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

We previously reported that mice lacking bombesin receptor subtype-3 (BRS-3) exhibit mild late-onset obesity and glucose intolerance [Nature 390 (1997) 160]. To examine the mechanism by which glucose intolerance is developed in these mice, we studied insulin release and proinsulin biosynthesis in isolated pancreatic islets and glucose uptake and facilitative glucose transporter (GLUT)-4 translocation in adipose tissues. Although islet insulin contents and the size and number of islets of Langerhans in BRS-3-deficient mice decreased, there was no difference in glucose-stimulated insulin release and proinsulin biosynthesis between BRS-3-deficient and wild-type control mice. In contrast, adipose tissues exhibited a marked difference: the uptake of [(14)C]2-deoxy-D-glucose by adipocytes isolated from BRS-3-deficient mice was not stimulated by 10(-7)M insulin addition, and membrane fractionation analysis showed that GLUT4 was barely detected in the fraction of plasma membrane in BRS-3-deficient mice in the presence of 10(-7)M insulin. Quantitative reverse transcription-PCR (RT-PCR) showed that mRNA levels of GLUT4, insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2, syntaxin 4, SNAP23, and VAMP-2 in adipose tissues of BRS-3-deficient mice were unchanged compared with those in wild-type control mice. We concluded that impaired glucose metabolism observed in BRS-3-deficient mice was mainly caused by impaired GLUT4 translocation in adipocytes.
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PMID:Functions of pancreatic beta cells and adipocytes in bombesin receptor subtype-3-deficient mice. 1514 94

Unlike the intensive research in pursuit of understanding the molecular mechanisms of insulin signaling and resistance to its biological action associated most significantly with obesity and type 2 diabetes, the influence of the plasma membrane on insulin sensitivity has been intermittently studied over the years-mainly because it was thought that mediators of insulin action, such as the insulin receptor and the insulin-responsive glucose transporter GLUT4, localize more or less uniformly in the lipids that form cell membranes. Recent insights into membrane physiology suggest that the plasma membrane impacts the function of membrane proteins mediating insulin action. Furthermore, membrane disturbances may be the basis of insulin resistance. Relevant insulin signal transduction data in terms of plasma membrane and insulin resistance are the focus of this review. The discussion visits the cell membrane hypothesis of insulin resistance that suggests insulin action could be related to changes in cell membrane properties.
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PMID:Fluidity of insulin action. 1520 55

Endurance exercise training induces an increase in the respiratory capacity of muscle, resulting in an increased capacity to generate ATP as well as improved efficiency of muscle contraction. Such adaptations are largely the result of a coordinated genetic response that increases mitochondrial proteins, fatty acid oxidation enzymes and the exercise- and insulin-stimulated glucose transporter GLUT4, and shifts the contractile and regulatory proteins to their more efficient isoforms. In recent years a number of the transcriptional regulators involved in this genetic response have been identified and these factors can be classified into two different groups. The first group comprises transcription factors such as nuclear respiratory factors (NRF) 1 and 2 and PPAR alpha that bind DNA in a sequence-specific manner. The second group, referred to as transcriptional co-activators, alter transcription without directly binding to DNA. The PPAR gamma co-activator (PGC) family of proteins have been identified as the central family of transcriptional co-activators for induction of mitochondrial biogenesis. PGC-1 alpha is activated by exercise, and is sufficient to produce the endurance phenotype through direct interactions with NRF-1 and PPAR alpha, and potentially NRF-2. Furthering the understanding of the activation of PGC proteins following exercise has implications beyond improving athletic performance, including the possibility of providing targets for the treatment of frailty in the elderly, obesity and diseases such as mitochondrial myopathies and diabetes.
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PMID:Involvement of PPAR gamma co-activator-1, nuclear respiratory factors 1 and 2, and PPAR alpha in the adaptive response to endurance exercise. 1529 42

The regulation of adipocyte metabolism is of importance for adipose tissue growth and therefore also for the development of obesity. This study was designed to investigate the regulation of basal and insulin-induced lipogenesis, glucose transport, and glucose transporter protein expression in human and rat adipocytes from different age groups. The study included 21 infants, 21 children, nine adults, and 80 male weaned and 20 male adult Fischer rats. The lipogenesis experiments were performed under conditions at which glucose transport is rate limiting. Basal lipogenesis was approximately three times higher in infants and children than in adults, whereas insulin-induced lipogenesis was two times higher in infants than in children and adults. In rats, basal lipogenesis, insulin-induced lipogenesis, and insulin sensitivity were two times higher in weaned than in adult animals. Moreover, basal and insulin-induced glucose transport were two times higher in weaned than in adult rats. No differences were detected in GLUT1 or GLUT4 content between any of the age groups in human or in rat adipocytes. In conclusion, basal and insulin-stimulated lipogenesis are increased in adipocytes early in life. This may promote adipose tissue growth in early age. The data indicate that age-dependent variation in basal and insulin-stimulated lipogenesis is differently regulated.
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PMID:Age-dependent regulation of lipogenesis in human and rat adipocytes. 1535 69

The facilitative glucose transporter, GLUT4, mediates insulin-stimulated glucose uptake in adipocytes and muscles, and the participation of GLUT4 in the pathogenesis of various clinical conditions associated with obesity, visceral fat accumulation and insulin resistance has been proposed. Glucose uptake by some members of the GLUT family, mainly GLUT1, is inhibited by flavonoids, the natural polyphenols present in fruits, vegetables and wine. Therefore it is of interest to establish if these polyphenolic compounds present in the diet, known to be effective antioxidants but also endowed with several other biological activities such as protein-tyrosine kinase inhibition, interfere with GLUT4 function. In the present study, we show that three flavonoids, quercetin, myricetin and catechin-gallate, inhibit the uptake of methylglucose by adipocytes over the concentration range of 10-100 microM. These three flavonoids show a competitive pattern of inhibition, with K(i)=16, 33.5 and 90 microM respectively. In contrast, neither catechin nor gallic acid inhibit methylglucose uptake. To obtain a better understanding of the interaction among GLUT4 and flavonoids, we have derived a GLUT4 three-dimensional molecular comparative model, using structural co-ordinates from a GLUT3 comparative model and a mechanosensitive ion channel [PDB (Protein Data Bank) code 1MSL] solved by X-ray diffraction. On the whole, the experimental evidence and computer simulation data favour a transport inhibition mechanism in which flavonoids and GLUT4 interact directly, rather than by a mechanism related to protein-tyrosine kinase and insulin signalling inhibition. Furthermore, the results suggest that GLUT transporters are involved in flavonoid incorporation into cells.
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PMID:Myricetin, quercetin and catechin-gallate inhibit glucose uptake in isolated rat adipocytes. 1546 17

Obesity is a serious health problem, and its prevention is promoted through life style including diet and exercise. In this study, we investigated the suppressive effects of tea catechin on the differentiation of 3T3-L1 preadipocytes to adipocytes. (-)-Catechin 3-gallate (CG), (-)-epigallocatechin (EGC), (-)-epicatechin 3-gallate, and (-)-epigallocatechin 3-gallate at 5 muM suppressed intracellular lipid accumulation. The suppressive effects of CG and EGC were stronger than the others, and CG and EGC also suppressed the activity of glycerol-3-phosphate dehydrogenase as a differentiation marker. These catechins inhibited the expression of peroxisome proliferator-activated receptor (PPAR) gamma2 and CCAAT/enhancer-binding protein (C/EBP) alpha, both of which act as key transcription factors at an early stage of differentiation, followed by the expression of glucose transporter (GLUT) 4 at a later stage. In addition, the catechins did not affect the phosphorylation status of the insulin signal pathway. Thus, catechin suppressed adipocyte differentiation accompanied by the down-regulation of PPARgamma2, C/EBPalpha, and GLUT4. These results suggest that tea catechin prevents obesity through the suppression of adipocyte differentiation.
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PMID:Tea catechin suppresses adipocyte differentiation accompanied by down-regulation of PPARgamma2 and C/EBPalpha in 3T3-L1 cells. 1556 76

Intrauterine growth restriction (IUGR) leads to obesity, glucose intolerance, and type 2 diabetes mellitus in the adult. To determine the mechanism(s) behind this "metabolic imprinting" phenomenon, we examined the effect of total calorie restriction during mid- to late gestation modified by postnatal ad libitum access to nutrients (CM/SP) or nutrient restriction (SM/SP) vs. postnatal nutrient restriction alone (SM/CP) on skeletal muscle and white adipose tissue (WAT) insulin-responsive glucose transporter isoform (GLUT4) expression and insulin-responsive translocation. A decline in skeletal muscle GLUT4 expression and protein concentrations was noted only in the SM/SP and SM/CP groups. In contrast, WAT demonstrated no change in GLUT4 expression and protein concentrations in all experimental groups. The altered in utero hormonal/metabolic milieu was associated with a compensatory adaptation that persisted in the adult and consisted of an increase in the skeletal muscle basal plasma membrane-associated GLUT4 concentrations. This perturbation led to no further exogenous insulin-induced GLUT4 translocation, thereby disabling the insulin responsiveness of the skeletal muscle but retaining it in WAT. These changes, which present at birth, collectively maximize basal glucose transport to the compromised skeletal muscle with a relative resistance to exogenous/postprandial insulin. Preservation of insulin responsiveness in WAT may serve as a sink that absorbs postprandial nutrients that can no longer efficiently access skeletal muscle. We speculate that, in utero, GLUT4 aberrations may predict type 2 diabetes mellitus, whereas postnatal nutrient intake may predict obesity, thereby explaining the heterogeneous phenotype of the IUGR adult offspring.
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PMID:GLUT4 expression and subcellular localization in the intrauterine growth-restricted adult rat female offspring. 1562 86

Skeletal muscle is a major mass peripheral tissue that accounts for approximately 40% of total body weight and 50% of energy expenditure and is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. Excessive caloric intake is sensed by the brain and induces beta-adrenergic receptor (beta-AR)-mediated adaptive thermogenesis. Beta-AR null mice develop severe obesity on a high fat diet. However, the target gene(s), target tissues(s), and molecular mechanism involved remain obscure. We observed that 30-60 min of beta-AR agonist (isoprenaline) treatment of C2C12 skeletal muscle cells strikingly activated (>100-fold) the expression of the mRNA encoding the nuclear hormone receptor, Nur77. In contrast, the expression of other nuclear receptors that regulate lipid and carbohydrate metabolism was not induced. Stable transfection of Nur77-specific small interfering RNAs (siNur77) into skeletal muscle cells repressed endogenous Nur77 mRNA expression. Moreover, we observed attenuation of gene and protein expression associated with the regulation of energy expenditure and lipid homeostasis, for example AMP-activated protein kinase gamma3, UCP3, CD36, adiponectin receptor 2, GLUT4, and caveolin-3. Attenuation of Nur77 expression resulted in decreased lipolysis. Finally, in concordance with the cell culture model, injection and electrotransfer of siNur77 into mouse tibialis cranialis muscle resulted in the repression of UCP3 mRNA expression. This study demonstrates regulatory cross-talk between the nuclear hormone receptor and beta-AR signaling pathways. Moreover, it suggests Nur77 modulates the expression of genes that are key regulators of skeletal muscle lipid and energy homeostasis. In conclusion, we speculate that Nur77 agonists would stimulate lipolysis and increase energy expenditure in skeletal muscle and suggest selective activators of Nur77 may have therapeutic utility in the treatment of obesity.
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PMID:Nur77 regulates lipolysis in skeletal muscle cells. Evidence for cross-talk between the beta-adrenergic and an orphan nuclear hormone receptor pathway. 1564 Jan 43

Skeletal muscle is a major glucose-utilizing tissue in the absorptive state and the major glucose transporter expressed in muscle in adulthood is GLUT4. GLUT4 expression is exquisitely regulated in muscle and this seems important in the regulation of insulin-stimulated glucose uptake by this tissues. Thus, muscle GLUT4 overexpression in transgenic animals ameliorates insulin resistance associated with obesity or diabetes. Recent information indicates that glut4 gene transcription is regulated by a number of factors in skeletal muscle that include MEF2, MyoD myogenic proteins, thyroid hormone receptors, Kruppel-like factor KLF15, NF1, Olf-1/Early B cell factor and GEF/HDBP1. In addition, studies in vivo indicate that under normal conditions the activity of the muscle-specific GLUT4 enhancer is low in adult skeletal muscle compared with the maximal potential activity that it can attain at high levels of the MRF transcription factors, MEF2, and TRalpha1. This finding indicates that glut4 transcription may be greatly up-regulated via activation of this enhancer through an increase in the levels of expression or activity of these transcription factors. Understanding the molecular basis of the expression of glut4 will be useful for the appropriate therapeutic design of treatments for insulin-resistant states. The nature of the intracellular signals that mediate the stimulation of glucose transport in response to insulin or exercise is also reviewed.
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PMID:Mechanisms regulating GLUT4 glucose transporter expression and glucose transport in skeletal muscle. 1565 19

Defective uptake of glucose into muscle and fat cells, or insulin resistance, is a central feature of obesity and type 2 diabetes. As we brace ourselves for the diabetes epidemic, it is reassuring to know that real progress is being made in defining the molecular biology of how insulin stimulates glucose uptake and what goes awry in obesity and type 2 diabetes. An understanding of the molecular determinants of insulin-stimulated glucose transport has been one of the holy grails of hormone action research. A major breakthrough was the discovery that insulin stimulates the translocation of a specific glucose transport protein, GLUT4, from intracellular vesicles to the cell surface. Elucidating how this process is regulated has remained a challenge because it represents a convergence of 2 disparate and complex fields of research--namely, vesicle transport and signal transduction. A study reported in this issue of the JCI using mice lacking Munc18c, one of the vesicle-trafficking proteins involved in GLUT4 translocation, has provided new insights into the signaling/trafficking intersection that controls insulin-stimulated GLUT4 movement.
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PMID:MUNC-ing around with insulin action. 1569 75


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