FOXC2 Is a Winged Helix Gene that Counteracts Obesity, Hypertriglyceridemia, and Diet-Induced Insulin Resistance

Cederberg, Anna; Grønning, Line M.; Åhrén, Bo; Taskén, Kjetil; Carlsson, Peter; Enerbäck, Sven

doi:10.1016/s0092-8674(01)00474-3

Cited by 495 publications

(441 citation statements)

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“…*p<0.05. bpm, beats per min It was recently demonstrated that Gnasxl m+P− mice are lean as a result of increased lipid mobilisation and oxidation in adipose tissue due to increased sympathetic tone [42]. A similar metabolic profile was also observed in mouse models with increased β-adrenergic/G protein α subunit/ cAMP signalling in adipocytes, such as adipose-specific overproduction of the forkhead transcription factor FOXC2 [29], and in mice in which the C/ebpα (also known as Cebpa) gene was replaced with the C/ebpβ (also known as Cebpb) gene [43]. Taken together, these results indicate that β-adrenergic/G protein α subunit/cAMP signalling in adipocytes is an important regulator of whole-body homeostasis.…”

Section: Discussionmentioning

confidence: 75%

“…The emergence of these ectopic cells in the WAT of rats [26] and of mice [27] was found to be induced by cold acclimatisation or by the administration of selective β3-AR agonists [27,28]. Interestingly, the emergence of brown fat cells in white fat depots was associated with a lean phenotype in several transgenic mouse models, including β1-AR transgenic mice [22], FOXC2 transgenic mice [29] and Tif2 −/− (also known as Ncoa2 −/− ) mice [30].…”

Section: Introductionmentioning

confidence: 99%

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Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

et al. 2008

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Aims/hypothesis Proinflammatory cytokines, including IL-1, exert pleiotropic effects on the neuro-immuno-endocrine system. Previously, we showed that mice with knockout of the gene encoding IL-1 receptor antagonist (Il1ra −/− , also known as Il1rn −/− ) have a lean phenotype. The present study was designed to analyse the mechanisms leading to this lean phenotype.Methods Il1ra −/− mice were fed a high-fat diet following weaning. Energy expenditure, body temperature, heart rate, blood parameters, urinary catecholamines and adipose tissue were analysed. Results Il1ra −/− mice exhibited resistance to obesity induced by a high-fat diet; this resistance was associated with increased energy expenditure and a decreased respiratory quotient, indicating that the ratio of fat:carbohydrate metabolism in Il1ra −/− mice is greater than in controls. Activity level in Il1ra −/− mice was significantly decreased and body temperature was significantly increased, compared with wild-type (WT) mice. Inguinal white adipose tissues in Il1ra −/− mice express increased levels of Ucp1 and mitochondrial respiratory chain genes compared with WT mice. Histological analysis of adipose tissue in Il1ra −/− mice revealed that brown adipose tissue is hyperactive and inguinal white adipose tissue contains smaller cells, which exhibit the distinctive multilocular appearance of brown adipocytes. Urinary epinephrine and norepinephrine excretion in Il1ra −/− mice was significantly increased compared with WT mice, suggesting that Il1ra −/− mice have increased sympathetic tone. Consistent with this, heart rate in Il1ra −/− mice was also significantly increased. Conclusions/interpretation Our results show that Il1ra −/− mice have increased energy expenditure, fat:carbohydrate oxidation ratio, body temperature, heart rate and catecholamine production. All of these observations are consistent with an enhanced sympathetic tone.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

et al. 2008

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“…Genetic and other types of functional studies have uncovered the involvement of forkhead domain encoding genes in the regulation of a variety of developmental and differentiation processes, the control of metabolism and life span, and as effectors of signal transduction events (for recent references, see Chen et al, 1996;Ogg et al, 1997;Brunet et al, 2001a, b;Cederberg et al, 2001;Kos et al, 2001;Kume et al, 2001;Mahlapuu et al, 2001;Sasai et al, 2001;Topczewska et al, 2001;Zaffran et al, 2001). Moreover, forkhead domain genes were found to be affected in tumorigenesis and in several human congenital syndromes (Li and Vogt, 1993;Barr, 1997;Chatila et al, 2000;Crisponi et al, 2001;Karkkainen et al, 2001;Lai et al, 2001;Wildin et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Survey of forkhead domain encoding genes in the Drosophila genome: Classification and embryonic expression patterns

Lee

Frasch

2004

Developmental Dynamics

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Genetic approaches in Drosophila led to the identification of Forkhead, the prototype of forkhead domain transcription factors that are now known to comprise an evolutionarily conserved family of proteins with essential roles in development and differentiation. Sequence analysis of the recently published genomic scaffold sequence from Drosophila melanogaster has allowed us to determine the presumably full complement of forkhead domain encoding genes in this species. We show herein that the Drosophila genome contains 17 forkhead domain encoding genes; 13 of these genes have orthologs in chordate species, and their products can be assigned to 10 of the 17 forkhead domain subclasses known from chordates. One Drosophila forkhead domain gene only has a Caenorhabditis elegans ortholog and may represent a subclass that is absent in chordates, while the remaining three cannot be classified. We present the mRNA expression patterns of seven previously uncharacterized members of this gene family and show that they are expressed in tissues from all three germ layers, including central and peripheral nervous system, epidermis, salivary gland primordia, endoderm, somatic mesoderm, and hemocyte progenitors. Furthermore, the expression patterns of two of these genes, fd19B and fd102C, suggest a role for them as gap genes during early embryonic head segmentation.

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“…In summary, although animal and in vitro studies have suggested a role of FOXC2 in obesity, insulin resistance and Type 2 diabetes [4], the common −512 promoter polymorphism in this gene does not seem to have a major metabolic effect in the German population.…”

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confidence: 84%

Lack of association between metabolic traits and the -512 polymorphism in FOXC2 in German people with normal glucose tolerance

et al. 2004

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Letters 757Lack of association between metabolic traits and the −512 polymorphism in FOXC2 in German people with normal glucose toleranceTo the Editor: A recent paper reported an association between the −512C>T promoter polymorphism in the forkhead box C2 (FOXC2) gene and increased serum C-peptide and hypertriglyceridaemia in normal-glucose-tolerant subjects from Denmark [1]. An association with Type 2 diabetes was not observed in this population. Previous papers had found conflicting data on this common polymorphism regarding an association with obesity and diabetes-related traits [2,3].We genotyped this polymorphism in 732 subjects (264 male, 468 female; aged 36±12 years [SD]) with normal glucose tolerance according to WHO criteria, and studied any associations with metabolic traits. The subjects were participants of the ongoing Tübingen family study of Type 2 diabetes in the south-west of Germany. About one half of the subjects had a family history of Type 2 diabetes. All subjects underwent a 2-h oral glucose tolerance test. Informed written consent was obtained from all participants and the studies were approved by the local ethics committee. For statistical analyses, the parameters were logarithmically transformed. With the exception of BMI and percentage body fat, all parameters were tested for association with the genotype using a multivariate linear regression model to adjust for age, sex and BMI.As shown in Table 1, we found no association between this polymorphism and any of the metabolic traits studied. Since a previous study [2] found a sex-specific effect on triglycerides, we performed the analysis in men and women separately, but also found no significant association with the −512 genotype. In particular, no associations with plasma insulin, C-peptide or serum triglycerides were observed. Absence or presence of family history of Type 2 diabetes had no influence on the results.One explanation for the lack of differences between the genotypes is that there are differences in sample selection. For example, in comparison with the Danish report [1], we studied younger subjects with a higher proportion of positive family history of Type 2 diabetes. The Danish study reported marginally higher fasting insulin and significantly higher fasting C-peptide in carriers of the T-allele. This was interpreted as an indication of insulin resistance. It is worth noting, however, that in this paper the carriers of the T-allele had a somewhat higher WHR and this variable was not included in the multivariate regression analysis. Although the WHR difference was not quite significant, it may have contributed to the borderline 758 Letters difference in insulin resistance. In addition, it should be mentioned that other studies have found just the opposite, namely an association of the T-allele with enhanced insulin sensitivity [3] and lower plasma triglycerides [2,3]. To detect a 10% difference between genotypes, the statistical power of our data set was more than 80% for the relevant parameters tested. Therefore, we shou...

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FOXC2 Is a Winged Helix Gene that Counteracts Obesity, Hypertriglyceridemia, and Diet-Induced Insulin Resistance

Cited by 495 publications

References 42 publications

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

Survey of forkhead domain encoding genes in the Drosophila genome: Classification and embryonic expression patterns

Lack of association between metabolic traits and the -512 polymorphism in FOXC2 in German people with normal glucose tolerance

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