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

An 8-year-old male with a complex developmental syndrome and severe obesity was heterozygous for a de novo missense mutation resulting in a Y722C substitution in the neurotrophin receptor TrkB. This mutation markedly impaired receptor autophosphorylation and signaling to MAP kinase. Mutation of NTRK2, which encodes TrkB, seems to result in a unique human syndrome of hyperphagic obesity. The associated impairment in memory, learning and nociception seen in the proband reflects the crucial role of TrkB in the human nervous system.
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PMID:A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. 1549 31

We have examined the expression and role of autocrine fibroblast growth factors (FGFs) in human preadipocytes through their differentiation in vitro. A high-molecular weight form of FGF-2 was initially strongly expressed, but 6-9 d after induction of differentiation, its expression decreased markedly. This coincided with the first appearance of visible lipid droplets within the cells. FGF-2 (18 kDa) was not found. FGF receptor (FGFR) 1 was detected as a single band of 125 kDa that also decreased with differentiation. Its decrease preceded that of FGF-2. Despite the decrease in cell-associated FGF-2 with differentiation, secreted FGF-2 was 2.5-fold higher in the differentiated preadipocytes. To determine whether FGF-2 had an autocrine role, FGFR signaling was inhibited using recombinant adenovirus expressing dominant negative FGFR1 (RAdDN-FGFR1) and a specific inhibitor of FGFR1 signaling, PD166866. Preadipocytes transduced with RAdDN-FGFR1 expressed a truncated, 79-kDa FGFR1. Differentiation, assessed by lipid droplet formation, was completely prevented by RAdDN-FGFR1 and by PD166866. The protein content in the cell layer and glucose uptake were significantly reduced by both agents. The insulin-sensitizing drug, rosiglitazone, did not prevent the actions of RAdDN-FGFR1 or PD166866. Controlling adipose tissue growth by limiting FGF actions may provide a means to combat obesity.
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PMID:Essential role of fibroblast growth factor signaling in preadipoctye differentiation. 1552 30

Obesity as well as low physical fitness and inactivity are associated with an increased incidence of cardiovascular risk factors and coronary artery disease (CAD). Increased inflammation has recently been addressed to play an important role for the relationship between obesity and CAD, as adipose tissue expresses and releases pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). As this relationship is less clear in childhood, we investigated 197 children aged 10-15 years assessing obesity, physical fitness, and a metabolic cardiovascular risk profile including markers of inflammation. Obese children had significantly higher concentrations of inflammatory parameters such as fibrinogen, ferritin, IL-6, and TNF-alpha than non-obese subjects (P<0.01). When dividing the children into groups regarding obesity (BMI < 22.5 kg/mz, BMI > or = 22.5 kglm2) and fitness (< 5 MET, > or = 5 MET), we found that obese, unfit children showed the highest systemic inflammation, whereas fit but obese individuals had as low levels as lean and fit children. These data reveal that even in childhood inflammatory parameters are elevated in obesity and that physical fitness counteracts this association.
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PMID:Low-grade systemic inflammation in overweight children: impact of physical fitness. 1563 87

Green tea catechins, especially (-)-epigallocatechin gallate (EGCG), have been proposed as a chemopreventative for obesity, diabetes, cancer, and cardiovascular diseases. However, relatively little is known about the mechanism of the action of EGCG on fat cell function. This study was designed to investigate the pathways of EGCG's modulation of the mitogenesis of 3T3-L1 preadipocytes. Preadipocyte proliferation as indicated by an increased number of cells and greater incorporation of bromodeoxyuridine (BrdU) was inhibited by EGCG in dose-, time-, and growth phase-dependent manners. Also, EGCG dose and time dependently decreased levels of phospho-ERK1/2, Cdk2, and cyclin D(1) proteins, reduced Cdk2 activity, and increased levels of G(0)/G(1) growth arrest, p21(waf/cip), and p27(kip1), but not p18(ink), proteins and their associations to Cdk2. However, neither MEK1, ERK1/2, p38 MAPK, phospho-p38, JNK, nor phospho-JNK was changed. Increased phospho-ERK1/2 content and Cdk2 activity, respectively, via the transfection of MEK1 and Cdk2 cDNA into preadipocytes prevented EGCG from reducing cell numbers. These data demonstrate the ERK- and Cdk2-dependent antimitogenic effects of EGCG. Moreover, EGCG was more effective than epicatechin, epicatechin gallate, and epigallocatechin in changing the mitogenic signals. The signal of EGCG in reducing growth of 3T3-L1 preadipocytes differed from that of 3T3 fibroblasts. Results of this study may relate to the mechanism by which EGCG modulates body weight.
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PMID:Antimitogenic effect of green tea (-)-epigallocatechin gallate on 3T3-L1 preadipocytes depends on the ERK and Cdk2 pathways. 1564 88

Eating disorders (ED), such as anorexia nervosa (AN) and bulimia nervosa (BN), are complex psychiatric disorders where different genetic and environmental factors are involved. Several lines of evidence support that brain-derived neurotrophic factor (BDNF) plays an essential role in eating behaviour and that alterations on this neurotrophic system participates in the susceptibility to both AN and BN. Accordingly, intraventricular administration of BDNF in rats determines food starvation and body weight loss, while BDNF or its specific receptor NTRK2 knockout mice develop obesity and hyperphagia. Case-control studies also suggest a BDNF contribution in the aetiology of ED: we have previously reported a strong association between the Met66 variant within the BDNF gene, restricting AN (ANR) and minimum body mass index (minBMI) in a Spanish sample, and a positive association between the Val66Met and -270C/T BDNF SNPs and ED in six different European populations. To replicate these results, avoiding population stratification effects, we recruited 453 ED trios from eight European centres and performed a family-based association study. Both haplotype relative risk (HRR) and haplotype-based haplotype relative risk (HHRR) methods showed a positive association between the Met66 allele and ANR. Consistently, we also observed an effect of the Met66 variant on low minBMI and a preferential transmission of the -270C/Met66 haplotype to the affected ANR offspring. These results support the involvement of BDNF in eating behaviour and further suggest its participation in the genetic susceptibility to ED, mainly ANR and low minBMI.
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PMID:Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations. 1565 4

The ERK, p38 and JNK mitogen activated protein kinases (MAPKs) are intracellular signalling pathways that play a pivotal role in many essential cellular processes such as proliferation and differentiation. MAPKs are activated by a large variety of stimuli and one of their major functions is to connect cell surface receptors to transcription factors in the nucleus, which consequently triggers long-term cellular responses. This review focuses on their in vitro and in vivo roles in adipocyte differentiation and obesity. Hyperplasia of adipose tissue is a critical event for the development of obesity. Several studies have analysed the role of MAPKs in vitro in adipocyte differentiation of preadipocyte established cell lines. In the case of ERK, although the first data appeared contradictory, a consensus scenario arises: ERK would be necessary to initiate the preadipocyte into the differentiation process and, thereafter, this signal transduction pathway needs to be shut-off to proceed with adipocyte maturation. The limitation of these cellular models is that only terminal adipocyte differentiation can be analysed, eluding the early proliferative steps of adipogenesis. New insights are now emerging by investigations conducted either in vitro with the use of embryonic stem (ES) cells or in vivo with mice where these genes are invalidated. These studies not only confirm and/or precise the various functions of MAPKs in adipogenesis but, importantly, reveal unsuspected roles, for example JNK in obesity or ERK in adipogenesis of ES cells, and, for a given pathway, assign specific functions to each isoform. It appears now that a fine tuning of the MAPKs regulates both normal and pathological adipogenesis. The precise understanding of the cascade of these molecular events and the way to regulate them will be certainly crucial in order to efficiently fight obesity.
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PMID:The role of MAPKs in adipocyte differentiation and obesity. 1573 37

Transgenic hyperexpression of melanin-concentrating hormone (MCH) produces a phenotype of obesity and glucose intolerance. However, it is not known whether under this specific condition, glucose intolerance develops as a direct consequence of hyperexpressed MCH or is secondary to increased adiposity. Here, rats were treated i.c.v. with MCH or with an antisense oligonucleotide to MCH (MCH-ASO). MCH promoted an increase in blood glucose and a decrease in blood insulin levels during a glucose tolerance test. MCH also caused a decrease in the constant of glucose disappearance during an insulin tolerance test. All these effects of MCH were independent of body weight variation and were accompanied by reduced insulin receptor substrate (IRS)-1 engagement of phosphatidylinositol-3 kinase (PI3-kinase) in white and brown adipose tissues, skeletal muscle and liver and by reduced Akt activation in skeletal muscle. MCH also led to a significant reduction in ERK activation in white adipose tissue. Finally, inhibition of hypothalamic MCH expression promoted a significant increase in ERK activation in brown adipose tissue. We conclude that hypothalamic MCH controls glucose homeostasis through mechanisms that are, at least in part, independent of adiposity.
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PMID:Melanin-concentrating hormone induces insulin resistance through a mechanism independent of body weight gain. 2825 9

The aim of this study is to compare out- and inpatient health services utilization by obese and normal weight adults. In a subsample of the KORA-Survey S4 1999/2001 in the Augsburg region, Germany (n = 947, age: 25-74 years), number of visits to general practitioners (GP) and inpatient hospital days were self-reported in three computer-aided telephone interviews (CATI) over half a year. Body mass index, based on measured body height and weight, was used to define obesity according to WHO classification. Participants, stratified in normal weight (18.5 < or = BMI < 25), preobese (25 < r = BMI < 30), obese class 1 (30 < or = BMI < 35) and obese classes 2-3 (BMI > or = 35), were compared via logistic, zero-truncated negative binomial, and multinomial models to elucidate obesity's associations with utilization at all, its frequency, and high utilization. Sex, age, social class, health insurance, and place of residence were adjusted for in all models. Respondents in obesity class 1 were more prone to report at least one visit to a GP than those normal weight (OR = 1.84, p < 0.01), while obesity classes 2-3 were associated with frequent (IRR = 1.63, p < 0.05) and high utilization (OR = 3.57, p < 0.05). Regarding days in hospital, only the extremely obese (i. e. classes 2-3) reported significantly more utilization than those normal weight (days if hospitalized at all: IRR = 3.24, p < 0.05; high utilization: OR = 5.4, p < 0.01). Sex did not play a significant role in any model. Older respondents reported more utilization in terms of GP-visits, while only tending to do so regarding inpatient utilization. Both those with statutory (vs. private) health insurance and rural (vs. urban) place of residence had higher odds to visit a GP at all. Results point to an excess utilization of out- and inpatient health services by especially extremely obese adults, and underline the need to contrast obesity classes 2-3 vs. 1 in health services utilization research.
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PMID:Utilization of out- and inpatient health services by obese adults: a population-based study in the Augsburg region, Germany. 1603 34

To date, most ring formations of chromosome 4 lose distal 4p and usually include the Wolf-Hirschhorn syndrome region [WHS]. We describe a case with r(4) in a girl who presented without features of WHS; she had mild developmental delay, deafness, short stature, obesity, and the onset of type 2 diabetes in adolescence, a distinctive phenotype. Although 4p was significantly deleted on Giemsa banding, the 4p junction was distal to the WHS and FGFR3 but proximal to the D4S3360 marker. The 4q breakpoint was close to the telomere. The phenotype appears different from previous patients with 4p- or r(4), which have had more extensive 4p deletion.
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PMID:Ring chromosome 4 in a patient with early onset type 2 diabetes, deafness, and developmental delay. 1608 3

Our understanding of the IGF-I system has increased dramatically in recent yr due in part to the advances in molecular and cellular biology. Not only can we now measure circulating levels of the members of this axis in order to address the possibly pathophysiological changes, but genetic alterations can now be identified as the underlying cause of specific clinical situations. In normal children, circulating levels of IGF-I and the IGF binding proteins (IGFBPs) change throughout development and in some cases are gender dependent. Children and adolescents with a variety of illnesses and metabolic disorders have altered circulating IGF-I and IGFBP levels. Hence, in children or adolescents with exogenous obesity, anorexia nervosa, coeliac disease, leukaemia and other types of cancer, as well as in cases of GH deficiency, this axis can be altered. These data may help us to understand the physiology and pathophysiology of this system, but the clinical or diagnostic utility of these measurements is still largely debated. Indeed, in most of the above mentioned illnesses, circulating IGF and IGFBP levels overlap with normal values. Furthermore, these measurements do not provide data concerning levels of these factors at target tissues or of local synthesis and autocrine-paracrine effects. However, measurements of IGF-I and its binding proteins, as well as GH and its binding proteins, can help us to focus our analysis of patients suspected to have genetic abnormalities on the GH receptor, IGF-I, its receptor, IGFALS, or intracellular signalling proteins such as STAT5b or ERK. Possibly, the most clear clinical utility of circulating IGF-I measurements in children is in cases of GH deficiency or insensitivity or under GH treatment. However, the fact there are cases of children with non-detectable levels of circulating IGF-I that yet normal height and growth velocity, or with non-detectable levels of GH yet normal growth and IGF-I levels, raises many questions. Furthermore, circulating IGF-I levels may be within the normal control levels and the child may have a pathological growth pattern. Hence, just how useful are these measurements? Another clinically important question pertains to GH treatment in patients, such as in the Turner Syndrome, where supraphysiological levels of serum IGF-I are reached in order to induce growth. The interpretation and clinical utility of measurements of circulating IGF-I and its BPs are currently being widely discussed. As our knowledge of this system increases, with the identification of new members of this family and its intracellular mechanisms of action, as well as new genetic alterations in patients, the interpretation of laboratory results will also improve and help to better our diagnostic capability.
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PMID:The IGF system in childhood: physiology and clinical implications. 1611 74


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