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  • Title: Inhibition of the chemokine (C-C motif) ligand 2/chemokine (C-C motif) receptor 2 pathway attenuates hyperglycaemia and inflammation in a mouse model of hepatic steatosis and lipoatrophy.
    Author: Yang SJ, IglayReger HB, Kadouh HC, Bodary PF.
    Journal: Diabetologia; 2009 May; 52(5):972-81. PubMed ID: 19277603.
    Abstract:
    AIMS/HYPOTHESIS: Using a mouse model of lipoatrophic diabetes, we hypothesised that the chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-C motif) receptor 2 (CCR2) pathway contributes to hepatic macrophage accumulation and insulin resistance through induction of a chronic inflammatory state. METHODS: Metabolic variables of insulin resistance and inflammation were characterised in wild-type and lipoatrophic A-ZIP/F-1 transgenic (AZIP-Tg) mice. The AZIP-Tg mice were then treated with a CCR2 antagonist (RS504393, 2 mg kg(-1) day(-1)) or vehicle for 28 days via a subcutaneous mini-osmotic pump to examine the role of the CCL2/CCR2 pathway in lipoatrophic diabetes. RESULTS: The lipoatrophic AZIP-Tg mice were diabetic with high fasting glucose and serum insulin concentrations compared with littermate controls. The livers of AZIP-Tg mice were more than threefold enlarged and exhibited increased triacylglycerol content. CCL2 levels were highly elevated in both liver and serum of the AZIP-Tg mice compared with controls. In addition, the circulating CCL2 concentration was associated with increased macrophage accumulation and inflammation as documented by upregulation of Cd68 gene and Tnf-alpha [also known as Tnf] gene in livers from the AZIP-Tg mice. Treatment of the lipoatrophic AZIP-Tg mice with the CCR2 antagonist ameliorated the hyperglycaemia, hyperinsulinaemia and hepatomegaly in conjunction with a reduction in liver inflammation. CONCLUSIONS/INTERPRETATION: These findings demonstrate a significant role of the CCL2/CCR2 pathway in lipoatrophy-induced diabetes and provide clear evidence that metabolic improvements resulting from the inhibition of this inflammatory pathway are not adipose tissue-dependent.
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