Homocysteine upregulates resistin production from adipocytes in vivo and in vitro.
OBJECTIVE
Homocysteine (Hcy) is epidemiologically related to insulin resistance, which has been speculated to be a low-grade systemic inflammatory condition. Resistin acts as a critical mediator of insulin resistance associated with inflammatory conditions. We aimed to determine whether Hcy can induce insulin resistance by directly regulating the expression and secretion of resistin from adipose tissue.


METHODS
The effect of Hcy on the expression and secretion of resistin and insulin resistance was investigated using primary rat adipocytes and mice with hyperhomocysteinemia (HHcy).


RESULTS
Hcy impaired glucose transport and, particularly, the insulin signaling pathway as shown by decreased insulin-stimulated tyrosine phosphorylation of insulin receptor and insulin receptor substrate (IRS)-1, increased serine phosphorylation of IRS-1, and inhibited Akt phosphorylation both in vitro and in vivo, and these impairments were accompanied by an increase in resistin expression. Compared with normal mice, HHcy mice with a clinically relevant level of plasma Hcy (19 micromol/l) showed significantly increased resistin production from adipose tissue (33.38 +/- 3.08 vs. 19.27 +/- 1.71 ng/ml, P < 0.01). Hcy (300-1000 micromol/l) also increased mRNA expression of resistin in primary rat adipocytes in a time- and concentration-dependent manner, with maximal induction at 24 h of approximately fourfold with 1,000 micromol/l. In addition, Hcy-induced resistin expression attenuated by treatment with reactive oxygen species (ROS) scavengers, protein kinase C (PKC), and nuclear factor (NF)-kappaB inhibitors implies a role in the process for ROS, PKC, and NF-kappaB.


CONCLUSIONS
HHcy may promote insulin resistance through the induction of resistin expression and secretion from adipocytes via the activation of the ROS-PKC-NF-kappaB pathway.
Li
Yin
Y
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
Jiang
Changtao
C
Xu
Guoheng
G
Wang
Nanping
N
Zhu
Yi
Y
Tang
Chaoshu
C
Wang
Xian
X
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004822:Epididymis; D005786:Gene Expression Regulation; D006710:Homocysteine / Q000494:pharmacology*; D020138:Hyperhomocysteinemia / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D052243:Resistin / Q000235:genetics*
D016328:NF-kappa B; D052243:Resistin; D006710:Homocysteine; D011493:Protein Kinase C