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Human Obesity (human + obesity)
Selected AbstractsDorothy Hodgkin Lecture 2008 Gastric inhibitory polypeptide (GIP) revisited: a new therapeutic target for obesity,diabetes?DIABETIC MEDICINE, Issue 7 2008P. R. Flatt Abstract There is increasing realization that gastric inhibitory polypeptide (GIP) has actions outside of the pancreas and gastrointestinal tract. Most significant is the presence of functional GIP receptors on adipocytes and the appreciation that GIP, secreted strongly in response to fat ingestion, plays a role in the translation of excessive amounts of dietary fat into adipocyte tissue stores. Such effects open up the possibility of exploiting GIP receptor antagonism for the treatment of obesity and insulin resistance. This is borne out by studies in high-fat-fed mice or ob/ob mice with either genetic knockout of GIP receptor or chemical ablation of GIP action using the GIP receptor antagonist, (Pro3)GIP. By causing preferential oxidation of fat, blockade of GIP signalling clears triglyceride deposits from liver and muscle, thereby respectively restoring mechanisms for suppression of hepatic glucose output and cellular glucose uptake. Further studies are needed to determine the applicability of this research to human obesity,diabetes. However, proof of concept is provided by emerging evidence that rapid cure of diabetes in grossly obese subjects undergoing Roux-en-Y bypass surgery is mediated in part by surgical bypass of GIP-secreting K-cells in the upper small intestine. [source] Targeting of the central histaminergic system for treatment of obesity and associated metabolic disordersDRUG DEVELOPMENT RESEARCH, Issue 8 2006Kjell Malmlöf Abstract There is currently a need for effective pharmacological therapies for treatment of obesity. In this communication, the involvement of the neurotransmitter histamine in the regulation of food intake is reviewed, together with results obtained in animals with pharmacologically increased brain histamine levels. A survey of the literature reveals that histaminergic circuits, arising from nerve cell bodies in the tuberomammillary nucleus and projecting into the paraventricular nucleus, the arcuate nucleus, and the ventromedial hypothalamus, are strongly involved in regulation of food intake and possibly also energy expenditure. Current literature also suggests the histaminergic circuits connect to other neuronal pathways involved in the regulation of energy balance and body weight. Studies performed in rodents demonstrate that H3 receptor antagonists increase hypothalamic histamine and decrease food intake, which result in decreased body weight. Lipid oxidation is increased and, at higher doses, body fat is also decreased. These changes are associated with lower circulating levels of insulin during an oral glucose challenge suggesting an increase in insulin sensitivity. The effects on food intake have also been confirmed in pigs and rhesus monkeys. It can thus be concluded that results obtained with H3 antagonist in animals warrant future clinical studies to evaluate whether this principle is effective in the treatment of human obesity. Drug Dev. Res. 67:651,665, 2006. © 2006 Wiley-Liss, Inc. [source] CDK4 IVS4-nt40G,A and T2D-associated obesity in ItaliansJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2009Ramachandran Meenakshisundaram Cell cycle regulators play crucial roles in the preadipocyte proliferation and adipocyte differentiation. Cyclin-dependent kinase 4 (CDK4) mediates with D-type cyclins entry of cells into cell cycle in response to external stimuli. CDK4 plays a role in body weight, adipogenesis, and beta cell proliferation. CDK4 null mice develop type 2 diabetes (T2D). Furthermore, CDK4 variants are associated with obesity-associated tumors/cancer. We aimed at identifying a role of CDK4 IVS4-nt40G,,,A variant in T2D-associated obesity (body mass index, BMI,,,30) by association tests in an Italian T2D subjects dataset. We recruited from Italy 128 unrelated T2D subjects with BMI,<30,kg/m2 and 54 unrelated T2D subjects with BMI,,,30,kg/m2. We performed statistical power calculations in our dataset. DNA samples were directly sequenced with specific primers for CDK4 IVS4-nt40G,,,A variant. We identified a significant association of the G allele with T2D-associated obesity and of the A allele with T2D-associated BMI,<,30. In our study, we found that the CDK4 IVS4-nt40GG genotype is a risk variant for T2D-associated obesity and that the AA genotype is associated with BMI,<,30 in T2D. Hence, CDK4 IVS4-nt40A allele is protective and G allele confers risk for obesity in T2D patients. This study should prompt further work aiming at establishing CDK4 role in contributing to human obesity and T2D-associated obesity. J. Cell. Physiol. 221: 273,275, 2009. © 2009 Wiley-Liss, Inc. [source] Brain regulation of food intake and appetite: molecules and networksJOURNAL OF INTERNAL MEDICINE, Issue 4 2005C. BROBERGER Abstract. In the clinic, obesity and anorexia constitute prevalent problems whose manifestations are encountered in virtually every field of medicine. However, as the command centre for regulating food intake and energy metabolism is located in the brain, the basic neuroscientist sees in the same disorders malfunctions of a model network for how integration of diverse sensory inputs leads to a coordinated behavioural, endocrine and autonomic response. The two approaches are not mutually exclusive; rather, much can be gained by combining both perspectives to understand the pathophysiology of over- and underweight. The present review summarizes recent advances in this field including the characterization of peripheral metabolic signals to the brain such as leptin, insulin, peptide YY, ghrelin and lipid mediators as well as the vagus nerve; signalling of the metabolic sensors in the brainstem and hypothalamus via, e.g. neuropeptide Y and melanocortin peptides; integration and coordination of brain-mediated responses to nutritional challenges; the organization of food intake in simple model organisms; the mechanisms underlying food reward and processing of the sensory and metabolic properties of food in the cerebral cortex; and the development of the central metabolic system, as well as its pathological regulation in cancer and infections. Finally, recent findings on the genetics of human obesity are summarized, as well as the potential for novel treatments of body weight disorders. [source] An epidemiological study of environmental factors associated with canine obesityJOURNAL OF SMALL ANIMAL PRACTICE, Issue 7 2010E. A. Courcier Objectives: To assess the relationships between socioeconomic and other environmental factors with canine obesity. Methods: This was a cross-sectional questionnaire study of dog owners attending five primary veterinary practices in the UK. Owners were asked about dog age, neuter status, feeding habits, dog exercise, household income and owner age. The body condition score of the dogs was also assessed. Factors hypothesised to be associated with obesity were investigated. Results: In total, data from 696 questionnaires were evaluated. Out of those data evaluated, 35·3% of dogs (n=246) were classed as an ideal body shape, 38·9% (n=271) were overweight, 20·4% (n=142) were obese and 5·3% (n=37) were underweight. Identified risk factors associated with obesity included owner age, hours of weekly exercise, frequency of snacks/treats and personal income. Clinical Significance: Environmental risk factors associated with canine obesity are multifactorial and include personal income, owner age, frequency of snacks/treats and amount of exercise the dog receives. Awareness about health risks associated with obesity in dogs is significantly less in people in lower income brackets. This phenomenon is recognised in human obesity. [source] Genetic factors in human obesityOBESITY REVIEWS, Issue 2007I. S. Farooqi [source] Perspectives: molecular genetic research in human obesityOBESITY REVIEWS, Issue 3 2003J. Hebebrand Summary Within the past decade the molecular basis of single forms of monogenic obesity has been elucidated. With the exception of functionally relevant mutations in the melanocortin-4 receptor gene, which occur in approximately 2,4% of extremely obese individuals, all other currently known monogenic forms are rare and additionally associated with distinct endocrinological abnormalities. A large number of association studies have been performed in ,normal' obesity. Whereas many associations have been reported, it is largely unclear which of these represent true positive findings. Over 20 genome scans pertaining to obesity and related phenotypes have been performed; specific chromosomal peak regions have been identified in different scans. We review the current status and discuss relevant issues related to phenotyping, association and linkage studies. We recommend that the procedure via which a consensus is reached as to what constitutes a true positive association finding requires formalization. [source] Taste, food intake and obesityOBESITY REVIEWS, Issue 4 2001J. Nasser PhD Abstract Research in human eating behaviour prior to 1990 has shown that taste impacts the palatability and selection of food for intake; sensory-specific satiety; satiation; and thermic effect of food. Research in the last decade has added information to these areas; expanded the field to comparisons of the impact of ,wanting' vs. ,liking' food on intake, and provided insight into the relationship of food intake and brain functioning through new imaging techniques. This article will review literature from the last decade on research in the area of taste and its impact on food intake. Emphasis will be placed on differences seen between lean and obese humans and how these may contribute to the development of human obesity. Suggestions for future research directions will also be discussed. [source] The peripheral sympathetic nervous system in human obesityOBESITY REVIEWS, Issue 1 2001M. A. van Baak Summary The peripheral sympathetic nervous system is a key factor in the regulation of energy balance in humans. Differences in sympathetic nervous system activity may contribute to variations in 24 h energy expenditure between individuals. ,-Adrenoceptors play a more important role than ,-adrenoceptors in this regulation. The involvement of both ,1-and ,2-adrenoceptor subtypes has been demonstrated, the role of the ,3-adrenoceptor subtype is not yet clear. Normal or increased levels of sympathetic nervous system activity and reduced reactivity appear to be present in established obesity. Furthermore, the sensitivity for ,-adrenoceptor stimulation is impaired in obesity. The blunted reactivity and sensitivity may contribute to the maintenance of the obese state. There are data to suggest that they may also play a role in the aetiology of obesity, because the impairments often remain after weight reduction. Furthermore, a negative correlation between baseline sympathetic nervous system activity and weight gain during follow-up has been found in Pima Indians. Recently, genetic evidence about the involvement of adrenoceptors in obesity has become available. Although the results of association and linkage studies on polymorphisms in the ,2-, ,3- and ,2-adrenoceptor genes are inconsistent, the functional correlates of some of these polymorphisms (changes in agonist-promoted down-regulation, protein expression levels, lipolytic sensitivity, basal metabolic rate, sympathetic nervous system activity) suggest that they may be important in the aetiology of obesity. [source] Obesity is Associated with Genetic Variants That Alter Dopamine AvailabilityANNALS OF HUMAN GENETICS, Issue 3 2006A. C. Need Summary Human and animal studies have implicated dopamine in appetite regulation, and family studies have shown that BMI has a strong genetic component. Dopamine availability is controlled largely by three enzymes: COMT, MAOA and MAOB, and by the dopamine transporter SLC6A3, and each gene has a well-characterized functional variant. Here we look at these four functional polymorphisms together, to investigate how heritable variation in dopamine levels influences the risk of obesity in a cohort of 1150, including 240 defined as obese (BMI , 30). The COMT and SLC6A3 polymorphisms showed no association with either weight, BMI or obesity risk. We found, however, that both MAOA and MAOB show an excess of the low-activity genotypes in obese individuals (MAOA:,2= 15.45, p = 0.004; MAOB:,2= 8.05, p = 0.018). Additionally, the MAOA genotype was significantly associated with both weight (p = 0.0005) and BMI (p = 0.001). When considered together, the ,at risk genotype' - low activity genotypes at both the MAOA and MAOB loci - shows a relative risk for obesity of 5.01. These results have not been replicated and, given the experience of complex trait genetics, warrant caution in interpretation. In implicating both the MAOA and MOAB variants, however, this study provides the first indication that dopamine availability (as opposed to other effects of MAOA) is involved in human obesity. It is therefore a priority to assess the associations in replication datasets. [source] Review article: Is obesity an inflammatory illness?BJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 10 2006Role of low-grade inflammation, macrophage infiltration in human white adipose tissue There are at least two scientific evidences of human obesity as a chronic inflammatory illness: first, the well-described moderate increase of inflammatory factors in the circulation in obese subjects, and second, the recent identification of macrophage cells infiltrating the white adipose tissue (WAT). These observations led to a revision of the physiopathology of obesity and its co-morbidities. It has been suggested that the ,low-grade' inflammatory state associates with metabolic and cardiovascular complications of obesity. Weight loss is able to improve this inflammatory state by both significantly decreasing circulating inflammatory molecules and macrophage cell infiltration in WAT depots. However, the mechanisms of WAT macrophage recruitment into the adipose tissue and their role in obesity complications have not been defined. This review aims to point out the knowledge on inflammatory cytokines associated with obesity and focuses on macrophage infiltration in human WAT, discussing their recruitment and role. The interactions of macrophages with adipocytes will certainly be the subject of intense investigations in the future. [source] Identification and functional characterization of three novel human melanocortin-4 receptor gene variants in an obese Chinese populationCLINICAL ENDOCRINOLOGY, Issue 2 2006Rong Rong Summary Objective, Mutations in the melanocortin-4 receptor gene (MC4R) are the most common monogenic form of human obesity. However, the contribution of MC4R mutations to obesity in Chinese has not been investigated. We studied the frequency of MC4R mutations in an obese southern Chinese population and the functional consequences of the novel variants identified. Methods, We screened for MC4R mutations in 227 obese [body mass index (BMI) 35·29 ± 5·75 kg/m2] and 100 lean (BMI 21·57 ± 0·29 kg/m2) southern Chinese subjects using PCR-direct sequencing. In vitro functional studies, including cell surface expression, ligand binding, and cyclic adenosine monophosphate (cAMP) accumulation, were performed to examine the functional properties of three novel missense mutations. Results, Apart from two previously reported polymorphisms, V103I and ,176 A > C, three novel missense heterozygous variants (Y35C, C40R and M218T) were identified. The polymorphisms ,176 A > C and Y35C were detected in both obese and normal subjects with similar frequency. C40R was identified only in an obese subject. Pedigree analysis revealed M218T carriers in both lean and obese subjects. The prevalence of V103I carriers in normal-weight controls was significantly higher than that in obese subjects (5·3%vs. 1·3%, P < 0·05). In vitro functional studies showed that all three novel missense variants have normal functions. Conclusions, Two known polymorphisms and three novel variants of the MC4R were identified. No overt functional defects were observed for the three novel MC4R variants, suggesting that they might not be the cause of obesity in variant carriers. [source] T lymphopaenia in relation to body mass index and TNF-, in human obesity: adequate weight reduction can be correctiveCLINICAL ENDOCRINOLOGY, Issue 3 2001S.-I. Tanaka OBJECTIVE Although individuals with obesity are susceptible to infection, the underlying causes have not been fully identified. To investigate whether obesity affects immunity, we studied subjects with isolated obesity. DESIGN AND SUBJECTS Thirty-four obese persons from our outpatient obesity clinic and 50 nonobese healthy control subjects were studied. The effects of weight reduction were evaluated in obese subjects on a very-low-energy diet. We examined blastogenic response, lymphocyte subsets, circulatory TNF-,, soluble TNF-, receptor 1, soluble TNF-, receptor 2, and in vitro TNF-, production in obesity. MEASUREMENTS Lymphocyte subsets were analysed with flowcytometry. TNF-, and soluble TNF receptors levels were assayed using commercially available enzyme-linked immunosorbent assay kits. RESULTS Blastogenic responses to phytohemagglutinin or concanavalin A of T cells, CD3+, CD4+, CD8+, CD4+CD45RO+, and TCR ,, T cells were significantly diminished in obese subjects. Strong negative correlations were observed between TCR ,, and body weight and BMI in obese subjects. Circulatory levels of TNF-,, soluble TNF-, receptors, and in vitro TNF-, production were significantly increased compared to nonobese subjects. In obese subjects, there were significant positive correlations between serum levels of TNF-, and waist-hip ratio, serum levels of soluble TNF-, receptor 1 and body weight, soluble TNF-, receptor 2 and BMI, and soluble TNF-, receptor 2 and waist-hip ratio. The T cell responses and previously reduced non-CD8 T cell subsets were increased significantly following weight reduction. CONCLUSIONS Our results suggest that subsets of T cell populations and their function may be reduced in human obesity, and that this may be related, at least in part, to the elevated TNF-, production. Furthermore, this T cell dysfunction can be recovered by adequate weight reduction. [source] | |||||||||||||