Homocysteine Upregulates Resistin Production From Adipocytes In Vivo and In Vitro

Abstract

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. RESEARCH DESIGN AND 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 μmol/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 μmol/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 μmol/l. In addition, Hcy-induced resistin expression attenuated by treatment with reactive oxygen species (ROS) scavengers, protein kinase C (PKC), and nuclear factor (NF)-κB inhibitors implies a role in the process for ROS, PKC, and NF-κB. CONCLUSIONS—HHcy may promote insulin resistance through the induction of resistin expression and secretion from adipocytes via the activation of the ROS-PKC–NF-κB pathway.

Consumption of Sericin Reduces Serum Lipids, Ameliorates Glucose Tolerance and Elevates Serum Adiponectin in Rats Fed a High-Fat Diet

“…26) An elevated level of homocysteine is known to promote insulin resistance. 27,28) It is thus of interest to test whether the promoting effect of sericin on insulin sensitivity would be partly mediated by its high content of serine relative to methionine. Further studies are required to examine if the specific amino acid pattern and the protease-resistant property of sericin are related to the mechanism for the effects on lipid and carbohydrate metabolism.…”

Relationship between adipocytokines and cardiovascular risk factors in patients with type 2 diabetes mellitus

“…We found that Hcy levels were correlated positively with leptin, resistin and visfatin levels and negatively correlated with adiponectin level. HHcy may promote insulin resistance through increased resistin secretion from adipocytes via the activation of reactive oxygen species (ROS)-protein kinase C (PKC)-nuclear factor (NF)-κβ pathway (50).…”

Adipose Tissue Dysfunction and Alcoholic Liver Disease

“…Increased oxidative stress due to CYP2E1 over expression in adipose tissue represented one of the mechanisms [19]. Studies using both genetic and dietary animal models provided evidence supporting that hyper homocysteinemia (HHcy) is associated with adipose tissue dysfunction [29][30][31][32], suggesting that methionine metabolism regulates adipose tissue function. We are the first to report that, similar to its effect on the liver, chronic alcohol feeding induces methionine metabolism abnormality in adipose tissue, which is characterized by SAM deficiency, and Hcy and SAH accumulation, leading to significant decrease of SAM/SAH ratio, a strong indicator of inhibitory transmethylation reactions (hypomethylation).…”