No abstract

The regulation of transcription of the gene for the beta subunit of the FoF1 ATP synthase (ATPsynbeta) in brown adipose tissue has been studied as a model to determine the molecular mechanisms for mitochondrial biogenesis associated with brown adipocyte differentiation. The expression of the ATPsynbeta mRNA is induced during the brown adipocyte differentiation that occurs during murine prenatal development or when brown adipocytes differentiate in culture. This induction occurs in parallel with enhanced gene expression for other nuclear and mitochondrially-encoded components of the respiratory chain/oxidative phosphorylation system (OXPHOS). Transient transfection assays indicated that the expression of the ATPsynbeta gene promoter is higher in differentiated HIB-1B brown adipocytes than in non-differentiated HIB-1B cells. A major transcriptional regulatory site was identified between nt -306 and -266 in the ATPsynbeta promoter. This element has a higher enhancer capacity in differentiated brown adipocyte HIB-1B cells than in non-differentiated cells. Electrophoretic shift analysis indicated that Sp1and nuclear respiratory factor-2/GA-binding protein (NRF2/GABP) were the main nuclear proteins present in brown adipose tissue that bind this site. Double-point mutant analysis indicated a major role for the NRF2/GABP site in the enhancer capacity of this element in brown fat cells. It is proposed that NRF2/GABP plays a pivotal role in the co-ordinated enhancement of OXPHOS gene expression associated with mitochondrial biogenesis in brown adipocyte differentiation.

Cs line the lumen of the entire vascular system and regulate the dynamic passage of materials and cells. They are located ubiquitously over a uniquely large surface of 4,000-7,000 m 2 covering the interface between the blood and tissues 1 . This vast contact area permits precise environmental sensing, nutrient transport and signaling integration from surrounding tissues. Therefore, ECs are regarded as the nutrient gatekeepers of the organism. Despite of this, the role of ECs in the regulation of systemic metabolism and as potential mediators of metabolic disorders remains enigmatic 2,3 .Adult ECs are largely quiescent except in some metabolic tissues where vascular expansion is considered the direct response to tissue requirements. This is the case for WAT during lipid accumulation 2 or muscle during exercise 4,5 in which adaptations to tissue function are accompanied by vascular growth. ECs mainly expand by angiogenesis, a process in which ECs sprout, branch, connect and remodel into functional vessel circuits 6,7 . Angiogenesis is guided by several extracellular cues, including growth factors, mechanical forces, flow and extracellular matrix proteins that collectively converge on intracellular growth pathways such as phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR and RAS/MAPK/ERK 7,8 . Despite ECs being the first line of nutrient sensing and distribution, the role of nutrients in relation to angiogenesis and their potential impact in pathophysiology is unclear.PTEN (phosphatase and tensin homolog) is a lipid phosphatase that dephosphorylates membrane phospholipids generated by the class I PI3Ks 9,10 , the so-called phosphatidylinositol