Pathogenesis Of Human Obesity Research Articles

Fine-Scale Haplotype Mapping Reveals an Association of the FTO Gene with Osteoporosis and Fracture Risk in Postmenopausal Women.

The Fat Mass and Obesity-Associated (FTO) gene encodes a demethylase, which modulates RNA N6-methyladenosine (m6A) and plays a regulatory role in adipocyte differentiation and the pathogenesis of human obesity. To understand the potential role of FTO in osteoporosis (OP), we investigated five single nucleotide variations (SNVs) in intron 1 (rs8057044, rs8050136, rs9939609, rs62033406, and rs9930506) of the FTO gene, and a missense SNV i.e., rs3736228 (A1330V), located in exon 18 of the LRP5 gene, in a cohort of postmenopausal women (n = 188) from Central Europe. Genotyping was performed with an allele discrimination assay, while haplotypes were reconstructed in the population by PHASE 2.1. The rs9930506 was strongly associated with OP (p < 0.0035), which was supported by Bonferroni correction (p < 0.0175), and all SNVs located in the FTO gene were more strongly associated with severe OP with fragility fractures. Among seventeen haplotypes detected for the FTO gene, two haplotypes (H1 and H9) were frequent (frequency > 10%) and distributed in three main haplotypes pairs (H1/H1, H1/H9 and H9/H9, respectively). The pathogenic pair H1/H9 was associated with a leaner phenotype, increased fracture risk, and a lower bone mineral density (BMD), and carried the heterozygous GA of rs9930506, while the protective pair H9/H9 was associated with an increased obesity risk and carried AA alleles of rs9939609. Concordant associations with OP, an increased fracture risk, and a lower BMD at all skeletal sites indicate that the FTO gene is a promising candidate for OP, explaining the complex relationship with obesity and offering new perspectives for the study of the epigenetic regulation of bone metabolism.

HPA Axis Responsiveness Associates with Central Serotonin Transporter Availability in Human Obesity and Non-Obesity Controls.

Alterations of hypothalamic-pituitary-adrenal (HPA) axis activity and serotonergic signaling are implicated in the pathogenesis of human obesity and may contribute to its metabolic and mental complications. The association of these systems has not been investigated in human obesity. To investigate the relation of HPA responsiveness and serotonin transporter (5-HTT) availability in otherwise healthy individuals with obesity class II or III (OB) compared to non-obesity controls (NO). Twenty-eight OB (21 females; age 36.6 ± 10.6 years; body mass index (BMI) 41.2 ± 5.1 kg/m2) were compared to 12 healthy NO (8 females; age 35.8 ± 7.4 years; BMI 22.4 ± 2.3 kg/m2), matched for age and sex. HPA axis responsiveness was investigated using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test, and curve indicators were derived for cortisol and adrenocorticotropic hormone (ACTH). The 5-HTT selective tracer [11C]DASB was applied, and parametric images of the binding potentials (BPND) were calculated using the multilinear reference tissue model and evaluated by atlas-based volume of interest (VOI) analysis. The self-questionnaires of behavioral inhibition system/behavioral activation system (BIS/BAS) with subscales drive, fun-seeking and reward were assessed. OB showed significant positive correlations of ACTH curve parameters with overall 5-HTT BPND (ACTHAUC: r = 0.39, p = 0.04) and 5-HTT BPND of the caudate nucleus (ACTHAUC: r = 0.54, p = 0.003). In NO, cortisol indicators correlated significantly with BPND in the hippocampus (cortisolAUC: r = 0.59, p = 0.04). In OB, BAS reward was inversely associated with the ACTHAUC (r = -0.49, p = 0.009). The present study supports a serotonergic-neuroendocrine association, which regionally differs between OB and NO. In OB, areas processing emotion and reward seem to be in-volved. The finding of a serotonergic HPA correlation may have implications for other diseases with dysregulated stress axis responsiveness, and for potential pharmacologic interven-tions.

Fasting Ghrelin Levels Are Decreased in Obese Subjects and Are Significantly Related With Insulin Resistance and Body Mass Index

BACKGROUND:Ghrelin is a 28-amino acid peptide that predominantly produced by the stomach. Strong evidence indicates the effects of ghrelin in the regulation of metabolic functions and its potential role in the aetiology of obesity.AIM:The aim of this study was to investigate the relationship of ghrelin levels with obesity, insulin resistance and glucose in normal and obese subjects.METHODS:Thirteen normal (n = 13) and seven (n = 7) obese weight subjects aged 20-22 participated in the study. Fasting plasma ghrelin, insulin and glucose levels were measured after overnight fasting. HOMA-IR was calculated to evaluate insulin resistance.RESULTS:Ghrelin and insulin levels were found to be statistically significantly lower and higher in obese subjects (P < 0.001), respectively. Glucose levels were clinically higher in obese subjects but not statistically significant. Fasting plasma ghrelin was negatively correlated with BMI (r = -0.77, P < 0.001), fasting insulin levels (r = -0.55, P < 0.001) and HOMA-IR (r = -0.66, P < 0.001). There was no correlation between ghrelin and glucose. In multiple regression analysis, insulin levels (Beta:-2.66, 95%CI:-2.49, -2.78, P < 0.001) HOMA-IR (Beta:-2.41, 95%CI:-2.33, -2.55, P < 0.001) and BMI (Beta:-1.77, 95%CI:-1.66, -1.89, P < 0.001) were significant independent determinants of fasting ghrelin.CONCLUSION:Obese subjects have low fasting ghrelin levels that they are significantly related to insulin resistance and body mass index. More prospective studies are needed to establish the role of ghrelin in the pathogenesis of human obesity.

Energy expenditure in the etiology of human obesity: spendthrift and thrifty metabolic phenotypes and energy-sensing mechanisms

The pathogenesis of human obesity is the result of dysregulation of the reciprocal relationship between food intake and energy expenditure (EE), which influences daily energy balance and ultimately leads to weight gain. According to principles of energy homeostasis, a relatively lower EE in a setting of energy balance may lead to weight gain; however, results from different study groups are contradictory and indicate a complex interaction between EE and food intake which may differentially influence weight change in humans. Recently, studies evaluating the adaptive response of one component to perturbations of the other component of energy balance have revealed both the existence of differing metabolic phenotypes ("spendthrift" and "thrifty") resulting from overeating or underfeeding, as well as energy-sensing mechanisms linking EE to food intake, which might explain the propensity of an individual to weight gain. The purpose of this review is to debate the role that human EE plays on body weight regulation and to discuss the physiologic mechanisms linking EE and food intake. An increased understanding of the complex interplay between human metabolism and food consumption may provide insight into pathophysiologic mechanisms underlying weight gain, which may eventually lead to prevention and better treatment of human obesity.

Plasma Citrulline: A New Marker of Gut Epithelium Alteration in Obese Patients?

Objectives: In the last decade gut microbial diversity was associated with the pathogenesis of obesity in humans. Plasma citrulline was a simple and accurate biomarker for the severity of intestinal failure and was associated with short bowel syndrome and alteration of gut permeability, being developed as an alternative to D-xylose tolerance test for the diagnosis of an abnormal small intestinal absorption of nutrients. This study was performed to ascertain whether obesity might be associated with dysregulation of epithelial gut function. Methods: Fifteen obese individuals (5 M/10 F; BMI 37.4 ± 6.1 Kg/m2; 42 ± 6 yrs) and 15 healthy gender- and age-matched controls (6 M/9 F BMI: 22.7 ± 2.1 Kg/m2; 39 ± 7 yrs) underwent D-xylose load (25 g) and plasma citrulline, plasma insulin, glucose and lipid profile testing. Results: Plasma citrulline was significantly lower in the obese group (p = 0.045) with respect to controls, whilst total cholesterol, LDL and trygliceri- des concentration, insulin level and HOMA-IR were significantly higher in obese patients. In contrast, after D-xylose load no difference in serum xylose was found between the two groups (p = ns). Conclusions: Obese patients show a decreased citrulline concentration with respect to lean subjects. Since citrulline is a known marker of intestinal health, alterations in the gut epithelium are likely to be associated with the obesity syndrome. We propose to measure citrulline level in obese patients on a routine basis.

Kruppel‐like factor‐3: role in lipid secretion, transport and beta oxidation (537.3)

Lipid metabolic disorder is a critical risk factor for metabolic syndrome,triggering diseases like obesity and diabetes.Obesity raises the risk for many chronic illnesses including diabetes,and heart disease.A unifying view is that insulin resistance,which arises from an excess of body fat,links T2D to obesity.Consistent with this view it has been observed that fat deposition in insulin effector cells decreases their sensitivity to insulin causing insulin resistance.While genetics and environmental components play a major role in the onset of disease caused by fat accumulation.There has been progress in our understanding of metabolic diseases given the complexity of vertebrate systems that employ many factors acting in overlapping and partially redundant pathways.Highly complicated metabolic networks and sensing mechanisms coordinate the flow of fats through synthesis,storage and breakdown pathways and therefore a composite view of nutrient uptake,transport,storage and utilization is required for its understanding.Mammalian Krüppel‐like factors KLFs play essential function in over all energy metabolisms.Many important factors controlling energy metabolism are conserved between mammals and C.elegans providing a new and powerful strategy to dissect the role of KLF in molecular pathways involved in fat metabolism.The worm intestine is our model system where genetics,molecular biology,and cell biology are used to identify and understand genes required in fat metabolism.Thus,we have found an important role of worm KLF in FA biosynthesis,mitochondrial proliferation,lipid secretion,and beta‐oxidation.We have began to understand the mechanism by which KLF controls these events in lipid metabolism.We have recently observed that worm KLF3 selectively acts on insulin components to regulate insulin pathway activity.There are many factors that control energy metabolism and defects in this control system are implicated in the pathogenesis of human obesity and diabetes.

A C. elegans model to study human metabolic regulation

Lipid metabolic disorder is a critical risk factor for metabolic syndrome, triggering debilitating diseases like obesity and diabetes. Both obesity and diabetes are the epicenter of important medical issues, representing a major international public health threat. Accumulation of fat in adipose tissue, muscles and liver and/or the defects in their ability to metabolize fatty acids, results in insulin resistance. This triggers an early pathogenesis of type 2 diabetes (T2D). In mammals, lipid metabolism involves several organs, including the brain, adipose tissue, muscles, liver, and gut. These organs are part of complex homeostatic system and communicate through hormones, neurons and metabolites. Our study dissects the importance of mammalian Krüppel-like factors in over all energy homeostasis. Factors controlling energy metabolism are conserved between mammals and Caenorhabditis elegans providing a new and powerful strategy to delineate the molecular pathways that lead to metabolic disorder. The C. elegans intestine is our model system where genetics, molecular biology, and cell biology are used to identify and understand genes required in fat metabolism. Thus far, we have found an important role of C. elegans KLF in FA biosynthesis, mitochondrial proliferation, lipid secretion, and β-oxidation. The mechanism by which KLF controls these events in lipid metabolism is unknown. We have recently observed that C. elegans KLF-3 selectively acts on insulin components to regulate insulin pathway activity. There are many factors that control energy homeostasis and defects in this control system are implicated in the pathogenesis of human obesity and diabetes. In this review we are discussing a role of KLF in human metabolic regulation.

Differential expression of liver proteins between obesity-prone and obesity-resistant rats in response to a high-fat diet

Rodents respond to a chronic high-fat diet (HFD) in two ways: some readily become obese (obesity prone, OP) and others do not (obesity resistant, OR). Although several hypotheses have been proposed, the mechanisms underlying the inter-individual susceptibility to diet-induced obesity remain to be fully defined. In the present study, two-dimensional gel electrophoresis (2-DE) combined with matrix-assisted laser desorption ionisation time-of-flight MS was carried out for identification of differentially expressed liver proteins in OP and OR rats fed a HFD, in an attempt to discover marker proteins involved in susceptibility and/or resistance to obesity in rat liver. The 2-DE analysis demonstrated that forty spots from 380 visualised spots were differentially regulated between the groups. Among these forty spots, twelve were differentially expressed proteins between OP and OR rats, reaching statistical significance. Of these, five proteins have already been linked to obesity; however, seven proteins involved in obesity susceptibility or resistance were identified for the first time in the present study. In order to validate the proteomic results and gain insight into the metabolic changes between the OP and OR groups, we further confirmed the expression pattern of some proteins of interest by Western blot analysis. Combined results of proteomic analysis with Western blot analysis revealed that reduced lipogenesis and increased fat oxidation were achieved in the livers of OR rats. In conclusion, the present proteomic study is an important advance over the previous steps required for identification of OP and OR rats, and should prove valuable in the search for the pathogenesis of obesity in humans.

Genetic and physiological aspects in the pathogenesis of human obesity

Event Abstract Back to Event Genetic and physiological aspects in the pathogenesis of human obesity Sadaf Farooqi1* 1 University of Cambridge, Department of Clinical Biochemistry, Cambridge Institute for Medical Research, United Kingdom Conference: 2nd Selfish Brain Conference New research on the neurobiology of ingestive behaviour, 23554 Luebeck, Germany, 27 May - 28 May, 2010. Presentation Type: Oral Presentation Topic: Talks Citation: Farooqi S (2010). Genetic and physiological aspects in the pathogenesis of human obesity. Front. Neurosci. Conference Abstract: 2nd Selfish Brain Conference New research on the neurobiology of ingestive behaviour. doi: 10.3389/conf.fnins.2010.08.00005 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 12 Apr 2010; Published Online: 12 Apr 2010. * Correspondence: Sadaf Farooqi, University of Cambridge, Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Paris, United Kingdom, isf20@cam.ac.uk Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Sadaf Farooqi Google Sadaf Farooqi Google Scholar Sadaf Farooqi PubMed Sadaf Farooqi Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

FTO variants are associated with obesity in the Chinese and Malay populations in Singapore.

OBJECTIVE— Association between genetic variants at the FTO locus and obesity has been consistently observed in populations of European ancestry and inconsistently in non-Europeans. The aim of this study was to examine the effects of FTO variants on obesity and type 2 diabetes in Southeast Asian populations.RESEARCH DESIGN AND METHODS— We examined associations between nine previously reported FTO single nucleotide polymorphisms (SNPs) with obesity, type 2 diabetes, and related traits in 4,298 participants (2,919 Chinese, 785 Malays, and 594 Asian Indians) from the 1998 Singapore National Health Survey (NHS98) and 2,996 Malays from the Singapore Malay Eye Study (SiMES).RESULTS— All nine SNPs exhibited strong linkage disequilibrium (r2 = 0.6–0.99), and minor alleles were associated with obesity in the same direction as previous studies with effect sizes ranging from 0.42 to 0.68 kg/m2 (P < 0.0001) in NHS98 Chinese, 0.65 to 0.91 kg/m2 (P < 0.02) in NHS98 Malays, and 0.52 to 0.64 kg/m2 (P < 0.0001) in SiMES Malays after adjustment for age, sex, smoking, alcohol consumption, and exercise. The variants were also associated with type 2 diabetes, though not after adjustment for BMI (with the exception of the SiMES Malays: odds ratio 1.17–1.22; P ≤ 0.026).CONCLUSIONS— FTO variants common among European populations are associated with obesity in ethnic Chinese and Malays in Singapore. Our data do not support the hypothesis that differences in allele frequency or genetic architecture underlie the lack of association observed in some populations of Asian ancestry. Examination of gene-environment interactions involving variants at this locus may provide further insights into the role of FTO in the pathogenesis of human obesity and diabetes.

Sympathetic nervous system activity may link hyperphagia and fat deposition in human obesity

to the editor: The increasing prevalence of human obesity is posing a major threat to global health. This concern has prompted great interest in the mechanisms responsible for the development of obesity. In their review paper, Nedergaard et al. ([6][1]) discuss the evidence indicating that the brown

Association analysis of vitamin D-binding protein gene polymorphisms with variations of obesity-related traits in Caucasian nuclear families

Vitamin D-binding protein (DBP) gene is well known for its function on glucose and vitamin D metabolism in human populations. Previous studies suggested that the in vivo DBP level may play a role in the etiology of obesity. However, few studies explored the contribution of DBP gene to the variance of obesity phenotypes. To investigate the relationship of DBP polymorphisms and obesity in Caucasian nuclear families. We genotyped 14 single-nucleotide polymorphisms (SNPs) located in and around the DBP gene in 1873 Caucasian subjects from 405 nuclear families. Three obesity-related quantitative phenotypes were investigated, including body mass index (BMI), fat mass and percentage of fat mass (PFM). Single SNPs and haplotypes (three blocks) were tested by family-based association using the FBAT software. SNP2 (rs17467825) and its corresponding haplotype GAA (frequency 0.270) in block 1 showed strongest associations with PFM (P=0.0011 and 0.0023, respectively). In multivariate test significant association was also observed for SNP2 with fat mass&BMI&PFM (P=0.0098). Subsequent sex-stratified analyses demonstrated nominal association for SNP2 and haplotype GAA with PFM in the female subgroup. Polymorphisms of DBP gene were significantly association with human PFM, especially in female, suggesting the importance of DBP gene in the pathogenesis of human obesity.

Potential role of hypothalamic ghrelin in the pathogenesis of human obesity

Ghrelin is a potent appetite stimulator, mainly synthesized in the stomach but also made in the brain. Paradoxically, obese subjects have lower plasma ghrelin than lean subjects and increase their weight in spite of low ghrelin levels. We hypothesize that central, and not peripheral ghrelin, is primarily responsible for overeating in humans. The aim of this study was to determine hypothalamic ghrelin levels in lean vs obese subjects. We collected anterior hypothalamus from lean and obese patients at the time of autopsy, and Western blots and semiquantitative RT-PCR for ghrelin and neuropeptide Y (NPY) were carried out. Our results showed that ghrelin expression was significantly higher in the hypothalamus of obese subjects compared to lean ones. This finding correlates with similar increases in NPY in the obese group. Ghrelin and NPY mRNA levels followed the same trend and were significantly higher in the hypothalamus in obese compared to lean subjects, suggesting a central origin for the increased protein content in the obese subjects. In conclusion, obesity in humans is associated with elevated central ghrelin. This data questions the significance of the role of peripheral ghrelin in the regulation of appetite in humans and suggests an important role for central ghrelin in the pathogenesis of obesity in humans.

Genetic Linkage and Association of the Growth Hormone Secretagogue Receptor (Ghrelin Receptor) Gene in Human Obesity

The growth hormone secretagogue receptor (GHSR) (ghrelin receptor) plays an important role in the regulation of food intake and energy homeostasis. The GHSR gene lies on human chromosome 3q26 within a quantitative trait locus strongly linked to multiple phenotypes related to obesity and the metabolic syndrome. Because the biological function and location of the GHSR gene make it an excellent candidate gene, we tested the relation between common single nucleotide polymorphisms (SNPs) in the GHSR gene and human obesity. We performed a comprehensive analysis of SNPs, linkage disequilibrium (LD), and haplotype structure across the entire GHSR gene region (99.3 kb) in 178 pedigrees with multiple obese members (DNA of 1,095 Caucasians) and in an independent sample of the general population (MONICA Augsburg left ventricular hypertrophy substudy; DNA of 1,418 Caucasians). The LD analysis revealed a disequilibrium block consisting of five SNPs, consistent in both study cohorts. We found linkage among all five SNPs, their haplotypes, and BMI. Further, we found suggestive evidence for transmission disequilibrium for the minor SNP alleles (P < 0.05) and the two most common haplotypes with the obesity affection status ("susceptible" P = 0.025, "nonsusceptible" P = 0.045) in the family cohort using the family-based association test program. Replication of these findings in the general population resulted in stronger evidence for an association of the SNPs (best P = 0.00001) and haplotypes with the disease ("susceptible" P = 0.002, "nonsusceptible" P = 0.002). To our knowledge, these data are the first to demonstrate linkage and association of SNPs and haplotypes within the GHSR gene region and human obesity. This linkage, together with significant transmission disequilibrium in families and replication of this association in an independent population, provides evidence that common SNPs and haplotypes within the GHSR region are involved in the pathogenesis of human obesity.

Reduced Adipose Glucocorticoid Reactivation and Increased Hepatic Glucocorticoid Clearance as an Early Adaptation to High-Fat Feeding in Wistar Rats

Altered peripheral glucocorticoid metabolism may be important in the pathogenesis of obesity in humans and animal models. Genetically obese Zucker rats, Lep/ob mice, and obese humans exhibit increased regeneration of active glucocorticoids selectively in adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) and increased glucocorticoid clearance by hepatic A-ring reductases. We have examined whether dietary obesity in rats induces the same changes in glucocorticoid metabolism. Male Wistar rats were weaned onto high-fat (HF; 45% kcal from fat) or control (10% fat) diets. After 3 wk, HF rats showed no differences in weight but were glucose intolerant, had lower 11beta-HSD-1 activity in liver (3.8 +/- 0.2 vs. 4.9 +/- 0.2 pmol product/min.mg protein; P <0.01), sc fat (0.03 +/- 0.01 vs. 0.09 +/- 0.01 pmol product/min.mg protein; P <0.01), and omental fat (0.02 +/- 0.001 vs. 0.03 +/- 0.003 pmol/ product/min.mg protein; P <0.05) and higher hepatic 5beta-reductase activity (0.26 +/- 0.05 vs. 0.10 +/- 0.007 pmol product/min.mg protein; P <0.05). After 20 wk, HF rats were obese, hyperglycemic, and hyperinsulinemic, but differences in 11beta-HSD-1 and 5beta-reductase activities were no longer apparent. Mature male rats given HF diets for 24 or 72 h showed increased hepatic 5beta-reductase activity and a trend for decreased sc adipose 11beta-HSD-1 activity. Dietary obesity is not accompanied by the changes in 11beta-HSD-1 and 5beta-reductase expression and activity observed in genetically obese rodents. Acute exposure to HF diet alters glucocorticoid metabolism, predicting lower hepatic and adipose intracellular glucocorticoid concentrations, which may be a key mechanism protecting against the metabolic complications of obesity.

Identification of major quantitative trait loci controlling body weight variation in ob/ob mice.

The adipocyte hormone leptin constitutes an important component of the regulation of energy homeostasis; leptin-deficient animals, such as obese mice, are strikingly overweight. The seemingly uninhibited weight gain in obese mice belies the fact that control of energy homeostasis remains under precise, heritably modifiable control. Herein, we report large, heritable differences in body weight and food intake between BTBR-ob/ob and B6-ob/ob mice. We have identified two loci, called modifier of obese (Moo1 and Moo2), that explain the majority of the heritable variance in (BTBR x B6) F(2)-ob/ob mice. Using interval-specific congenic mouse lines, we mapped Moo1 to an 8-Mb segment of chromosome 2 and demonstrated that Moo1 exerts its effects primarily by regulating total fat mass. Although null alleles of leptin are rare, the majority of overweight adults are leptin resistant, suggesting that leptin-independent pathways, such as those studied here, are important regulators of energy homeostasis. Thus, the identification of these loci may provide important new insights into the pathogenesis of human obesity.

Genetic variation and obesity in Australian women: a prospective study.

A number of candidate genes have been implicated in the pathogenesis of obesity in humans. This study examines associations between longitudinal changes in body mass and composition and the presence of polymorphisms in the beta-3 adrenergic receptor, tumor necrosis factor-alpha, leptin, and leptin receptor (Lepr) in a cohort of Australian women. Healthy white Australian women (n = 335) were randomly selected from the Barwon region of Victoria and underwent baseline anthropometry and double-energy X-ray absorptiometry for assessment of body mass and adiposity. These measurements were repeated again at 2-year follow-up. Genomic DNA was extracted and used for polymerase chain reaction-based genotyping of all polymorphisms. The Pro1019Pro Lepr polymorphism was associated with longitudinal increases in body weight (p = 0.02), fat mass (p = 0.05), and body mass index (p = 0.01) in this study, and individuals homozygous for the A allele at this locus had a greater propensity to gain body fat over time. The largest effects on body composition seemed to be in individuals already obese at baseline. Changes in body weight, fat mass, percent body fat, and body mass index over a 2-year period were not associated with genetic variation in the beta-3 adrenergic receptor (Trp64Arg), tumor necrosis factor-alpha promoter, or leptin genes in non-obese or obese women. These results suggest that a Lepr polymorphism is involved in the regulation of body mass and adiposity in obese Australian white women, which may have implications for the treatment of obesity in this population.

Role of non-exercise activity in the pathogenesis of human obesity

Role of non-exercise activity in the pathogenesis of human obesity

Adrenomedullary function and its regulation in obesity.

Sympathoadrenal system (SAS) represents a major contributor to body homeostasis, regulating blood pressure heart rate, energy balance and intermediary metabolism. Thus, it is not unexpected that in last decades a consistent literature has been focused on the possible role of sympathoadrenal system in the pathogenesis of human obesity. There are, however, many factors confounding comparison of sympathoadrenal system activity between lean and obese subjects. Among these, one should be aware that SAS should be functionally separated into sympathetic nervous system (SNS) and adrenal medulla (AM), and that each of these two systems can be activated independently from the other by distinct physiological stimuli; this phenomenon in fact underlies the discordant pattern of findings for adrenomedullary and sympathetic activity in human obesity. While, in fact, obese subjects often display an increased basal SNS activity, there are numerous reports of blunted AM function in obese. Recent evidence suggests that this reduced adrenaline secretion is an acquired feature of human obesity, a finding that fits in well with the hypothesis that hormonal milieu, particularly sex steroids and cortisol, plays a role in the determination of blunted AM activity. Catecholamines have been recently demonstrated to play a role also in the regulation of whole energy balance. Adrenaline in fact acutely reduces both leptin mRNA as well as circulating leptin in human obese subjects, suggesting that catecholamines may influence the cross-talk between energy stores and the centrally mediated modulation of food intake. In summary, the study of adrenomedullary function and of possible mechanisms of its disturbances in human obesity, appears of great interest, and surely deserves further investigations.

Control of food intake via leptin receptors in the hypothalamus

Food intake is regulated via neural circuits located in the hypothalamus. During the past decade our knowledge on the specific mediators and neuronal networks that regulate food intake and body weight has increased dramatically. An important contribution to the understanding of hypothalamic control of food intake has been the characterization of the ob gene product (leptin) via positional cloning. Absence of circulating, functionally active, leptin hormone results in massive obesity as seen in ob/ob mice. Leptin inhibits food intake and increases energy expenditure via an interaction with specific leptin receptors located in the hypothalamus. Leptin receptors, of which there are several splice variants (Ob-Ra through Ob-Re), belong to the superfamily of cytokine receptors, which use the JAK-STAT pathway of signal transduction. Obese db/db mice, which have a mutation in the db locus, are unable to perform JAK-STAT signal transduction due to absence of functionally active (long form; Ob-Rb) leptin receptors. Ob-Rb is primarily expressed in the hypothalamus, with particularly high levels in the arcuate, paraventricular, and dorsomedial nuclei and in the lateral hypothalamic area. The abundance of leptin receptors in the ventromedial and lateral hypothalamus supports early observations that these two regions are intimately associated with the regulation of food intake. Leptin receptors have been identified in neuropeptide Y (NPY)/lagouti-related peptide (AgRP)- and proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART)-containing neurons of the ventromedial and ventrolateral arcuate nucleus, respectively, and in melanin-concentrating hormone (MCH)- and hypocretin/orexin-containing neurons of the lateral hypothalamus, suggesting that the above-mentioned messengers are mediators of leptin's action in the hypothalamus. Indeed, functional studies show that NPY, AgRP, POMC-derived peptides, CART, MCH, and hypocretins/orexins all are important regulators of food intake. Leptin is essential for normal body weight balance, but the exact mechanisms by which leptin activates hypothalamic neuronal circuitries is known to a limited extent. In order to find pharmaceutical approaches to treat obesity, further studies will be needed to reveal the exact mechanisms by which leptin lowers body weight and which role leptin and leptin receptors have in the pathogenesis of human obesity.