LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance.
Recent articles have reported an association between fatty liver disease and systemic insulin resistance in humans, but the causal relationship remains unclear. The liver may contribute to muscle insulin resistance by releasing secretory proteins called hepatokines. Here we demonstrate that leukocyte cell-derived chemotaxin 2 (LECT2), an energy-sensing hepatokine, is a link between obesity and skeletal muscle insulin resistance. Circulating LECT2 positively correlated with the severity of both obesity and insulin resistance in humans. LECT2 expression was negatively regulated by starvation-sensing kinase adenosine monophosphate-activated protein kinase in H4IIEC hepatocytes. Genetic deletion of LECT2 in mice increased insulin sensitivity in the skeletal muscle. Treatment with recombinant LECT2 protein impaired insulin signaling via phosphorylation of Jun NH2-terminal kinase in C2C12 myocytes. These results demonstrate the involvement of LECT2 in glucose metabolism and suggest that LECT2 may be a therapeutic target for obesity-associated insulin resistance.
Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan.
Fei
F
Lan
Hirofumi
H
Misu
Keita
K
Chikamoto
Hiroaki
H
Takayama
Akihiro
A
Kikuchi
Kensuke
K
Mohri
Noboru
N
Takata
Hiroto
H
Hayashi
Naoto
N
Matsuzawa-Nagata
Yumie
Y
Takeshita
Hiroyo
H
Noda
Yukako
Y
Matsumoto
Tsuguhito
T
Ota
Toru
T
Nagano
Masatoshi
M
Nakagen
Ken-ichi
K
Miyamoto
Kanako
K
Takatsuki
Toru
T
Seo
Kaito
K
Iwayama
Kunpei
K
Tokuyama
Seiichi
S
Matsugo
Hong
H
Tang
Yoshiro
Y
Saito
Satoshi
S
Yamagoe
Shuichi
S
Kaneko
Toshinari
T
Takamura
D000818:Animals; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; C103468:LECT2 protein, human; D005947:Glucose