The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes. The PPARgamma1 and gamma2 isoforms result from alternative splicing and have ligand-dependent and -independent activation domains. PPARgamma2 has an additional 28 amino acids at its amino terminus that renders its ligand-independent activation domain 5-10-fold more effective than that of PPARgamma1. Insulin stimulates the ligand-independent activation of PPARgamma1 and gamma2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARgamma2 in human adipocytes. Here, we report that a relatively common Pro12Ala substitution in PPARgamma2 is associated with lower body mass index (BMI; P=0.027; 0.015) and improved insulin sensitivity among middle-aged and elderly Finns. A significant odds ratio (4.35, P=0.028) for the association of the Pro/Pro genotype with type 2 diabetes was observed among Japanese Americans. The PPARgamma2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARgamma2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.

PPAR␥ is a member of the PPAR subfamily of nuclear receptors. In this work, the structure of the human PPAR␥ cDNA and gene was determined, and its promoters and tissue-specific expression were functionally characterized. Similar to the mouse, two PPAR isoforms, PPAR␥1 and PPAR␥2, were detected in man. The relative expression of human PPAR␥ was studied by a newly developed and sensitive reverse transcriptasecompetitive polymerase chain reaction method, which allowed us to distinguish between PPAR␥1 and ␥2 mRNA. In all tissues analyzed, PPAR␥2 was much less abundant than PPAR␥1. Adipose tissue and large intestine have the highest levels of PPAR␥ mRNA; kidney, liver, and small intestine have intermediate levels; whereas PPAR␥ is barely detectable in muscle. This high level expression of PPAR␥ in colon warrants further study in view of the well established role of fatty acid and arachidonic acid derivatives in colonic disease. Similarly as mouse PPAR␥s, the human PPAR␥s are activated by thiazolidinediones and prostaglandin J and bind with high affinity to a PPRE. The human PPAR␥ gene has nine exons and extends over more than 100 kilobases of genomic DNA. Alternate transcription start sites and alternate splicing generate the PPAR␥1 and PPAR␥2 mRNAs, which differ at their 5 -ends. PPAR␥1 is encoded by eight exons, and PPAR␥2 is encoded by seven exons. The 5 -untranslated sequence of PPAR␥1 is comprised of exons A1 and A2, whereas that of PPAR␥2 plus the additional PPAR␥2-specific N-terminal amino acids are encoded by exon B, located between exons A2 and A1. The remaining six exons, termed 1 to 6, are common to the PPAR␥1 and ␥2. Knowledge of the gene structure will allow screening for PPAR␥ mutations in humans with metabolic disorders, whereas knowledge of its expression pattern and factors regulating its expression could be of major importance in understanding its biology.White adipose tissue is composed of adipocytes, which play a central role in lipid homeostasis and the maintenance of energy balance in vertebrates. These cells store energy in the form of triglycerides during periods of nutritional affluence and release it in the form of free fatty acids at times of nutritional deprivation. Excess of white adipose tissue leads to obesity (1-3), whereas its absence is associated with lipodystrophic syndromes (4). In contrast to the development of brown adipose tissue, which mainly takes place before birth, the development of white adipose tissue is the result of a continuous differentiation/development process throughout life (2, 5). During development, cells that are pluripotent become increasingly restricted to specific differentiation pathways. Adipocyte differentiation results from coordinate changes in the expression of several proteins, which are mostly involved in lipid storage and metabolism, that give rise to the characteristic adipocyte phenotype. The changes in expression of these specialized proteins are mainly the result of alterations in the transcription rates of their genes.Several transcription fac...

Dietary fiber protects against chronic inflammatory diseases by dampening immune responses through short-chain fatty acids (SCFAs). Here we examined the effect of dietary fiber in viral infection, where the anti-inflammatory properties of SCFAs in principle could prevent protective immunity. Instead, we found that fermentable dietary fiber increased survival of influenza-infected mice through two complementary mechanisms. High-fiber diet (HFD)-fed mice exhibited altered bone marrow hematopoiesis, characterized by enhanced generation of Ly6c patrolling monocytes, which led to increased numbers of alternatively activated macrophages with a limited capacity to produce the chemokine CXCL1 in the airways. Blunted CXCL1 production reduced neutrophil recruitment to the airways, thus limiting tissue immunopathology during infection. In parallel, diet-derived SCFAs boosted CD8 T cell effector function by enhancing cellular metabolism. Hence, dietary fermentable fiber and SCFAs set an immune equilibrium, balancing innate and adaptive immunity so as to promote the resolution of influenza infection while preventing immune-associated pathology.