|
|
|
| Research progress of new target GDF15/GFRAL signaling pathways for the treatment of obesity and metabolic related diseases |
| XU Chuanyang1 WANG Zhaowei1 HE Lei1 PANG Zhijun1 ZHU Yichao2 LI Weina1 LI Zhengmin3▲ |
1.School of Pharmacy, the Fourth Military Medical University, Shaanxi Province, Xi′an 710032, China;
2.Brigade of Undergraduates, the Fourth Military Medical University, Shaanxi Province, Xi′an 710032, China;
3.Department of Anesthesiology, Tangdu Hospital, the Fourth Military Medical University, Shaanxi Province, Xi′an 710038, China |
|
|
|
Abstract Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor β superfamily and is involved in various biological processes such as energy homeostasis, body weight regulation, and cachexia driven caused by cancer and chronic diseases. GDF15 is able to control food intake and energy metabolism, which makes it important in the treatment of disorders such as obesity and anorexia. Further research into the biological function of this molecule has been limited due to the lack of its defined receptors, signaling mechanisms and target tissues. The GDNF family α-like receptor (GFRAL) has recently been identified as a receptor for the GDF15 molecule and is responsible for mediating the biological effects of controlling energy intake and energy metabolism regulation. The discovery of the GDF15/GFRAL signaling pathway provides new insights into the treatment of obesity and metabolic related diseases. In this paper, the biological function of energy stabilization of GDF15 and the influence of the discovery of GFRAL receptor on this field are briefly summarized.
|
|
|
|
|
|
[1] Paralkar VM，Vail AL，Grasser WA，et al. Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family [J]. J Biol Chem，1998，273（22）：13 760-13 767.
[2] Baek SJ，Kim KS，Nixon JB，et al. Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities [J]. Mol Pharmacol，2001，59（4）：901-908.
[3] Bottner M，Suter-Crazzolara C，Schober A，et al. Expression of a novel member of the TGF-beta superfamily，growth/differentiation factor-15/macrophage-inhibiting cytokine-1 （GDF-15/MIC-1） in adult rat tissues [J]. Cell Tissue Res，1999，297（1）：103-110.
[4] Lawton LN，Bonaldo MF，Jelenc PC，et al. Identification of a novel member of the TGF-beta superfamily highly expressed in human placenta [J]. Gene，1997，203（1）：17-26.
[5] Bootcov MR，Bauskin AR，Valenzuela SM，et al. MIC-1，a novel macrophage inhibitory cytokine，is a divergent member of the TGF-beta superfamily [J]. Proc Natl Acad Sci U S A，1997，94（21）：11 514-11 519.
[6] Hromas R，Hufford M，Sutton J，et al. PLAB，a novel placental bone morphogenetic protein [J]. Biochim Biophys Acta，1997，1354（1）：40-44.
[7] Breit SN，Johnen H，Cook AD，et al. The TGF-beta superfamily cytokine，MIC-1/GDF15：a pleotrophic cytokine with roles in inflammation，cancer and metabolism [J]. Growth Factors，2011，29（5）：187-195.
[8] Baek SJ，Okazaki R，Lee S H，et al. Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia [J]. Gastroenterology，2006，131（5）：1553-1560.
[9] Johnen H，Lin S，Kuffner T，et al. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1 [J]. Nat Med，2007，13（11）：1333-1340.
[10] Yang L，Chang CC，Sun Z，et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand [J]. Nat Med，2017，23（10）：1158-1166.
[11] Mullican SE，Lin-Schmidt X，Chin CN，et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates [J]. Nat Med，2017，23（10）：1150-1157.
[12] Hsu JY，Crawley S，Chen M，et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15 [J]. Nature，2017，550（7675）：255-259.
[13] Breit SN，Tsai VW，Brown DA. Targeting Obesity and Cachexia：Identification of the GFRAL Receptor-MIC-1/GDF15 Pathway [J]. Trends Mol Med，2017，23（12）：1065-1067.
[14] Emmerson PJ，Wang F，Du Y，et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL [J]. Nat Med，2017，23（10）：1215-1219.
[15] Bauskin AR，Zhang HP，Fairlie WD，et al. The propeptide of macrophage inhibitory cytokine （MIC-1），a TGF-beta superfamily member，acts as a quality control determinant for correctly folded MIC-1 [J]. EMBO J，2000，19（10）：2212-2220.
[16] Martinez JM，Sali T，Okazaki R，et al. Drug-induced expression of nonsteroidal anti-inflammatory drug-activated gene/macrophage inhibitory cytokine-1/prostate-derived factor，a putative tumor suppressor，inhibits tumor growth [J]. J Pharmacol Exp Ther，2006，318（2）：899-906.
[17] Kleinert M，Clemmensen C，Sjoberg KA，et al. Exercise increases circulating GDF15 in humans [J]. Mol Metab，2018，9：187-191.
[18] Ding Q，Mracek T，Gonzalez-Muniesa P，et al. Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes [J]. Endocrinology，2009，150（4）：1688-1696.
[19] Fairlie WD，Moore AG，Bauskin AR，et al. MIC-1 is a novel TGF-beta superfamily cytokine associated with macrophage activation [J]. J Leukoc Biol，1999，65（1）：2-5.
[20] Bauskin AR，Jiang L，Luo XW，et al. The TGF-beta superfamily cytokine MIC-1/GDF15：secretory mechanisms facilitate creation of latent stromal stores [J]. J Interferon Cytokine Res，2010，30（6）：389-397.
[21] Moore AG，Brown DA，Fairlie WD，et al. The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women [J]. J Clin Endocrinol Metab，2000，85（12）：4781-4788.
[22] Yoshioka H，Kamitani H，Watanabe T，et al. Nonsteroidal anti-inflammatory drug-activated gene （NAG-1/GDF15） expression is increased by the histone deacetylase inhibitor trichostatin A [J]. J Biol Chem，2008，283（48）：33 129-33 137.
[23] Mimeault M，Batra SK. Divergent molecular mechanisms underlying the pleiotropic functions of macrophage inhibitory cytokine-1 in cancer [J]. J Cell Physiol，2010， 224（3）：626-635.
[24] Bauskin AR，Brown DA，Kuffner T，et al. Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer [J]. Cancer Res，2006，66（10）：4983-4986.
[25] Kempf T，Guba-Quint A，Torgerson J，et al. Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals：results from the XENDOS trial [J]. Eur J Endocrinol，2012，167（5）：671-678.
[26] Dostalova I，Roubicek T，Bartlova M，et al. Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus：the influence of very low calorie diet [J]. Eur J Endocrinol，2009，161（3）：397-404.
[27] Xiong Y，Walker K，Min X，et al. Long-acting MIC-1/GDF15 molecules to treat obesity：Evidence from mice to monkeys [J]. Sci Transl Med，2017，9（412）.pii：eaan8732.
[28] Tsai VW，Husaini Y，Manandhar R，et al. Anorexia/cachexia of chronic diseases：a role for the TGF-beta family cytokine MIC-1/GDF15 [J]. J Cachexia Sarcopenia Muscle，2012，3（4）：239-243.
[29] Vila G，Riedl M，Anderwald C，et al. The relationship between insulin resistance and the cardiovascular biomarker growth differentiation factor-15 in obese patients [J]. Clin Chem，2011，57（2）：309-316.
[30] Lerner L，Gyuris J，Nicoletti R，et al. Growth differentiating factor-15 （GDF-15）：A potential biomarker and therapeutic target for cancer-associated weight loss [J]. Oncol Lett，2016，12（5）：4219-4223.
[31] Lerner L，Hayes TG，Tao N，et al. Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients [J]. J Cachexia Sarcopenia Muscle，2015，6（4）：317-324.
[32] Breit SN，Carrero JJ，Tsai VW，et al. Macrophage inhibitory cytokine-1 （MIC-1/GDF15） and mortality in end-stage renal disease [J]. Nephrol Dial Transplant，2012，27（1）：70-75.
[33] Macia L，Tsai VW，Nguyen AD，et al. Macrophage inhibitory cytokine 1 （MIC-1/GDF15） decreases food intake，body weight and improves glucose tolerance in mice on normal & obesogenic diets [J]. PLoS One，2012，7（4）：e34868.
[34] Chrysovergis K，Wang X，Kosak J，et al. NAG-1/GDF-15 prevents obesity by increasing thermogenesis，lipolysis and oxidative metabolism [J]. Int J Obes （Lond），2014， 38（12）：1555-1564.
[35] Tschop MH，Speakman JR，Arch JR，et al. A guide to analysis of mouse energy metabolism [J]. Nat Methods，2011，9（1）：57-63.
[36] Artz A，Butz S，Vestweber D. GDF-15 inhibits integrin activation and mouse neutrophil recruitment through the ALK-5/TGF-betaRII heterodimer [J]. Blood，2016，128（4）：529-541.
[37] Unsicker K，Spittau B，Krieglstein K. The multiple facets of the TGF-beta family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1 [J]. Cytokine Growth Factor Rev，2013，24（4）：373-384.
[38] Liu DD，Lu JM，Zhao QR，et al. Growth differentiation factor-15 promotes glutamate release in medial prefrontal cortex of mice through upregulation of T-type calcium channels [J]. Sci Rep，2016，6：28 653.
[39] Tsai VW，Manandhar R，Jorgensen SB，et al. The anorectic actions of the TGFbeta cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract [J]. PLoS One，2014，9（6）：e100370.
[40] Mullican SE，Rangwala SM. Uniting GDF15 and GFRAL：Therapeutic Opportunities in Obesity and Beyond [J]. Trends Endocrinol Metab，2018，29（8）：560-570.
[41] Hatinen T，Holm L，Airaksinen MS. Loss of neurturin in frog--comparative genomics study of GDNF family ligand-receptor pairs [J]. Mol Cell Neurosci，2007，34（2）：155-167.
[42] Jones JE，Cadena SM，Gong C，et al. Supraphysiologic Administration of GDF11 Induces Cachexia in Part by Upregulating GDF15 [J]. Cell Rep，2018，22（12）：3375. |
|
|
|
