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PubMed1997

Body composition and age in African-American and Caucasian women: relationship to plasma leptin levels.

Leptin is a recently isolated peptide hormone released from adipocytes that has been postulated to play a role in appetite regulation and energy metabolism. Aging affects both food intake and body composition. Body composition is also affected by ethnicity. We have evaluated the relationships between serum leptin levels, age, body composition (by dual-energy x-ray absorptiometry), and hormonal parameters in a cross-sectional study of 94 women, 53 African-American (AAF) and 41 Caucasian (CF). Our hypotheses were as follows: (1) changes in body composition would be related to age in a sinusoidal pattern, (2) changes in serum leptin would parallel changes in body fat, (3) serum leptin levels would be influenced by body fat distribution, and (4) serum leptin would be related to serum concentrations of sex hormones. Serum leptin paralleled changes in body fat and body mass index (BMI) with age. In the entire group, serum leptin correlated closely with measures of body fat, including BMI and total fat mass, and there was no difference in leptin levels between the two ethnic groups. In simple regression analysis, serum leptin was related to both serum estradiol and testosterone. The relationship between serum leptin and trunk fat was linear in both groups, but significantly different in AAF and CF (P = .014). Serum leptin was associated with the trunk to lower-extremity fat ratio in CF (r = .67, P = .001) but not in AAF. Body fat was increased with advancing age until about 65 years and then declined. Measures of lean body mass declined linearly with age in the entire group, as well as both subgroups. In the entire group, total lean body mass and lean body mass corrected for BMI (lean body mass/BMI) were inversely related to age. In subjects aged less than 60 years AAF were stronger (P < .05) and had both a larger BMI and fat mass (P < .05) than CF. However, the patterns of age-related changes in fat body mass, lean body mass, and BMI were similar in both groups. In the entire group, multiple regression analysis indicated that the age, free thyroxine index (FTI), and leptin concentration were predictors of the body composition and distribution of trunk to lower-body fat. These observations indicate that there is a sinusoidal relationship between body fat and age, with a decline in body fat in extreme old age in both AAF and CF, and that serum leptin concentrations are more closely related to body fat and BMI than to age or ethnicity.

Absorptiometry, Photon↗
PubMed2002

The use of dextroamphetamine to treat obesity and hyperphagia in children treated for craniopharyngioma.

BACKGROUND: Obesity and attention difficulties are known complications following surgical treatment for craniopharyngioma. Treatments to date have been largely disappointing. OBJECTIVE: To examine the use of the central nervous system stimulant dextroamphetamine sulfate to regulate appetite and subsequent weight gain in children treated for craniopharyngioma. SETTING: A multidisciplinary clinic specializing in pediatric brain tumors. PATIENTS: Five consecutive patients with significant weight gain and poor attention following surgical treatment for craniopharyngioma were selected for the study. INTERVENTION: Children enrolled in the study were treated with dextroamphetamine, and growth, laboratory, and behavioral assessments were conducted for 24 months. RESULTS: Mean +/- SD body mass index (weight in kilograms divided by height in meters squared) increased from 21 +/- 3.5 before the operation to 32 +/- 2.8 by the start of the protocol. Body mass indices remained stable throughout the protocol. No changes were observed in insulin levels or caloric intake, but the children were more active when taking dextroamphetamine. Parents noted a significant improvement in hyperactivity (mean +/- SD, 1.2 +/- 0.4 to 0.6 +/- 0.2; P =.05), scored with the Conners Parent and Teacher Rating Scales. Teachers noted a similar improvement. CONCLUSIONS: During dextroamphetamine treatment, weight gain stabilized in children who had experienced obesity following surgical resection for craniopharyngioma. In addition, parents and teachers noted significant improvements in children's overall activity and attention. Further studies are needed to determine if the improvements are stable and if earlier intervention can prevent the initial obesity.

Analysis of Variance↗
PubMed1997

Acute idiopathic gastric dilation with gastric necrosis in individuals with Prader-Willi syndrome.

Individuals with Prader-Willi syndrome (PWS) have excessive appetite with the ability to consume large quantities of food. Absence of vomiting and a high pain threshold are considered manifestations of the disorder. We present 6 patients with PWS with acute dramatic gastric distention. In 3 young adult women with vomiting and apparent gastroenteritis, clinical course progressed rapidly to massive gastric dilatation with subsequent gastric necrosis. One individual died of overwhelming sepsis and disseminated intravascular coagulation. In 2 children, gastric dilatation resolved spontaneously. Gastrectomy specimens--in 2 cases subtotal and distal, in the other with accompanying partial duodenectomy and pancreatectomy--showed similar changes. All cases demonstrated signs of ischaemic gastroenteritis. All specimens showed diffuse mucosal infarction with multifocal transmural necrosis. Vascular dilatation and small bifrin thrombi were apparent within the infarcted areas. These 6 women with PWS had acute idiopathic gastric dilatation. It is possible that a predisposition to acute gastric dilatation may be related to abnormal gastric homeostasis on a genetic basis. Understanding the mechanisms responsible for this event could increase the understanding of gastrointestinal and appetite regulation in individuals with PWS.

Adult↗
PubMed2004

Association study of cannabinoid receptor gene (CNR1) alleles and anorexia nervosa: differences between restricting and binging/purging subtypes.

Anorexia nervosa (AN) is a severe and disabling psychiatric disorder, characterized by profound weight loss and body image disturbance. Family and twin studies indicate a significant genetic contribution to this disorder although no genetic mutation has yet been identified. The endocannabinoid system has recently been implicated in many physiological functions including appetite regulation. We, therefore, undertook a family based study to test the hypothesis whether a polymorphism of the CNR1 gene, which encodes human CB1 receptor, a subclass of the central cannabinoid receptor, contributes to the susceptibility to AN. Fifty two families (parents with one or two affected siblings) were genotyped for the (AAT) trinucleotide repeat of CNR1 gene. Using the haplotype relative risk (HRR) method, the distribution of alleles transmitted to the patients was not found to be significantly different from the non-transmitted parental alleles. However, upon dividing the samples to restricting and binging/purging subtypes of AN, the extended transmission disequilibrium test (ETDT) revealed that there is preferential transmission of different alleles in each of the subtypes. The 14 repeat allele was preferentially transmitted in the binging/purging AN group (P = 0.05) but not in the restricting AN group, whereas the 13 repeat allele was preferentially transmitted in the restricting AN group (almost significant, P = 0.07) but not in the binging/purging AN group. Our study suggests that restricting AN and binging/purging AN may be associated with different alleles of the CNR1 gene.

Adolescent↗
PubMed2004

A 5-HT2C receptor promoter polymorphism (HTR2C - 759C/T) is associated with obesity in women, and with resistance to weight loss in heterozygotes.

The serotonin 5-HT(2C) receptor (HTR2C) helps regulate appetite and body weight. An HTR2C promoter polymorphism (-759C/T) has been associated with obesity and with weight gain in response to antipsychotic (neuroleptic) drugs. We studied this polymorphism in 120 obese women (BMI > or = 30) and 104 non-obese (BMI < or = 25) women. The C allele was commoner in the obese group (OR = 1.72 [95% CI, 1.13-2.64], P = 0.008). Ninety-five of the obese women participated in a randomized trial of psychological treatments for weight loss. Among these women, heterozygotes lost less weight during the trial than did homozygotes (6.8 vs. 9.7 kg; P = 0.047) and weighed more 6 months (90.1 vs. 83.6 kg; P = 0.006) and 12 months (91.8 vs. 84.6 kg; P = 0.009) later. Heterozygotes also had higher triglyceride levels than homozygotes. C/C subjects in the obesity trial did not differ from T/T subjects in terms of weight loss or triglycerides. In a separate RT-PCR study of 43 subjects, we found that HTR2C mRNA abundance in frontal cortex was unaffected by -759C/T status. Our data extend the evidence that HTR2C promoter variation may be a risk factor for obesity and, perhaps through heterosis, influences weight loss by obese women. Pharmacogenetic testing of HTR2C promoter variants may be valuable when evaluating anti-obesity drugs which act directly or indirectly on the receptor.

Adult↗
PubMed2005

Prostaglandin E and prostacyclin receptor expression in tumor and host tissues from MCG 101-bearing mice: a model with prostanoid-related cachexia.

Preclinical and clinical studies in our laboratory have suggested that prostaglandin (PG) E2 is involved in anorexia and cachexia development, although the role of COX pathways on the pathogenesis of cancer cachexia remains to be clarified. Expressions of PGE (EP1, EP2, EP3alpha,beta,gamma and EP4) and PGI (IP) receptors in the central nervous system (brain cortex, hypothalamus and brain stem), in peripheral (liver, white adipose tissue and skeletal muscle) and tumor tissue from MCG-101-bearing mice with and without indomethacin treatment were investigated by RT-PCR and immunohistochemistry. Expression of EP1 in the liver and EP4 receptor in white adipose tissue were upregulated and responded to indomethacin treatment, while downregulated expression of EP3 in skeletal muscle from tumor-bearing mice was unresponsive to indomethacin treatment despite improved carcass weight. Expression of EP and IP receptors in brain and tumor tissue from tumor-bearing mice were neither related nor responsive to systemic PGE2 levels including increased IL-1beta, IL-6 and TNF-alpha host activities. The expression IP receptor in CNS, peripheral tissue and tumor tissue was unchanged by cachexia development. Our results suggest that transcription of EP receptors in liver, fat and skeletal muscle tissue may be a control level for host metabolic alterations during tumor progression, while overall EP and IP receptor expression in CNS did not indicate an important control level for appetite regulation in MCG 101-bearing mice despite prostanoid related anorexia.

Animals↗
PubMed1995

A very-low-calorie conventional Japanese diet: its implications for prevention of obesity.

A very-low-calorie conventional Japanese diet of 370 kcal/day has been shown to be useful for weight reduction and its long-term maintenance. Sources of the diet were mainly from chicken fillet, egg white, fish white-meat, mushroom, seaweed and low- or non-calorie fiber-rich vegetable, and contained 4.4g fat, 38.1g protein, 45.2g carbohydrate and essential minerals and vitamins. However, metabolic and neural implications of a commercial very-low-calorie liquid formula diet have rarely been investigated from the view point of food intake and appetite regulation. Animal studies have demonstrated the rationale for efficacy of the very-low calorie conventional Japanese diet as follows: (1) Increased hypothalamic histamine suppressed food intake through H1-receptors in the ventromedial hypothalamus (VMH) and paraventricular nucleus, the satiety centers. (2) Low energy intake enhanced satiety and decreased food intake through histaminergic activation of VMH neurons. (3) Mastication activated afferent signal transmission from proprioceptors in the oral cavity to the mesencephalic trigeminal nucleus(Me5). Histaminergic systems in the hypothalamus were activated by mastication and low energy supply, which was accompanied by satiation through the action of histamine in the VMH. Usefulness of the very-low-calorie conventional Japanese diet derives from utilization of conventional Japanese food stuffs as a fiber rich, low energy food source, and from enhancement of satiation by increased mastication required of the diet. The properties of the diet seemed to effect a closed positive feedback loop between histaminergic activation in hypothalamic satiety centers and behavioral changes to enhance satiation and cause feeding suppression.

Diet, Reducing↗
PubMed1999

Is leptin concentration associated with the insulin resistance syndrome in nondiabetic men?

OBJECTIVE: Insulin resistance has been strongly associated with cardiovascular risk. Recently, leptin, a hormone that regulates appetite, has been associated with both obesity and insulin resistance. However, the possible relation of leptin to the insulin resistance syndrome has been controversial. RESEARCH METHODS AND PROCEDURES: To explore this issue, we examined the relation of leptin to blood pressure, lipid levels, low density lipoprotein (LDL) size, and glucose levels in 87 normoglycemic men. RESULTS: Leptin levels were significantly correlated with body mass index (BMI) (r = 0.494), fasting insulin (r = 0.576), whole-body glucose disposal rate (GDR) (r = -0.566), fasting glucose (r = 0.510) total triglycerides (r = 0.294), apolipoprotein B (r = 0.223), systolic blood pressure (r = 0.223), and LDL size (r = -0.244). After adjustment for BMI and GDR, leptin levels remained significantly correlated with fasting insulin, fasting glucose, triglyceride, apolipoprotein B, and systolic blood pressure. Leptin levels were also correlated with the number of metabolic risk factors (dyslipidemia, systolic blood pressure, and fasting glucose). DISCUSSION: We conclude that leptin concentrations may be associated with several cardiovascular risk factors related to insulin resistance syndrome. These associations are only partly explained by leptin's relationship with BMI and GDR.

Apolipoproteins B↗
PubMedDate not supplied

Phylogenic and neurologic aspects of the vomiting process.

Hindbrain morphology is compared in a variety of animals representing species that vomit and those that do not. Special attention is given to the nucleus of the tractus solitarius (NTS) and its synaptic connections with surrounding structures. The role of the area postrema is examined from the standpoints of containing the chemoreceptor trigger zone (CTZ) for vomiting, of its functional relationship to the blood-brain barrier, and of its significance as part of the circumventricular organ system. A survey is made of the manifold behavioral contributions of NTS to cardiovascular and respiratory regulation, appetite control, arousal, water balance, and digestive and neuroendocrine functions. An overview is presented of neurochemical distribution in the brain stem with respect to aminergic, cholinergic, and peptidergic substances. Finally, causes and prevention of vomiting are discussed in light of the above considerations.

Animals↗
PubMed2003

Long-term control of food intake and body weight by hydrodynamics-based delivery of plasmid DNA encoding leptin or CNTF.

BACKGROUND: Obesity contributes to many common diseases, including cardiovascular and metabolic disorders such as diabetes, hypertension, and stroke. Leptin and ciliary neurotrophic factor (CNTF), two members of the cytokine family, play important roles in controlling food intake and body weight in rodents. Here, we used the hydrodynamics-based gene delivery technique to introduce leptin and CNTF expression plasmids, pCAGGS-leptin and pCAGGS-CNTF, into mice and to assess whether they could induce high expression of leptin or CNTF and reduce food intake and body weight in the mice. METHODS: Plasmid DNA (50 microg) in lactated Ringer's solution (0.1 ml/g body weight) was rapidly injected into the tail vein of 4-week-old male MCH-ICR mice. RESULTS: After a single injection, serum leptin peaked (at 32.0 +/- 3.1 ng/ml) 2 days after the injection, and serum CNTF peaked (at 22.0 +/- 0.8 microg/ml) 1 day after the injection. The high expression of either leptin or CNTF was sustained and dramatically reduced food intake (CNTF and leptin group vs. control group; 2.3 +/- 0.5 and 3.1 +/- 0.5 g/day vs. 4.8 +/- 0.6 g/day; p < 0.001) and body weight (3 weeks after the injection; CNTF and leptin group vs. control group; -19.5% and +3.3% vs. +33.3-47.5%; p < 0.001) in the mice, suggesting potent in vivo activities for these exogenously expressed proteins. CONCLUSIONS: These results suggest that hydrodynamics-based gene delivery could have broad applications in the study of appetite regulation and metabolism.

Animals↗
PubMed2005

Peptide dynamic fingerprints: a tool for investigating the role of conformational flexibility for GLP-1 analogs affinity.

Glucagon-like peptide-1 (GLP-1) is a 30-residue peptide implicated in short-term appetite regulation. Its analogs are presumed to be potential drugs against obesity and non-insulin dependent diabetes mellitus (NIDDM or type 2 diabetes). This study examined how the dynamic fingerprints can be used for establishing dynamics-activity relationships in a series of peptides for which the mechanism of action is unknown and in which mutations can cause an increase or decrease in biological activity. The 3D autocorrelation method was used to generate maps of both active and inactive analogs. As the active conformation of GLP-1 is not yet clearly defined, the dynamic fingerprints of peptides in an aqueous environment were compared to explain the high affinity of the peptide for its receptor. The suggestion that the peptide could bind to the receptor in a folded conformation has been examined. In the case of the GLP-1 analogs, it was shown that the folding tendency cannot be directly related to affinity values and the results do not favor a folded active conformation model of GLP-1.

Animals↗
PubMed1995

Biology of enterostatin. II. Development of enzyme-linked immunosorbentassay (ELISA) for enterostatin (Val-Pro-Asp-Pro-Arg), the procolipase activation peptide.

Enterostatins belong to a family of pentapeptides (e.g., Val-Pro-Asp-Pro-Arg in pig, horse, dog, and rat; Ala-Pro-Gly-Pro-Arg in human and chicken; and Val-Pro-Gly-Pro-Arg in rat) derived from the amino-terminus of procolipase after the action of trypsin. Pharmacologic studies with Val-Pro-Asp-Pro-Arg have suggested a role for this peptide in appetite regulation and pancreatic insulin secretion. Studies into the distribution of enterostatins or the role of endogenous peptides have not been possible due to the lack of a suitable method for enterostatin assay. To this end, we raised a highly specific antibody and developed an enzyme-linked immunosorbent assay for Val-Pro-Asp-Pro-Arg. Using the newly developed assay we have shown the presence of Val-Pro-Asp-Pro-Arg-like immunoreactivity (2455 +/- 440 pmol/g) in the rat brain.

Amino Acid Sequence↗
PubMed2002

Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression.

To assess the contribution of potential central nervous system pathways implicated in the control of appetite regulation and energy metabolism, it is essential to first identify appropriate animal models. Melanin-concentrating hormone (MCH), a conserved cyclic neuropeptide implicated in the modulation of food intake, has been shown to bind and activate two G-protein-coupled receptors, called GPR24 and MCHR2, expressed in human brain and other tissues. Here we show that several non-human species (rat, mouse, hamster, guinea pig, and rabbit) do not have functional MCHR2 receptors, or encode a nonfunctional MCHR2 pseudogene while retaining GPR24 expression. We identified three species for further evaluation that express both MCH receptor subtypes. We cloned and functionally characterized dog, ferret, and rhesus GPR24 and MCHR2 in mammalian cells and studied their brain distribution patterns by in situ hybridization. The homology, expression profile, and functional similarity of the receptors in the dog, ferret, and rhesus to that of human support the potential use of these species as preclinical animal models in the development of therapeutic agents for obesity or other MCH-mediated disorders.

Amino Acid Sequence↗
PubMed2000

Energy homeostasis and body weight in obesity: new physiopathological and therapeutic considerations.

This paper reviews recent developments and findings regarding the role of the hypothalamus as the main site in the central nervous system (CNS) for regulating appetite. It contains a specific neural network consisting of the main central monoaminergic neurotransmitters (adrenaline, noradrenaline, dopamine, serotonin) and many neuropeptides with orexigenic and anorexigenic functions. The crucial relationship between CNS and obesity and the complex interconnections of CNS and peripheral peptides are becoming clearer. The mechanisms by which these hormones affect energy homeostasis through long and short-term anabolic and catabolic pathways are described. New anti-obesity therapeutic strategies based on drugs or molecules with new mechanisms of action, some not yet available in Italy but will soon be on the market, are considered.

Appetite Depressants↗
PubMed2005

Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin.

AIMS/HYPOTHESIS: Peptide YY (PYY) is a gut-derived hormone that has been shown to reduce short-term food intake in animals and humans. It has been proposed that deficiency of PYY contributes to obesity in humans. However, the physiology of PYY regulation by factors such as caloric restriction, or by other molecules important in energy homeostasis, e.g. leptin, remains to be fully elucidated. MATERIALS AND METHODS: We evaluated the effect on PYY levels of: (1) caloric ingestion (a mixed meal) in five healthy normal-weight subjects; (2) fasting for 2 or 3 days in eight lean men and seven lean women respectively; and (3) recombinant human leptin administration at physiological replacement and pharmacological doses. RESULTS: PYY levels increased 50% after a mixed meal (p=0.01), and short-term complete fasting for 2 or 3 days decreased leptin and PYY levels to 20-30% and 40-60% of baseline, respectively (both p<0.05). However, recombinant human leptin administration at physiological doses to restore the fasting-induced decrease of leptin levels and at pharmacological doses over the short term had no effect on PYY levels. CONCLUSIONS/INTERPRETATION: PYY increases after meal ingestion and decreases after fasting in a manner consistent with a meal-related signal of energy homeostasis. Importantly, circulating levels of this gut-secreted molecule are independent of regulation by leptin over the short term. These findings contribute towards our understanding of the homeostatic systems that regulate appetite in humans, including the possible redundancy of gastrointestinally secreted and adipocyte-secreted signals. This may be of importance for the future development of medications to treat obesity.

Eating↗
PubMed2006

Variants in the 5' region of the neuropeptide Y receptor Y2 gene (NPY2R) are associated with obesity in 5,971 white subjects.

AIMS/HYPOTHESIS: The gene encoding neuropeptide Y receptor Y2 (NPY2R) is widely expressed in the central nervous system, with particularly high abundance in the hypothalamus, which is known to be important for appetite regulation. We tested whether variations in NPY2R are associated with obesity. METHODS: The coding region of NPY2R was analysed for mutations in 48 obese Danish white subjects and two silent substitutions were identified: SNPs 1 and 2 (rs1047214 and rs2880415). SNP1 and additional reported variants (SNPs 3-6 [rs11099992, rs12649641, rs2342676 and rs6857530]) located in the 5' region were examined in 5,971 Danish white subjects. Since SNPs 1-2 and 4-6, respectively, were in tight linkage disequilibrium large-scale analyses of genetic epidemiology were restricted to SNPs 1, 3 and 4. RESULTS: Homozygous carriers of the minor A allele of SNP4 were more common among obese subjects; the AA frequency was 15.9 (95% CI 15.2-16.6) among 4,837 non-obese subjects (BMI <30 kg/m(2)) vs 19.0 (95% CI 17.2-20.8) among 960 obese subjects (BMI > or =30 kg/m(2)), odds ratio 1.24 (95% CI 1.04-1.48), p=0.02. SNPs 1-3 were not associated with obesity. CONCLUSIONS/INTERPRETATION: Common variants rs12649641, rs2342676 and rs6857530 in the 5' region of NPY2R are associated with obesity in Danish white subjects.

5' Untranslated Regions↗