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.
OBJECTIVE
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
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.
Yang
S J
SJ
School of Kinesiology, University of Michigan, Ann Arbor, MI 48109, USA.
IglayReger
H B
HB
Kadouh
H C
HC
Bodary
P F
PF
D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D001835:Body Weight; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000473:pathology* / Q000503:physiopathology*; D003923:Diabetes Mellitus, Lipoatrophic / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000473:pathology* / Q000503:physiopathology*; D005260:Female; D006943:Hyperglycemia / Q000517:prevention & control*; D007249:Inflammation / Q000517:prevention & control*; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009929:Organ Size; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000235:genetics
D018932:Chemokine CCL2; D054390:Receptors, CCR2; C406806:Tg(AZIP-F)1Vsn protein, mouse; D014157:Transcription Factors