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

Fatty acids are important metabolic substrates and may also be involved in pathological syndromes such as the insulin resistance of diabetes and obesity. We demonstrate here that fatty acids can regulate specific gene expression; mRNAs encoding the fatty acid binding protein adipocyte P2 (aP2) and the Fos-related transcription factor Fra1 are specifically induced at least 20-fold upon treatment of preadipocytes with oleate. For aP2, the effect requires long chain fatty acids and occurs without a generalized activation of the genes linked to adipocyte differentiation. Other fibroblastic cells without preadipocyte characteristics do not induce aP2 mRNA in response to fatty acids. Unlike aP2, Fra1 induction by fatty acids also can be detected in NIH 3T3 and 3T3-C2 fibroblasts. Nuclear transcription assays in 3T3-F442A preadipocytes demonstrate that fatty acids elicit no transcriptional increase in the aP2 gene. Fra1, on the other hand, shows a 3-4-fold increase in transcription. These results demonstrate at least two distinct mechanisms by which fatty acids may influence gene expression.
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PMID:Fatty acid regulation of gene expression. Transcriptional and post-transcriptional mechanisms. 137 97

Adipsin is a serine protease with complement factor D activity that is synthesized by adipocytes and secreted into the blood stream. Expression of adipsin is deficient in models of genetic (ob/ob, db/db) and acquired (monosodium glutamate-lesioned) obesity, but the cellular mechanisms responsible for this deficiency are unknown. Because hyperinsulinemia is frequently associated with obesity, we evaluated the effects of this hormone and insulin-like growth factor 1 (IGF-1) on adipsin secretion and adipsin messenger RNA (mRNA) levels in 3T3-F442A adipocytes. In the present study, we report that in fully differentiated adipocytes (after 11 days post confluence), insulin exposure progressively decreases adipsin secretion by 40%, 67%, and 78% after 2, 4, and 6 days of treatment. The inhibition of adipsin secretion by insulin is the result of a corresponding decrease in adipsin mRNA and is specific since two other differentiation-dependent fat cell mRNAs encoding aP2 (a fatty acid binding protein) and glycerophosphate dehydrogenase (GPD), are unaffected. Insulin suppresses adipsin gene expression via high affinity insulin receptors, because physiological levels of insulin produce this effect, and dose-response curves for insulin stimulation of 2-deoxyglucose uptake and glucose utilization are similar to insulin's effect on adipsin. In contrast, insulin when present during days 1-8 post confluence (during differentiation) markedly increases adipsin secretion and adipsin mRNA levels. This stimulation is due to the ability of insulin to accelerate differentiation as evidenced by corresponding increases in aP2 and GPD mRNAs as well. Insulin and IGF-1 are equipotent in this effect, suggesting that both insulin and IGF-1 receptors can mediate this response. In summary, during the differentiation of 3T3-F442A adipocytes, insulin stimulates adipsin gene expression by accelerating differentiation. As the cells become mature adipocytes, they acquire some differentiation-dependent factor, which couples insulin receptor stimulation to inhibition of adipsin gene expression. This model should aid our search for the molecular links between insulin receptor stimulation and altered gene expression.
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PMID:Differentiation dependent biphasic regulation of adipsin gene expression by insulin and insulin-like growth factor-1 in 3T3-F442A adipocytes. 224 32

When lean and obese Zucker rats were fed a low-fat diet (6.5 percent lipid-derived energy) their hepatic fatty acid binding protein (FABP) concentrations and activities were comparable. After 18 days of fat-feeding (57 percent lipids) FABP concentration and activities were significantly increased to the same extent in both genotypes. Thus hepatic FABP levels are subject to modulation by dietary lipids but not by genetic obesity.
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PMID:Influence of genetic obesity and of fat-feeding on hepatic FABP concentration and activity. 323 71

Understanding the genetic factors of obesity requires consideration of the genetic basis of the underlying etiological factors including energy expenditure and substrate utilization. Genetic susceptibility studies suggest that altered energy expenditure and/or preferential substrate utilization are likely to be involved in the etiology of obesity. Twin and family studies suggest that there is a strongly heritable component to resting energy expenditure, substrate utilization, and the thermic response to feeding. Physical activity energy expenditure has been less well studied; new data are presented in young sib pairs that suggest moderate heritability of nonresting energy expenditure. Only a few candidate gene studies have been performed to examine the role of basic proteins involved in energy expenditure (the sodium-potassium ATPase and the uncoupling protein) or substrate utilization (fatty acid binding protein). The lack of information in this area warrants further investigation into genetic aspects of energy and substrate metabolism.
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PMID:Genetic influences on human energy expenditure and substrate utilization. 951 64

We report a study of 10 candidate genes presumably involved in diabetes or insulin resistance or obesity among Pondicherian Tamil Indians, an isolated population with a high prevalence of diabetes. Forty-nine families with at least two affected patients in the sibship (567 individuals) were selected and tested by PCR-RFLP techniques for reported mutations in 10 diabetes or obesity candidate genes: glucagon receptor, insulin receptor substrate 1, insulin receptor, human beta 3 adrenergic receptor, fatty acid binding protein 2, mitochondrial tRNA(Leu(UUR)), sulphonylurea receptor, human uncoupling protein and the glycogen-associated regulatory subunit of protein phosphatase-1. Glucokinase gene was also screened for mutations. No mutations were found in glucokinase, glucagon receptor and mitochondrial genes in any of the 49 probands. Frequencies of polymorphisms at other loci were similar to those reported in Caucasian populations, except for 4 of the loci at which a higher frequency of variants was observed: human beta 3 adrenergic receptor, human uncoupling type 1 protein, fatty acid binding protein 2 and the glycogen-associated regulatory subunit of protein phosphatase-1. However, no evidence of association between any of these gene variants and non-insulin-dependent diabetes mellitus (NIDDM) or quantitative traits related to NIDDM (including body mass index, waist/hip ratio, insulinaemia, glycaemia, triglycerides and total cholesterol) was found in our sample. These results suggest that none of these gene variants commonly found in the Pondicherian Tamil population of South India is a major NIDDM predisposing locus, although it cannot be excluded that they may contribute to the polygenic background of the metabolic syndrome in Pondichery.
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PMID:Genetic studies of polymorphisms in ten non-insulin-dependent diabetes mellitus candidate genes in Tamil Indians from Pondichery. 969 58

An alanine to threonine substitution at codon 54 of the fatty acid binding protein 2 (FABP2) gene has been associated with insulin resistance in Pima Indians and with obesity in aboriginal Canadians. We investigated whether this polymorphism contributes to obesity and insulin resistance in 258 Japanese subjects. Thirty-six subjects (13.9%) were homozygous for the Thr54 allele, 106 (41.1%) were heterozygous for the Ala54/Thr54 allele, and 116 (45.0%) were homozygous for the Ala54 allele. The frequency of the Thr54 allele was 0.34 and did not differ significantly between men and women. The incidence of non-insulin-dependent diabetes mellitus (NIDDM) was not different among the three genotypes. The variation at codon 54 of the FABP2 gene was not associated with obesity, hypertension, dyslipidemia, hyperuricemia, or hyperinsulinemia. These results suggest that the polymorphism at codon 54 of the FABP2 gene is not a major contributing factor to obesity and insulin resistance in Japanese subjects.
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PMID:Variation of the fatty acid binding protein 2 gene is not associated with obesity and insulin resistance in Japanese subjects. 1033 70

We conducted a community-based case-control study of African-American men and women in the Atherosclerosis Risk in Communities Study. The allele frequencies of the Gly972Arg variant of the insulin receptor substrate-1 (IRS-1) gene and the Ala54Thr variant of the fatty acid binding protein 2 (FABP2) gene were compared in 992 normal control subjects and three patient groups: 1) 321 type 2 diabetic individuals, 2) 260 severely obese individuals, and 3) 258 markedly hyperinsulinemic individuals without diabetes. Allele frequencies of Gly972Arg IRS-1 and Ala54Thr FABP2 were 0.07 and 0.22, respectively; there were no differences in allele or genotype frequencies between patients and control subjects for either gene variant. In weighted linear regression of all patients and control subjects, the presence of the IRS-1 gene variant was associated with a 0.85 (0.42) kg/m2 higher BMI (P = 0.04). In addition, individuals with at least one IRS-1 Arg972 allele and two FABP2 Thr54 alleles had a BMI of 33.3 (7.9) kg/m2, compared with 30.0 (6.3) kg/m2 for those with neither allele (P = 0.05). These results suggest that in African-Americans, these variants in the IRS-1 and FABP2 genes are not associated with the risk of type 2 diabetes, severe obesity, or marked hyperinsulinemia, but that their independent and joint effects may be associated with small increases in BMI.
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PMID:Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in African-Americans: the Atherosclerosis Risk in Communities Study. 1048 Jun 21

Long chain fatty acid transport is selectively up-regulated in adipocytes of Zucker fatty rats, diverting fatty acids from sites of oxidation toward storage in adipose tissue. To determine whether this is a general feature of obesity, we studied [(3)H]oleate uptake by adipocytes and hepatocytes from 1) homozygous male obese (ob), diabetic (db), fat (fat), and tubby (tub) mice and from 2) male Harlan Sprague-Dawley rats fed for 7 weeks a diet containing 55% of calories from fat. V(max) and K(m) were compared with controls of the appropriate background strain (C57BL/6J or C57BLKS) or diet (13% of calories from fat). V(max) for adipocyte fatty acid uptake was increased 5-6-fold in ob, db, fat, and tub mice versus controls (p < 0.001), whereas no differences were seen in the corresponding hepatocytes. Similar changes occurred in fat-fed rats. Of three membrane fatty acid transporters expressed in adipocytes, plasma membrane fatty acid-binding protein mRNA was increased 9-11-fold in ob and db, which lack a competent leptin/leptin receptor system, but was not increased in fat and tub, i.e. in strains with normal leptin signaling capability; fatty acid translocase mRNA was increased 2.2-6.5-fold in tub, ob, and fat adipocytes, but not in db adipocytes; and only marginal changes in fatty acid transport protein 1 mRNA were found in any of the mutant strains. Adipocyte fatty acid uptake is generally increased in murine obesity models, but up-regulation of individual transporters depends on the specific pathophysiology. Leptin may normally down-regulate expression of plasma membrane fatty acid binding protein.
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PMID:Selective up-regulation of fatty acid uptake by adipocytes characterizes both genetic and diet-induced obesity in rodents. 1049 30

Obesity is the result of numerous, interacting behavioral, physiological, and biochemical factors. One increasingly important factor is the generation of additional fat cells, or adipocytes, in response to excess feeding and/or large increases in body fat composition. The generation of new adipocytes is controlled by several "adipocyte-specific" transcription factors that regulate preadipocyte proliferation and adipogenesis. Generally these adipocyte-specific factors are expressed only following the induction of adipogenesis. The transcription factor(s) that are involved in initiating adipocyte differentiation have not been identified. Here we demonstrate that the transcription factor, CREB, is constitutively expressed in preadipocytes and throughout the differentiation process and that CREB is stimulated by conventional differentiation-inducing agents such as insulin, dexamethasone, and dibutyryl cAMP. Stably transfected 3T3-L1 preadipocytes were generated in which we could induce the expression of either a constitutively active CREB (VP16-CREB) or a dominant-negative CREB (KCREB). Inducible expression of VP16-CREB alone was sufficient to initiate adipogenesis as determined by triacylglycerol storage, cell morphology, and the expression of two adipocyte marker genes, peroxisome proliferator activated receptor gamma 2, and fatty acid binding protein. Alternatively, KCREB alone blocked adipogenesis in cells treated with conventional differentiation-inducing agents. These data indicate that activation of CREB was necessary and sufficient to induce adipogenesis. Finally, CREB was shown to bind to putative CRE sequences in the promoters of several adipocyte-specific genes. These data firmly establish CREB as a primary regulator of adipogenesis and suggest that CREB may play similar roles in other cells and tissues.
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PMID:CREB activation induces adipogenesis in 3T3-L1 cells. 1062 58

To determine possible genetic influences on the steady-state concentrations of several key transcription factor transcripts and the transcript concentrations for adipocyte-characteristic proteins, young, genetically obese and lean pigs were given ad libitum access or feed or were restrictively fed at 50% of ad libitum intake for 5 wk. Obese pigs were smaller and fatter than lean pigs, whether intake was ad libitum or restrictive. Plasma protein, albumin, and cholesterol concentrations were greater in obese than in lean pigs. Plasma NEFA, blood urea nitrogen, triacylglycerols, and postprandial glucose and insulin concentrations were less (P < .02) in pigs fed restrictively than in pigs with ad libitum access to feed, regardless of genetic group. The adipose tissue glucose transporter 4, fatty acid synthase, and leptin transcript concentrations were greater (P < .05) in obese than in lean pigs. The CCAAT/enhancer binding proteins beta and alpha, adipocyte fatty acid binding protein, hormone-sensitive lipase, and the beta1-adrenergic receptor transcript concentrations tended (P < . 10) to be greater in adipose tissue from obese than in that from lean pigs. Several other transcripts were numerically greater in obese than in lean pigs. The data collectively suggest that messenger RNA concentration for several adipose tissue proteins is a contributing factor to the excess fat deposition in these obese pigs. Restricted feeding did not change the concentration of any transcript except that for adipocyte fatty acid binding protein, which was reduced. The accretion of fat was markedly reduced in the restrictively fed pigs, but this diminution does not seem to be regulated by modulation of messenger RNA concentration.
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PMID:Effect of feed restriction on adipose tissue transcript concentrations in genetically lean and obese pigs. 1078 83


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