Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance.
In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100050, China; Division of Endocrinology and Metabolism, UC, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: lipp@imm.ac.cn.
Pingping
P
Li
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100050, China.
Shuainan
S
Liu
Division of Endocrinology and Metabolism, UC, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Diabetes Early Discovery, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Min
M
Lu
Division of Endocrinology and Metabolism, UC, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Gautum
G
Bandyopadhyay
Division of Endocrinology and Metabolism, UC, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Dayoung
D
Oh
Pharmacology, Department of Medicine, Shiga University of Medical Science, 1 Tsukinowa, Seta, Otsu-city, Shiga 520-2192, Japan.
Takeshi
T
Imamura
Division of Endocrinology and Metabolism, UC, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Andrew M F
AMF
Johnson
Division of Endocrinology and Metabolism, UC, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Dorothy
D
Sears
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100050, China.
Zhufang
Z
Shen
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100050, China.
Bing
B
Cui
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100050, China.
Lijuan
L
Kong
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100050, China.
Shaocong
S
Hou
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100050, China.
Xiao
X
Liang
Diabetes Early Discovery, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Salvatore
S
Iovino
Lipomics Technologies, Inc., West Sacramento, CA 95691, USA.
Steven M
SM
Watkins
Division of Endocrinology and Metabolism, UC, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Wei
W
Ying
Division of Endocrinology and Metabolism, UC, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Olivia
O
Osborn
Division of Endocrinology and Metabolism, UC, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Joshua
J
Wollam
Diabetes Early Discovery, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Martin
M
Brenner
Division of Endocrinology and Metabolism, UC, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: jolefsky@ucsd.edu.
Jerrold M
JM
Olefsky
D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002633:Chemotaxis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D037502:Galectin 3 / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D037502:Galectin 3; D007328:Insulin
galectin-3; inflammation; insulin resistance