Obesity Associated with a Mutation in a Genetic Regulator of Adipocyte Differentiation

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.

Section: Adipogenesismentioning

confidence: 99%

Obesity and polymorphisms in genes regulating human adipose tissue

Dahlman

Arner

2007

“…23 For instance, heterozygosity for PPARg R115Q was reported in nonlipodystrophic subjects ascertained based upon marked obesity and diabetes. 24 However, the increased adiposity was postulated to have resulted from a gain-of-function, with increased receptor transactivation due to P115Q, inferred because phosphorylation of Ser114 reduced the ability of the receptor to mediate adipocyte differentiation and lipid accumulation. 25,26 Heterozygosity for either PPARg V290M or P467L was initially reported in nonlipodystrophic subjects with severe insulin resistance.…”

Section: Pparc Mutations In Partial Lipodystrophy (Fpld3)mentioning

confidence: 99%

Lessons from human mutations in PPARγ

Hegele

2005

Familial partial lipodystrophy (FPLD) is characterized by adipose tissue repartitioning with multiple metabolic disturbances, including insulin resistance and dyslipidemia. Classical FPLD results from mutations in LMNA encoding nuclear lamin A/C (FPLD2), but recently some families with partial lipodystrophy and normal LMNA sequence were found to have germline mutations in PPARg (FPLD3). For instance, all four affected subjects in a three-generation Canadian FPLD3 kindred ascertained based upon a clinical diagnosis of partial lipodystrophy were heterozygous for the PPARg F388L mutation, which altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPARg. The mutation was absent from normal subjects, and functional studies showed that the mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by rosiglitazone, with no evidence of a dominant-negative mechanism. Other reported FPLD3 patients with mutant PPARg were ascertained either directly based on a clinical diagnosis of lipodystrophy (R425C mutation), or based on insulin resistance with subsequent demonstration of lipodystrophy (V290M and P467L mutations). Compared to subjects with mutant LMNA, lipodystrophic subjects with mutant PPARg had less severe adipose involvement, together with more severe clinical and biochemical manifestations of insulin resistance, and more variable response to treatment with thiazolidinediones. Thus, rare natural mutations affecting PPARg ligand binding and/or transactivation functions cause partial lipodystrophy, with associated components that resemble the metabolic syndrome.

“…A rare Pro115Gln mutation in the NH 2 -terminal ligand-independent activation domain of PPARg results in a constitutively active PPARg leading to increased adipocyte differentiation and obesity. 5 A much more common Pro12A-la substitution in the PPARg2-specific exon B, resulting in a less active PPARg form, is associated with a lower BMI. 6 Since PPARg activity has dramatic effects on lipids and glucose homeostasis, much effort has been directed to study how PPARg activity is modulated.…”

Section: Pparcmentioning

confidence: 99%

Atypical transcriptional regulators and cofactors of PPARγ

Miard

Fajas

2005

Regulation of peroxisome proliferator-activated receptor gamma (PPARg) activity is the result of several events. The first control level is the regulation of the expression of PPARg. Examples of this regulation, during adipogenesis, is the transactivation of the PPARg promoter by transcription factors of the classical pathway, such as C/EBPs or ADD1/SREBP1, but also newly identified factors, such as E2Fs. When preadipocytes re-enter the cell cycle, PPARg expression is induced coincident with an increase in DNA synthesis, suggesting the involvement of the E2F family of cell cycle regulators. E2F1 induces PPARg transcription during clonal expansion, whereas E2F4 represses PPARg expression during terminal adipocyte differentiation. Hence, E2Fs represent the link between proliferative signaling pathways, triggering clonal expansion, and terminal adipocyte differentiation through regulation of PPARg expression. A second regulatory level of PPARg action is interaction with cofactors. We will focus our attention on the atypical PPARg modulators. We have described an interaction between PPARg and the retinoblastoma protein, RB, which is both dependent upon ligand binding by PPARg and upon the phosphorylation status of RB. The interaction between PPARg and RB decreases the transcriptional activity of PPARg through recruitment of the histone deacetylase HDAC3. Inhibition of HDAC activity consequently results in a strong activation of PPARg.