Association Between Uncoupling Protein 3 Gene and Obesity-Related Phenotypes in the Québec Family Study

Lanouette, Christian-Marc; Giacobino, Jean-Paul; Pérusse, Louis; Lacaille, Michel; Yvon, Cédric; Chagnon, Monique; Kühne, Françoise; Bouchard, Claude; Muzzin, Patrick; Chagnon, Yvon C.

doi:10.1007/bf03401848

Cited by 32 publications

(20 citation statements)

References 38 publications

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“…120 In addition, one UCP3 promoter SNP and one intronic repeat have been associated with obesity. 121,122 These associations have not been confirmed in other studies. 123 The UCP3 intronic repeat has been reported to be associated with fat loss following 20 weeks of training, 124 whereas the promoter SNP does not regulate weight change.…”

Section: Pathways Controlling Lipid Storage In Adipocytescontrasting

confidence: 68%

Obesity and polymorphisms in genes regulating human adipose tissue

Dahlman

Arner

2007

Int J Obes

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Obesity is the result of an imbalance between food intake and energy expenditure resulting in the storing of energy as fat. Adipose tissue contains the largest store of energy in the body and plays important roles in regulating energy partitioning. Developments in genomics, in particular microarray-based expression profiling, have provided scientists with a number of new candidate genes whose expression in adipose tissue is regulated by obesity. Integrating expression profiles with genome-wide linkage and/or association analyses is a promising strategy to identify new genes underlying susceptibility to obesity. This article provides a comprehensive review of adipose-tissue-expressed genes implicated in predisposition to human obesity. The authors consider the following genes of particular interest: peroxisome proliferator-activated receptor gamma and, potentially, INSIG2 acting in adipogenesis; the adrenoreceptors beta 2 and 3, as well as hormone-sensitive lipase acting on lipolysis; uncoupling protein 2 acting in mitochondria energy expenditure; and among secreted molecules the cytokine tumor necrosis factor alpha and the hormone leptin. With the rapid development in genome research, we predict that additional alleles in genes regulating adipose tissue function will be established as risk factors for common obesity in the coming years. This has important implications for the prevention of obesity and may also offer new therapeutic targets.

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Section: Pathways Controlling Lipid Storage In Adipocytescontrasting

confidence: 68%

Obesity and polymorphisms in genes regulating human adipose tissue

Dahlman

Arner

2007

Int J Obes

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“…DNA samples from 258 unrelated Caucasian subjects were obtained from the Quebec Family Study (31). These samples had been anonymized prior to their receipt in our laboratory.…”

Section: Methodsmentioning

confidence: 99%

Characterization of Common UGT1A8, UGT1A9, and UGT2B7 Variants with Different Capacities to Inactivate Mutagenic 4-Hydroxylated Metabolites of Estradiol and Estrone

et al. 2006

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The oxidative metabolism of estrone (E 1 ) and estradiol (E 2 ) to form carcinogenic 4-hydroxy-catecholestrogens (4-OHCE) is associated with uterine and breast carcinogenesis. In this study, we conducted functional analyses of genetic variants in the UDP-glucuronosyltransferase UGT1A8, UGT1A9, and UGT2B7 enzymes primarily involved in the inactivation of 4-OHCEs. Compared with UGT2B7*2 (H 268 Y), UGT2B7*1 exhibited a 2-fold lower efficiency (intrinsic clearance) at conjugating 4-hydroxyestrone and 4-hydroxyestradiol at positions 3 and 4 caused by altered capacities (V max ) and affinities (K m ). The À79 G>A promoter variation, characterizing the UGT2B7*2g haplotype, leads to a 50% reduction of transcription (P < 0.001) in human endometrial carcinoma-1B cells. Furthermore, a >12-fold decreased intrinsic clearance of the *1 proteins was induced by selected amino acid substitutions in UGT1A8 (*3 C 277 Y) and UGT1A9 (*3 M 33 T). Frequencies of the low-activity alleles in Caucasians were 45% for UGT2B7*1, 5% for the À79A promoter variant, 1.2% for UGT1A8*3, and 2.2% for UGT1A9*3. Supporting a protective role in two organs sensitive to 4-OHCE-induced damages, the expression of UGT enzymes was shown by immunohistochemistry in normal breast and endometrial tissues and confirmed by Western blotting in a subset of samples. Altogether, findings suggest that specific polymorphisms in UGT genes may modulate the exposure to carcinogenic metabolites of E 2 and potentially lead to an altered risk of breast and endometrial cancers in women carrying the variant alleles. (Cancer Res 2006; 66(1): 125-33)

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“…Recently, a new GA repeat microsatellite located in UCP3 gene intervening sequence 6 (GAIVS6) was analyzed in the Quebec family. Strong associations were observed between some alleles and the BMI and the percent body fat (54). Suggestive linkages were also found in the Heritage family between GAIVS6 and changes in fat mass and percent body fat after endurance training (55).…”

Section: Regulation Of Energy Expenditurementioning

confidence: 75%

Old and new determinants in the regulation of energy expenditure

Russell¹,

Giacobino²

2002

J Endocrinol Invest

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ABSTRACT. Bw gain is controlled by energy intake on one hand and expenditure on the other. The components of energy expenditure are basal metabolism, exercise induced thermogenesis and adaptive UNCOUPLING PROTE/N-1 (UCP1)In rodents, brown adipose tissue (BAT) is an important site of adaptive thermogenesis. Cold exposure has for long been known to induce, via stimulation of the sympathetic nervous system, an increase in BAT thermogenesis referred to as adaptive cold-induced thermogenesis (CIT), (1). Furthermore, it has been observed that voluntary overeating induced in rats by the administration of a palatable, so-called "cafeteria" diet also induced an increase in BAT thermogenesis which was called adaptive diet-induced thermogenesis (OIT) (2).The main producer of heat in BAT is the uncoupling protein-1 (UCP1). This mitochondria inner membrane protein uncouples oxidative phosphorylation by dissipating the proton gradient generated by the re-oxidation of NAOH H+ in the respiratory chain. The UCP1-mediated proton transport requires the presence of fatty acids and is specificalIy inhibited by purine di-and triphosphate nucleotides (3). The consequence of UCP1 activity is a decrease in the amount of ATP formed by the ATP synthase and energy dissipation as heat. UCP1 knockout mice were generated and they were unable to maintain their body temperature upon cold exposure but did not become obese (4).These data confirmed the importance of UCP1 in Key-words: ßTadrenoceptor. uncoupling CIT and suggested that, in UCP1 knockout mice, alternative mechanisms for maintaining body mass wh ich could not protect against the cold were turned on, In humans, BAT is present in newborn babies and decreases in 4-6 months after birth (5, 6). It is therefore generally believed that there is no UCP1 in human adults. THE ßTADRENOCEPTOR -UCP1 AX/SThe family of the ß-adrenoceptors were considered to consist of ß1-and ß-rsubtypes until1989 when a third subtype was cloned (7). This third subtype called the ß3-adrenoceptor was found to be the predominant ß-subtype in rodent BAT and white adipose tissue (WAT) (8,9). When the BAT sympathetic nervous system activity is increased by cold exposure or overfeeding, the stimulatory effect on UCP1 activity and expression is therefore mediated essentially by the ß3-adrenoceptor (9). Therefore, the ß3-adrenoceptor-UCP1-axis is a major determinant of rodent adaptive thermogenesis, The ß3-adrenoceptor was found to be down-regulated in obese fa/fa Zucker rat BAT and WAT (8) and in obese ob/ob mouse adipose tissues compa red to lean animals (10). In ß3-adrenoceptor knockout mice, the capacity to adapt to a cold environment was fully preserved, but there was an increase in fat deposition under basal conditions and in response to a high fat diet (11). These data confirmed the importance of the ß3-adrenoceptor in OIT and suggested that, in the ß3-adrenoceptor knockout mice, alternative mechanisms for maintaining body temperature were turned on. In rodents, cold exposure was found to recruit mul- A.P. Russe 1...

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Association Between Uncoupling Protein 3 Gene and Obesity-Related Phenotypes in the Québec Family Study

Abstract: Our results suggest that some alleles of UCP3 are involved in the etiology of human obesity.

Cited by 32 publications

References 38 publications

Obesity and polymorphisms in genes regulating human adipose tissue

Obesity and polymorphisms in genes regulating human adipose tissue

Characterization of Common UGT1A8, UGT1A9, and UGT2B7 Variants with Different Capacities to Inactivate Mutagenic 4-Hydroxylated Metabolites of Estradiol and Estrone

Old and new determinants in the regulation of energy expenditure

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