Paracrine regulation of fat cell formation in bone marrow cultures via adiponectin and prostaglandins.

Adiponectin, an adipocyte-derived hormone, was recently shown to have potential therapeutic applications in diabetes and obesity because of its influence on glucose and lipid metabolism. We found that brown fat in normal human bone marrow contains this protein and used marrow-derived preadipocyte lines and long-term cultures to explore potential roles in hematopoiesis. Recombinant adiponectin blocked fat cell formation in long-term bone marrow cultures and inhibited the differentiation of cloned stromal preadipocytes. Adiponectin also caused elevated expression of cyclooxygenase-2 (COX-2) by these stromal cells and induced release of prostaglandin E(2) (PGE(2)). The COX-2 inhibitor Dup-697 prevented the inhibitory action of adiponectin on preadipocyte differentiation, suggesting involvement of stromal cell-derived prostanoids. Furthermore, adiponectin failed to block fat cell generation when bone marrow cells were derived from B6,129S(Ptgs2tm1Jed) (COX-2(+/-)) mice. These observations show that preadipocytes represent direct targets for adiponectin action, establishing a paracrine negative feedback loop for fat regulation. They also link adiponectin to the COX-2-dependent PGs that are critical in this process.

[1]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1994, Nature.

[2]  T. Funahashi,et al.  Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. , 2001, Diabetes.

[3]  J. Gimble,et al.  Adipogenesis in a murine bone marrow stromal cell line capable of supporting B lineage lymphocyte growth and proliferation: Biochemical and molecular characterization , 1990, European journal of immunology.

[4]  B. Spiegelman,et al.  15-Deoxy-Δ 12,14-Prostaglandin J 2 is a ligand for the adipocyte determination factor PPARγ , 1995, Cell.

[5]  J. Lehmann,et al.  A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation , 1995, Cell.

[6]  Y. Nakano,et al.  Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. , 1996, Journal of biochemistry.

[7]  H. Lodish,et al.  Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Gimble,et al.  Bone morphogenetic proteins inhibit adipocyte differentiation by bone marrow stromal cells , 1995, Journal of cellular biochemistry.

[9]  J. Gimble,et al.  Response of bone marrow stromal cells to adipogenic antagonists , 1989, Molecular and cellular biology.

[10]  T. Russell,et al.  Conversion of 3T3 fibroblasts into adipose cells: triggering of differentiation by prostaglandin F2alpha and 1-methyl-3-isobutyl xanthine. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[11]  C. Darimont,et al.  Differential response of preadipocytes and adipocytes to prostacyclin and prostaglandin E2: physiological implications. , 1992, Endocrinology.

[12]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[13]  G. Ailhaud,et al.  Regulation by fatty acids of angiotensinogen gene expression in preadipose cells. , 1997, The Biochemical journal.

[14]  D. Bers,et al.  Steady-state twitch Ca2+ fluxes and cytosolic Ca2+ buffering in rabbit ventricular myocytes. , 1996, The American journal of physiology.

[15]  A. A. Spector,et al.  Prostaglandin production by 3T3-L1 cells in culture. , 1982, Biochimica et biophysica acta.

[16]  S. Kihara,et al.  Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. , 2000, Blood.

[17]  Philipp E. Scherer,et al.  The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor , 1998, Current Biology.

[18]  L. Cassis.  Angiotensin II in brown adipose tissue from young and adult Zucker obese and lean rats. , 1994, The American journal of physiology.

[19]  T. Funahashi,et al.  cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). , 1996, Biochemical and biophysical research communications.

[20]  H. Nakauchi,et al.  Changes in hematopoiesis-supporting ability of C3H10T1/2 mouse embryo fibroblasts during differentiation. , 1993, Blood.

[21]  J. Geisler,et al.  Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[22]  S. Yamashita,et al.  Enhanced expression of PAI–1 in visceral fat: Possible contributor to vascular disease in obeisty , 1996, Nature Medicine.

[23]  B. Richelsen.  Release and effects of prostaglandins in adipose tissue. , 1992, Prostaglandins, leukotrienes, and essential fatty acids.

[24]  R. L. Richardson,et al.  Transforming growth factor type beta (TGF-beta) and adipogenesis in pigs. , 1989, Journal of animal science.

[25]  M. Jensen,et al.  Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. , 1999, Endocrinology.

[26]  S. Kihara,et al.  Adiponectin, an Adipocyte-Derived Plasma Protein, Inhibits Endothelial NF-&kgr;B Signaling Through a cAMP-Dependent Pathway , 2000, Circulation.

[27]  T Nakamura,et al.  Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. , 1999, Biochemical and biophysical research communications.

[28]  K. Tachibana,et al.  Colony-stimulating factor 1 expression is down-regulated during the adipocyte differentiation of H-1/A marrow stromal cells and induced by cachectin/tumor necrosis factor , 1991, Molecular and cellular biology.

[29]  B. Spiegelman,et al.  15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. , 1995, Cell.

[30]  Philipp E. Scherer,et al.  A Novel Serum Protein Similar to C1q, Produced Exclusively in Adipocytes (*) , 1995, The Journal of Biological Chemistry.

[31]  T. Dexter,et al.  Differentiation and proliferation of hemopoietic cells in culture. , 1976, Methods in cell biology.

[32]  大内 乗有.  Novel modulator for endothelial adhesion molecules : Adipocyte-derived plasma protein adiponectin , 2001 .

[33]  Y. Matsuzawa,et al.  Limitin: An interferon-like cytokine that preferentially influences B-lymphocyte precursors , 2000, Nature Medicine.

[34]  E. Goetzl,et al.  Specificity of expression and effects of eicosanoid mediators in normal physiology and human diseases 1 , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[35]  G. Löffler,et al.  Influences of Ionomycin, Dibutyryl-cycloAMP and Tumour Necrosis Factor-alpha on Intracellular Amount and Secretion of apM1 in Differentiating Primary Human Preadipocytes , 2000, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[36]  W. Wilkison,et al.  Upregulation of adipocyte metabolism by agouti protein: possible paracrine actions in yellow mouse obesity. , 1996, The American journal of physiology.

[37]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[38]  H. Lodish,et al.  Two Compartments for Insulin-Stimulated Exocytosis in 3t3-L1 Adipocytes Defined by Endogenous Acrp30 and Glut4 , 1999, The Journal of cell biology.

[39]  J. Ntambi,et al.  The mechanism of inhibition of 3T3-L1 preadipocyte differentiation by prostaglandin F2alpha. , 1996, Endocrinology.

[40]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1995, Nature.

[41]  J. Gimble,et al.  The function of adipocytes in the bone marrow stroma: an update. , 1996, Bone.

[42]  Y. Terauchi,et al.  The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity , 2001, Nature Medicine.

[43]  T. Funahashi,et al.  Molecular Mechanism of Metabolic Syndrome X: Contribution of Adipocytokines · Adipocyte‐derived Bioactive Substances , 1999, Annals of the New York Academy of Sciences.

[44]  C. Darimont,et al.  Differentiation of preadipose cells: paracrine role of prostacyclin upon stimulation of adipose cells by angiotensin-II. , 1994, Endocrinology.

[45]  D. L. Crandall,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2000 by The Endocrine Society Autocrine Regulation of Human Preadipocyte Migration by Plasminogen Activator Inhibitor-1 , 2022 .

[46]  N. Moustaid‐Moussa,et al.  Secretory, endocrine and autocrine/paracrine function of the adipocyte. , 2000, The Journal of nutrition.

[47]  B. Spiegelman,et al.  AdipoQ Is a Novel Adipose-specific Gene Dysregulated in Obesity (*) , 1996, The Journal of Biological Chemistry.

[48]  T Nakahata,et al.  Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells. , 1997, Blood.

[49]  P. Scherer,et al.  The adipocyte-secreted protein Acrp30 enhances hepatic insulin action , 2001, Nature Medicine.