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

The signaling adapter p62 plays a coordinating role in mediating phosphorylation and ubiquitin-dependent trafficking of interacting proteins. However, there is little known about the physiologic role of this protein in brain. Here, we report age-dependent constitutive activation of glycogen synthase kinase 3beta, protein kinase B, mitogen-activated protein kinase, and c-Jun-N-terminal kinase in adult p62(-/-) mice resulting in hyperphosphorylated tau, neurofibrillary tangles, and neurodegeneration. Biochemical fractionation of p62(-/-) brain led to recovery of aggregated K63-ubiquitinated tau. Loss of p62 was manifested by increased anxiety, depression, loss of working memory, and reduced serum brain-derived neurotrophic factor levels. Our findings reveal a novel role for p62 as a chaperone that regulates tau solubility thereby preventing tau aggregation. This study provides a clear demonstration of an Alzheimer-like phenotype in a mouse model in the absence of expression of human genes carrying mutations in amyloid-beta protein precursor, presenilin, or tau. Thus, these findings provide new insight into manifestation of sporadic Alzheimer disease and the impact of obesity.
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PMID:Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration. 1834 6

Steroidogenic factor 1 (SF-1) plays key roles in adrenal and gonadal development, expression of pituitary gonadotropins, and development of the ventromedial hypothalamic nucleus (VMH). If kept alive by adrenal transplants, global knockout (KO) mice lacking SF-1 exhibit delayed-onset obesity and decreased locomotor activity. To define specific roles of SF-1 in the VMH, we used the Cre-loxP system to inactivate SF-1 in a central nervous system (CNS)-specific manner. These mice largely recapitulated the VMH structural defect seen in mice lacking SF-1 in all tissues. In multiple behavioral tests, mice with CNS-specific KO of SF-1 had significantly more anxiety-like behavior than wild-type littermates. The CNS-specific SF-1 KO mice had diminished expression or altered distribution in the mediobasal hypothalamus of several genes whose expression has been linked to stress and anxiety-like behavior, including brain-derived neurotrophic factor, the type 2 receptor for CRH (Crhr2), and Ucn 3. Moreover, transfection and EMSAs support a direct role of SF-1 in Crhr2 regulation. These findings reveal important roles of SF-1 in the hypothalamic expression of key regulators of anxiety-like behavior, providing a plausible molecular basis for the behavioral effect of CNS-specific KO of this nuclear receptor.
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PMID:Central nervous system-specific knockout of steroidogenic factor 1 results in increased anxiety-like behavior. 1837 44

Loss of function mutations in the receptor tyrosine kinase TrkB pathway resulted in hyperphagia and morbid obesity in human and rodents. Conversely, peripheral or central stimulation of TrkB by its natural ligands BDNF or NT4 reduced body weight and food intake in mice, supporting the idea that TrkB is a key anorexigenic signal downstream of the melanocortin-4 receptor (Mc4r) system. Here we show that in non-human primates TrkB agonists were anorexigenic when applied centrally, but surprisingly orexigenic, leading to gain in appetite, body weight, fat deposits and serum leptin levels, when given peripherally. The orexigenic and pro-obesity effects of peripherally administered TrkB agonists appear to be dose dependent, not associated with fluid retention nor with evidence of receptor down regulation. Our findings revealed that TrkB signaling exerts dual control on energy homeostasis in the primates that could be targeted for the treatment of either wasting disorders or obesity.
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PMID:Appetite enhancement and weight gain by peripheral administration of TrkB agonists in non-human primates. 1838 75

Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 x 10(-7). This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.
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PMID:Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. 1907 60

Hypothalamic brain-derived neurotrophic factor (BDNF) is a key element in the regulation of energy balance. Here we investigated the therapeutic efficacy of BDNF by gene transfer in mouse models of obesity and diabetes. Gene transfer of BDNF led to marked weight loss and alleviation of obesity-associated insulin resistance. To facilitate clinical translation and ensure that BDNF protein expression was appropriately decreased as weight loss progressed, thus preventing cachexia, we developed a molecular autoregulatory system involving a single recombinant adeno-associated virus vector harboring two expression cassettes, one constitutively driving BDNF and the other driving a specific microRNA targeting BDNF. The microRNA element was controlled by a promoter (that controlling the Agrp gene encoding agouti-related peptide) responsive to BDNF-induced physiological changes. Hence, as body weight decreased and agouti-related protein is induced, microRNA expression was activated, inhibiting transgene expression. In contrast to the progressive weight loss associated with a nonregulated approach, this microRNA-approach led to a sustainable plateau of body weight after notable weight loss was achieved. This strategy mimics the body's endogenous physiological feedback mechanisms, thereby resetting the hypothalamic set point to reverse obesity and metabolic syndrome.
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PMID:Molecular therapy of obesity and diabetes by a physiological autoregulatory approach. 1927 Jul 10

The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Besides environmental factors, genetic factors are known to play an important role in the pathogenesis of obesity. A number of genetic determinants of adult BMI have already been established through genome-wide association (GWA) studies. In this study, we examined 25 single-nucleotide polymorphisms (SNPs) corresponding to 13 previously reported genomic loci in 6,078 children with measures of BMI. Fifteen of these SNPs yielded at least nominally significant association to BMI, representing nine different loci including INSIG2, FTO, MC4R, TMEM18, GNPDA2, NEGR1, BDNF, KCTD15, and 1q25. Other loci revealed no evidence for association, namely at MTCH2, SH2B1, 12q13, and 3q27. For the 15 associated variants, the genotype score explained 1.12% of the total variation for BMI z-score. We conclude that among 13 loci that have been reported to associate with adult BMI, at least nine also contribute to the determination of BMI in childhood as demonstrated by their associations in our pediatric cohort.
Obesity (Silver Spring) 2009 Dec
PMID:The role of obesity-associated loci identified in genome-wide association studies in the determination of pediatric BMI. 1947 90

The eating disorders anorexia and bulimia nervosa have traditionally been regarded as entirely separate from obesity. Eating disorders have been regarded as Western culture-bound syndromes, arising in societies with excessive emphasis on weight, shape and appearance, and best treated by psychological therapies, in particular cognitive behavioural therapy or family-based interventions. In contrast, obesity has been considered a medical illness with metabolic and genetic origins, and thought to be best treated by mainstream medicine, involving dietary, drug or surgical treatment. We believe that this polarisation is fundamentally flawed, and research and treatment of both types of disorder would be better served by greater appreciation of the psychosocial components of obesity and the biological and genetic components of eating disorders. There are similarities in phenotype (such as excessive attempts at weight control, binge eating behaviours) and in risk factors (such as low self-esteem, external locus of control, childhood abuse and neglect, dieting, media exposure, body image dissatisfaction, weight-related teasing and shared susceptibility genes). One example of shared genetic risk is the brain-derived neurotrophic factor (BNDF) gene, in which the valine allele of the Val66Met amino acid polymorphism predisposes to obesity, whereas the methionine allele predisposes to eating disorders. Thus the evidence suggests that these disorders will have both shared and distinct susceptibility factors; some will predispose to both types of disorder, some will push in opposite directions, and some will separate them.
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PMID:Eating disorders and obesity: two sides of the same coin? 1952 39

Obesity is one of the most important health problems today. Obesity is mostly caused by a complex interaction between environmental and genetic factors. However, several monogenic forms of obesity also exist. The mutations causing these forms of obesity were all found in genes involved in the leptin-melanocortin pathway: leptin, leptin receptor, proopiomelanocortin, prohormone convertase 1, and melanocortin-4 receptor. Recently, several novel players with a role in this pathway have been identified and have increased our knowledge on the regulation of food intake. These include the melanocortin-3 receptor, BDNF, SIM1, and nesfatin-1. In this review, we will discuss the most important players involved in this pathway. We will focus on genetic studies concerning mouse models involving these genes and reported human variation in these genes. We intend to provide an extensive overview of all currently known proteins with a significant role in this pathway. Together, these data demonstrate the importance of this pathway in the regulation of food intake and the pathogenesis of obesity.
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PMID:The role of the leptin-melanocortin signalling pathway in the control of food intake. 1981 5

There is evidence that the obesity phenotype in the Caucasian populations is associated with variations in several genes, including neuronal growth regulator 1 (NEGR1), SEC16 homolog B (SCE16B), transmembrane protein 18 (TMEM18), ets variant 5 (ETV5), glucosamine-6-phosphate deaminase 2 (GNPDA2), prolactin (PRL), brain-derived neurotrophic factor (BDNF), mitochondrial carrier homolog 2 (MTCH2), Fas apoptotic inhibitory molecule 2 (FAIM2), SH2B adaptor protein 1 (SH2B1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog (MAF), Niemann-Pick disease, type C1 (NPC1), melanocortin 4 receptor (MC4R) and potassium channel tetramerisation domain containing 15 (KCTD15). To investigate the relationship between obesity and these genes in the Japanese population, we genotyped 27 single-nucleotide polymorphisms (SNPs) in 14 genes from obese subjects (n=1129, body mass index (BMI) > or =30 kg m(-2)) and normal-weight control subjects (n=1736, BMI <25 kg m(-2)). The SNP rs10913469 in SEC16B (P=0.000012) and four SNPs (rs2867125, rs6548238, rs4854344 and rs7561317) in the TMEM18 gene (P=0.00015), all of which were in almost absolute linkage disequilibrium, were significantly associated with obesity in the Japanese population. SNPs in GNPDA2, BDNF, FAIM2 and MC4R genes were marginally associated with obesity (P<0.05). Our data suggest that some SNPs identified by genome-wide association studies in the Caucasians also confer susceptibility to obesity in Japanese subjects.
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PMID:Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population. 1985 40

Obesity, which is assuming alarming proportions, has been attributed to genetic factors, hypothalamic dysfunction, and intestinal gut bacteria and an increase in the consumption of energy-dense food. Obesity predisposes to the development of type 2 diabetes mellitus, hypertension, coronary heart disease, and certain forms of cancer. Recent studies have shown that the intestinal bacteria in obese humans and mice differ from those in lean that could trigger a low-grade systemic inflammation. Consumption of a calorie-dense diet that initiates and perpetuates obesity could be due to failure of homeostatic mechanisms that regulate appetite, food consumption, and energy balance. Hypothalamic factors that regulate energy needs of the body, control appetite and satiety, and gut bacteria that participate in food digestion play a critical role in the onset of obesity. Incretins, cholecystokinin, brain-derived neurotrophic factor, leptin, long-chain fatty acid coenzyme A, endocannabinoids and vagal neurotransmitter acetylcholine play a role in the regulation of energy intake, glucose homeostasis, insulin secretion, and pathobiology of obesity and type 2 diabetes mellitus. Thus, there is a cross-talk among the gut, liver, pancreas, adipose tissue, and hypothalamus. Based on these evidences, it is clear that management of obesity needs a multifactorial approach.
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PMID:Obesity: genes, brain, gut, and environment. 2002 65


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