The HIV-1 TAT Protein Induces the Expression and Extracellular Appearance of Acidic Fibroblast Growth Factor

Susan R. Opalenik, Jordan T. Shin, John N. Wehby, Vinit K. Mahesh, John A. Thompson
1995 Journal of Biological Chemistry  
The number of brown adipocytes residing within murine white fat depots (brite adipocytes) varies a lot by depot, strain and physiological condition. Several endocrine fibroblast growth factors are implicated in the regulation of brite adipocyte abundance. The family of fibroblast growth factors can be categorized by their site of action into endocrine, paracrine and intracellular peptides. We here screened paracrine fibroblast growth factors for their potential to drive brite adipogenesis in
more » ... adipogenesis in differentiating epididymal white adipocytes and identified fibroblast growth factor 8b to induce uncoupling protein 1 expression, but at the same time to interfere in adipogenesis. In an in vivo trial, fibroblast growth factor 8b released into the epididymal fat depot failed to robustly increase the number of brite adipocytes. The specific action of fibroblast growth factor 8b on the uncoupling protein 1 promoter in cultured epididymal adipocytes provides a model system to dissect specific gene regulatory networks. Brown adipose tissue (BAT) is an organ equipping mammals with a means of non-shivering thermogenesis. In brown adipocyte mitochondria, uncoupling protein 1 (Ucp1) allows re-entry of protons from the intermembrane space into the matrix bypassing ATP synthase and thus uncoupling oxygen consumption from ATP production. By this mechanism, the energy stored in the form of proton motive force is released as heat (for a review, see 1 ). BAT and its ability to combust nutrient energy into heat has gained raising attention by the scientific community after the repeated and convincing demonstration that healthy human adults possess appreciable amounts of metabolically active BAT 2-4 . Physiological or pharmacological activation of BAT thermogenesis may prove effective in treating some of the most widespread diseases of our time including obesity, diabetes and dyslipidemia. The amount of human BAT, however, is limited and estimated to be in the range of 0.5% of the body mass as compared to a more than 10-fold higher amount in mice 5 . Thus, not only acute activators may be required to therapeutically employ the unique capabilities of BAT, but also agents that recruit a greater number of brown adipocytes. Brown adipocytes are not restricted to uniform classical BAT depots but are often found interspersed in otherwise white adipose tissue (WAT) depots. This second type of brown adipocyte has been termed beige or brite (brown in white) and seems to emerge from a different progenitor cell than classical brown fat cells (reviewed in 6 ). To convert WAT into BAT by means of recruiting brite cells offers a possibility to massively increase the BAT amount accessible to therapeutic activation and at the same time would decrease the amount of WAT, thereby replacing an energy-storing organ with an energy-dissipating one. This browning of white fat has been subject of intense research and several systemic interventions are known to increase at least to a certain degree the number of brite cells in mice, including cold exposure and treatment with beta-adrenergic agonists, cardiac natriuretic peptides or fibroblast growth factor 21 (FGF21) 7-11 . The effectiveness of FGF21 prompted us to investigate further members of the fibroblast growth factor (FGF) family. FGFs can be grouped by their mechanism of action into intracellular, paracrine and endocrine peptides. FGF21 belongs to the small group of endocrine FGFs and is therefore able to exhibit systemic effect on multiple target tissues. The largest group is formed by the paracrine FGFs which feature a protein domain binding to extracellular matrix components and are thereby less mobile and not found in circulation 12 . Their matrix anchor
doi:10.1074/jbc.270.29.17457 pmid:7542239 fatcat:dvgh4z6ylrbjhg4gxjzs55ncka