Leptin Deficiency Shifts Mast Cells toward Anti-Inflammatory Actions and Protects Mice from Obesity and Diabetes by Polarizing M2 Macrophages.
Mast cells (MCs) contribute to the pathogenesis of obesity and diabetes. This study demonstrates that leptin deficiency slants MCs toward anti-inflammatory functions. MCs in the white adipose tissue (WAT) of lean humans and mice express negligible leptin. Adoptive transfer of leptin-deficient MCs expanded ex vivo mitigates diet-induced and pre-established obesity and diabetes in mice. Mechanistic studies show that leptin-deficient MCs polarize macrophages from M1 to M2 functions because of impaired cell signaling and an altered balance between pro- and anti-inflammatory cytokines, but do not affect T cell differentiation. Rampant body weight gain in ob/ob mice, a strain that lacks leptin, associates with reduced MC content in WAT. In ob/ob mice, genetic depletion of MCs exacerbates obesity and diabetes, and repopulation of ex vivo expanded ob/ob MCs ameliorates these diseases.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Nephrology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
Yi
Y
Zhou
Department of Nephrology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China. Electronic address: yuxq@mail.sysu.edu.cn.
Xueqing
X
Yu
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Research Institute of Nephrology, Nanjing University School of Medicine, Nanjing 210002, China.
Huimei
H
Chen
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Sara
S
Sjöberg
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Joséphine
J
Roux
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Lijun
L
Zhang
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Al-Habib
AH
Ivoulsou
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Farid
F
Bensaid
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Cong-Lin
CL
Liu
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Biological Sciences, School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei 230009, China.
Jian
J
Liu
INSERM, U 872, Paris, F-75006 France, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris6, UMRS 872, Paris, F-75006 France; Université Paris Descartes, UMRS 872, Paris, F-75006 France.
Joan
J
Tordjman
INSERM, U 872, Paris, F-75006 France, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris6, UMRS 872, Paris, F-75006 France; Université Paris Descartes, UMRS 872, Paris, F-75006 France.
Karine
K
Clement
Department of Genetics and Complex Diseases, School of Public Health, Harvard University, Boston, MA 02115, USA.
Chih-Hao
CH
Lee
Department of Genetics and Complex Diseases, School of Public Health, Harvard University, Boston, MA 02115, USA.
Gokhan S
GS
Hotamisligil
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Peter
P
Libby
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: gshi@rics.bwh.harvard.edu.
Guo-Ping
GP
Shi
D000818:Animals; D003920:Diabetes Mellitus; D006801:Humans; D020738:Leptin / Q000172:deficiency*; D008264:Macrophages; D008407:Mast Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity
D020738:Leptin