leptin and Liposarcoma

Aberrations of specialized metabolic pathways might be implicated in the development of neoplasias. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors with important functions in metabolism. PPARβ/δ and PPARγ act in the proliferation and differentiation of adipose tissue progenitor cells. Thus, a potential use of PPARγ agonists for the treatment of liposarcoma had been suggested, but clinical trials failed to detect beneficial effects. We show here that PPARδ is highly expressed in liposarcoma compared to lipoma and correlates with proliferation. Stimulation of liposarcoma cell lines with a specific PPARδ agonist increases proliferation, which is abolished by a PPARδ-siRNA or a specific PPARδ antagonist. Expression of the adipose tissue secretory factor leptin is lower in liposarcoma compared to lipoma and leptin reduces proliferation of liposarcoma cell lines. PPARδ activation stimulates cell migration whereas leptin diminishes it. We demonstrate that PPARδ directly represses leptin as: (a) leptin becomes down-regulated upon PPARδ activation; (b) PPARδ represses leptin promoter activity in different sarcoma cell lines; (c) deletion of a PPAR/RxR binding element in the leptin promoter abolishes repression by PPARδ; and (d) in chromatin immunoprecipitation we confirm in vivo binding of PPARδ to the leptin promoter. Our data suggest inhibition of PPARδ as a potential novel strategy to reduce liposarcoma cell proliferation.

Topics: Adult; Aged; Aged, 80 and over; Cell Movement; Cell Proliferation; Down-Regulation; Female; Humans; Leptin; Lipoma; Liposarcoma; Male; Middle Aged; Neoplasm Proteins; PPAR delta; PPAR-beta; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured

Adipose tissue is the principal source of leptin, a cytokine-like peptide with many biologic functions. Leptin binds to the leptin receptor, present in the hypothalamus and in many other tissues, and modulates energy balance and maintenance of body weight. The expression of leptin and leptin receptor in tumors of adipocytic differentiation has not been previously examined. Because normal adipose tissue is the principal source of leptin and expresses leptin receptor, we hypothesized that tumors of adipose tissue differentiation may also express leptin and/or the long functional form of the leptin receptor (OB-Rb). Leptin and OB-Rb were analyzed by immunohistochemistry, in situ hybridization, RT-PCR, and western blotting in 21 lipomas, 2 hibernomas, and 16 liposarcomas. Immunostaining and in situ hybridization showed leptin and OB-Rb mRNA expression in all cases of lipomas, hibernomas, and liposarcomas, including dedifferentiated and pleomorphic liposarcomas. RT-PCR analysis showed leptin and OB-Rb mRNA in both lipomas (n = 5) and liposarcomas (n = 5). Western blotting identified the 16 kDa leptin protein in a lipoma and a liposarcoma. No important difference in the expression of leptin and OB-Rb mRNA was found between lipomas and liposarcomas, although the level of leptin protein was higher in a lipoma than a liposarcoma by western blotting. These results show for the first time that leptin and OB-Rb mRNA are expressed in lipomas, hibernomas, and liposarcomas. The presence of leptin and its receptor may provide new insights into the pathobiology of these tumors.

Topics: Adult; Aged; Aged, 80 and over; Blotting, Western; Carrier Proteins; Cell Differentiation; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; In Situ Hybridization; Leptin; Lipoma; Liposarcoma; Male; Middle Aged; Neoplasms, Adipose Tissue; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger