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Evidence for a role of developmental genes in the origin of obesity and body fat distribution.

ABSTRACT: Obesity, especially central obesity, is a hereditable trait associated with a high risk for development of diabetes and metabolic disorders. Combined gene expression analysis of adipocyte- and preadipocyte-containing fractions from intraabdominal and subcutaneous adipose tissue of mice revealed coordinated depot-specific differences in expression of multiple genes involved in embryonic development and pattern specification. These differences were intrinsic and persisted during in vitro culture and differentiation. Similar depot-specific differences in expression of developmental genes were observed in human subcutaneous versus visceral adipose tissue. Furthermore, in humans, several genes exhibited changes in expression that correlated closely with body mass index and/or waist/hip ratio. Together, these data suggest that genetically programmed developmental differences in adipocytes and their precursors in different regions of the body play an important role in obesity, body fat distribution, and potential functional differences between internal and subcutaneous adipose tissue.

SUBMITTER: Gesta S

PROVIDER: S-EPMC1458940 | biostudies-literature | 2006 Apr

REPOSITORIES: biostudies-literature

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Evidence for a role of developmental genes in the origin of obesity and body fat distribution.

Gesta Stephane S Blüher Matthias M Yamamoto Yuji Y Norris Andrew W AW Berndt Janin J Kralisch Susan S Boucher Jeremie J Lewis Choy C Kahn C Ronald CR

Proceedings of the National Academy of Sciences of the United States of America 20060414 17

Obesity, especially central obesity, is a hereditable trait associated with a high risk for development of diabetes and metabolic disorders. Combined gene expression analysis of adipocyte- and preadipocyte-containing fractions from intraabdominal and subcutaneous adipose tissue of mice revealed coordinated depot-specific differences in expression of multiple genes involved in embryonic development and pattern specification. These differences were intrinsic and persisted during in vitro culture a ...[more]

PMID: 16617105

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Project description:Tetrahydrobiopterin (BH4) is an essential cofactor for several metabolic enzymes, including the aromatic amino acid hydroxylases, alkylglycerol mono-oxygenase and NO synthases. BH4 deficiency due to an autosomal recessive defect in its biosynthetic enzyme 6-pyruvoyltetrahydropterin synthase (PTPS, encoded by the PTS gene) leads to a variant form of hyperphenylalaninemia concomitant with severe deficiency of brain monoamine neurotransmitters. In contrast, augmentation of BH4 by pharmacological supplementation or stimulation of its biosynthesis is thought to correct eNOS dysfunction, to protect from (cardio) vascular disease and/or to prevent from abdominal obesity and development of the metabolic syndrome. We have previously reported that complete Pts knock-out (ko) mice die after birth (Elzaouk et al JBC 2003). Here we generated a murine Pts-knock-in (ki) allele expressing a PTPS-p.Arg15Cys mutant enzyme with low residual activity (12% of wild-type in vitro) and investigated heterozygous Pts-ko/wt, homozygous Pts-ki/ki and compound heterozygous Pts-ki/ko mutant mice. All mice were viable and, depending on the severity of the Pts alleles, exhibited up to 90% reduction of PTPS activity in liver and brain tissues concomitant with high neopterin, but neither an elevation of blood L-Phe, nor a decrease in brain monoamine neurotransmitters dopamine or serotonin. Upon a standard systemic and comprehensive phenotyping of Pts-ki/ki mice, we found alterations in energy metabolites with reduced body mass, higher fat content, lower lean mass, and increased blood glucose and cholesterol in mutant animals. Furthermore, heterozygous Pts-ko/wt and/or homozygous Pts-ki/ki mice exhibited increased body weight and elevated intra-abdominal fat tissue when fed with normal chow or high fat diet. We conclude that a reduced BH4-biosynthetic activity in mice leads to abnormal body fat distribution and abdominal obesity potentially through a mildly compromised eNOS function.

Project description:INTRODUCTION: Although body fat and body fat distribution are known to be related to cardiovascular diseases (CVDs), it is unknown whether specific 30-year developmental patterns of body fat are associated with CVDs. This study examines the existence of distinct developmental patterns of total fat measured by the sum of four skinfolds (S4SFs) and body fat distribution measured by the skinfold thickness ratio (SFratio), and relates these patterns to micro- and macrovascular functions. METHODS: In 2006, 259 apparently healthy subjects were examined on micro- and macrovascular functions, using video microscopy and carotid ultrasound sonography. Body fat, using both S4SFs and SFratio, was measured for 10 times over 30 years, from 13 years onwards. Latent class growth analyses (LCGA) were used to obtain distinct developmental patterns of S4SFs and SFratio. This is a data-drive hypothesis-generating approach and could possibly give a new perspective on body fatness over time. In addition, a mixed-method approach is used to obtain individual growth parameters. Linear regression analyses were used to examine the relationship of these patterns and individual growth parameters with micro- and macrovascular functions. RESULTS: LCGA identified normal and unfavourable developmental patterns in S4SFs and SFratio. Both men and women with an unfavourable developmental pattern of S4SFs showed impaired carotid compliance (β=-0.216, P=0.004 and β=-0.109, P=0.039, respectively), carotid distensibility (β=-5.078, P=0.001 and β=-5.118, P<0.001, respectively) and Young's elastic modulus (β=0.066, P=0.065 and β=0.107, P<0.001, respectively). In contrast, no relationship for microvascular function with developmental patterns of S4SFs was found. Developmental patterns of the SFratio were associated with neither measures of micro- nor macrovascular functions. No associations were using the individual growth parameters. CONCLUSIONS: For macrovascular function, there is a relationship of 30-year developmental patterns of S4SFs, whereas no such relationship was found for the 30-year developmental patterns of S4SFs or SFratio with microvascular function.

Dataset Information

Evidence for a role of developmental genes in the origin of obesity and body fat distribution.

Publications

Evidence for a role of developmental genes in the origin of obesity and body fat distribution.

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