alteration in feeding was observed following administration of OBGRP 57-92. We hypothesized that the satiety effects of leptin reside in the N-terminal region of the peptide sequence. Significant, dose-related, and reversible inhibition of food intake was observed following central administration of the 35 amino acid fragment OBGRP 22-56. These results suggest that a small, readily synthesized fragment of the 167 amino acid peptide leptin may exert physiologically relevant satiety effects in brain revealing an endocrine feedback mechanism by which the adipocyte may modulate hypothalamic function.
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PMID:A 35 amino acid fragment of leptin inhibits feeding in the rat. 889 13

Whether leptin levels are related to insulin sensitivity or subject to acute regulation by insulin is not known. In 12 obese [body mass index (BMI) = 34.0 +/- 1.5 kg m-2] and 12 lean (BMI = 22.2 +/- 0.6 kg m-2) non-diabetic subjects, plasma leptin concentrations were measured in the fasting state and during 2 hours of euglycaemic hyperinsulinaemia (approximately 600 pmol L-1). Fasting plasma leptin was significantly higher in obese (26.6 +/- 3.2) than in lean subjects (6.4 +/- 1.2 ng mL-1, P = 0.0001), and in women (21.1 +/- 3.3) than in men (7.3 +/- 2.3 ng mL-1, P = 0.01). In univariate analysis, fasting plasma leptin was strongly related to all anthropometric measures (body weight, fat mass, percent fat mass, waist and hip circumferences). In multiple regression, per cent adiposity, hip circumference and duration of obesity explained 90% of the variability in fasting leptin concentrations. Fasting and stimulated (OGTT) insulin levels, insulin sensitivity (22.6 +/- 1.9 vs 36.7 +/- 2.0 mumol min-1 kg-1 in lean and obese subjects, respectively, P < 0.0001), glucose area, and serum triglycerides were positively related to fasting plasma leptin concentrations; none of these associations, however, was statistically significant after adjusting for BMI. During the clamp, plasma leptin concentrations remained constant in both lean and obese subjects. We conclude that neither insulin levels nor sensitivity relate to leptin levels independently of fat mass, and that leptin is not subject to acute (2 hours) regulation by insulin in lean or obese humans.
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PMID:Acute insulin administration does not affect plasma leptin levels in lean or obese subjects. 891 70

Recent data in the mouse demonstrate that leptin, a protein hormone produced by fat cells, is required for fertility. In the absence of leptin the mice become obese, diabetic and infertile. Polycystic ovary syndrome (PCOS), a common cause of infertility in women, is associated with obesity and insulin resistance. Because of the increased frequency of PCOS in obese women we tested the hypothesis that alterations in serum leptin concentrations might be associated with PCOS. Immunoreactive leptin concentrations were measured in 58 women with PCOS and 70 regularly menstruating (control) women. As has previously been shown there was a positive correlation between leptin levels and body mass index (BMI). Although the leptin levels in the majority of women with PCOS fell within the control range, 29% of PCOS women had leptin levels above the 99% prediction interval for their BMI and none had low leptin levels. There were also positive correlations of leptin levels with free testosterone and insulin sensitivity in control women. In women with PCOS, 13% and 9.5% exhibited higher than expected leptin concentrations with respect to free testosterone and insulin sensitivity, respectively. Insulin resistant PCOS women had higher leptin levels than controls. The data demonstrate that a substantial proportion of women with PCOS have leptin levels that are higher than expected for their BMI, free testosterone and insulin sensitivity. These results suggest that abnormalities in leptin signaling to the reproductive system may be involved in certain cases of PCOS.
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PMID:Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome. 892 78

Several twin and adoption studies as well as animal models have confirmed that obesity has a strong genetic component. It is apparent that obesity in humans has a complex polygenic background; that is, the phenotype is determined by an unknown number of genes together with environmental factors. However, there may well be single genes playing a major role within certain families, but the gene may vary from family to family. Two interesting gene candidates have been found in mouse experiments, the ob and the db gene, the products of which are probably a satiety hormone and its receptor, respectively, which regulate food intake. The recent cloning of the ob gene and its human homologue constitute a major breakthrough in this field. The 16-kD protein encoded by the ob gene is called leptin, and is well conserved among vertebrate species. The pig could be a valuable large animal model for human obesity. A fatness locus has been mapped to pig chromosome 4 and most probably a similar locus resides on human chromosome 1q. A more precise definition of the pig-human homology as regards this region is currently being investigated.
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PMID:Genes and obesity. 893 98

The obesity syndrome of ob/ob mice results from lack of leptin, a hormone released by fat cells that acts in the brain to suppress feeding and stimulate metabolism. Neuropeptide Y (NPY) is a neuromodulator implicated in the control of energy balance and is overproduced in the hypothalamus of ob/ob mice. To determine the role of NPY in the response to leptin deficiency, ob/ob mice deficient for NPY were generated. In the absence of NPY, ob/ob mice are less obese because of reduced food intake and increased energy expenditure, and are less severely affected by diabetes, sterility, and somatotropic defects. These results suggest that NPY is a central effector of leptin deficiency.
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PMID:Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. 917 44


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