Mutational Analysis of the <i>UCP2</i> Core Promoter and Relationships of Variants with Obesity

Dalgaard, Louise Torp; Andersen, Gitte; Larsen, Lesli H.; Sørensen, Thorkild I A; Andersen, T; Drivsholm, Thomas; Borch‐Johnsen, Knut; Fleckner, Jan; Hansen, Torben; Din, Nanni; Pedersen, Oluf

doi:10.1038/oby.2003.191

Cited by 47 publications

(43 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The −866G/A variant has further been shown to be associated with enhanced UCP2 mRNA expression in adipose tissue in vivo and obesity in middle-aged humans, suggesting that this variant may have an age-dependent effect on body weight [7]. In contrast, no association with obesity could be found in a Danish population [8] or in Mediterranean and central European Caucasian adolescents [9]. In this report we describe an association between a 45-bp ins/del variant in the 3′ untranslated region of UCP2 and 24-h metabolic rate in Pima Indians, which is consistent with a previous finding among 82 full-blooded Pima Indians reported by Walder et al [10].…”

Section: Discussionmentioning

confidence: 56%

Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians

Kovacs

Hanson

et al. 2005

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis: Uncoupling protein-2 (UCP2) is thought to play a role in insulin secretion and the development of obesity. In this study, we investigated the effects of genetic variation in UCP2 on type 2 diabetes and obesity, as well as on metabolic phenotypes related to these diseases, in Pima Indians. Methods: The coding and untranslated regions of UCP2, and approximately 1 kb of the 5′ upstream region, were sequenced in DNA samples taken from 83 extremely obese Pima Indians who were not first-degree relatives. Results: Five variants were identified: (1) a −866G/A in the 5′ upstream region; (2) a G/ A in exon 2; (3) a C/T resulting in an Ala55Val substitution in exon 4; and (4, 5) two insertion/deletions (ins/del; 45-bp and 3-bp) in the 3′ untranslated region. Among the 83 subjects whose DNA was sequenced, the −866G/A was in complete genotypic concordance with the Ala55Val and the 3-bp ins/del polymorphism. The G/A polymorphism in exon 2 was extremely rare. To capture the common variation in this gene for association analyses, the −866G/A variant (as a representative of Ala55Val and the 3-bp ins/ del polymorphism) and the 45-bp ins/del were also genotyped for 864 full-blooded Pima Indians. Neither of these variants was associated with type 2 diabetes or body mass index. However, in a subgroup of 185 subjects who had undergone detailed metabolic measurements, these variants were associated with 24-h energy expenditure as measured in a human metabolic chamber (p=0.007 for the 45-bp ins/del and p=0.03 for the −866G/A after adjusting for age, sex, family membership, fat-free mass and fat mass). Conclusions/interpretation: Our data indicate that variation in UCP2 may play a role in energy metabolism, but this gene does not contribute significantly to the aetiology of type 2 diabetes and/or obesity in Pima Indians.

show abstract

Section: Discussionmentioning

confidence: 56%

Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians

Kovacs

Hanson

et al. 2005

Diabetologia

View full text Add to dashboard Cite

show abstract

“…In Americans or Pima Indians, patients with the same genotype have higher metabolic rate, risk in obesity, and incidence of diabetes (37,38). I/D polymorphism was not associated with obesity, resting energy expenditure, BMI, and insulin secretion in substantial studies (39)(40)(41)(42). However, in some report, I-allele had significantly higher BMI and risk of developing obesity (43)(44)(45)(46).…”

Section: Genetic Association With Diseasementioning

confidence: 93%

Nutritional and hormonal regulation of uncoupling protein 2

et al. 2009

View full text Add to dashboard Cite

SummaryUncoupling proteins (UCPs) belong to a family of mitochondrial carrier proteins that are present in the mitochondrial inner membrane. Genetic and experimental studies have shown that UCP dysfunction can be involved in metabolic disorders and in obesity. Uncoupling protein-1 (UCP1; also known as thermogenin) was identified in 1988 and found to be highly expressed in brown adipose tissue. UCP1 allows the leak of protons in respiring mitochondria, dissipating the energy as heat; the enzyme has an important role in nonshivering heat production induced by cold exposure or food intake. In 1997, two homologs of UCP1 were identified and named UCP2 and UCP3. These novel proteins also lower mitochondrial membrane potential, but whether they can dissipate metabolic energy as heat as efficiently as UCP1 is open to dispute. Even after a decade of study, the physiological roles of these novel proteins have still not been completely elucidated. This review aims to shed light on the nutritional and hormonal regulation of UCP2 and on its physiological roles.

show abstract

“…Nondiabetic individuals homozygous for the A allele have lower glucosestimulated insulin secretion during oral glucose tolerance tests and in vitro than those with -866G/A or -866G/G genotypes [73]. The -866G/A polymorphism is also associated with another facet of the metabolic syndrome, hypertension [74] but generally not with obesity [75][76][77]. However, one other study noted an association of the G allele with T2DM [78].…”

Section: Genetic Association Of Ucp2 and Type 2 Diabetesmentioning

confidence: 98%

Uncoupling Proteins: Role in Insulin Resistance and Insulin Insufficiency

Chan¹,

Harper

2006

CDR

View full text Add to dashboard Cite

Uncoupling proteins (UCPs) are modulators of mitochondrial metabolism that have been implicated in the development of both insulin resistance and insulin insufficiency, the two major pathophysiological events associated with type 2 diabetes. UCP2 mRNA is expressed in a wide range of tissues; however UCP2 protein expression is restricted to fewer tissues, including the endocrine pancreas, spleen, stomach, brain and the lung. To date, its role in the pathophysiology of diabetes has been most strongly associated with impaired glucose-stimulated insulin secretion from the beta-cell, particularly after its induction by free fatty acids. The physiological role of UCP2 remains controversial, but it may act as a downstream signal transducer of superoxide. UCP3 mRNA and protein are expressed in relatively few tissues, predominantly skeletal muscle, brown adipose tissue and heart. Increased expression of UCP3 in skeletal muscle is associated with protection from diet-induced insulin resistance in mice. In patients with type 2 diabetes UCP3 protein in muscle is reduced by 50% compared to healthy controls. The primary physiological role of the novel UCPs does not appear to be protection against positive energy balance and obesity; this is based largely on findings from studies of UCP2 and UCP3 knockout mice and from observed increases in UCP3 expression with fasting. The mechanism(s) of action of UCP2 and UCP3 are poorly understood. However, findings support roles for UCP2 and UCP3 as modifiers of fatty acid metabolism and in mitigating damage from reactive oxygen species.

show abstract

Mutational Analysis of the UCP2 Core Promoter and Relationships of Variants with Obesity

Cited by 47 publications

References 31 publications

Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians

Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians

Nutritional and hormonal regulation of uncoupling protein 2

Uncoupling Proteins: Role in Insulin Resistance and Insulin Insufficiency

Contact Info

Product

Resources

About