Chronic ethanol-induced insulin resistance is associated with macrophage infiltration into adipose tissue and altered expression of adipocytokines.
BACKGROUND
Chronic ethanol consumption disrupts glucose homeostasis and is associated with the development of insulin resistance. While adipose tissue and skeletal muscle are the two major organs utilizing glucose in response to insulin, the relative contribution of these two tissues to impaired glucose homeostasis during chronic ethanol feeding is not known. As other models of insulin resistance, such as obesity, are characterized by an infiltration of macrophages into adipose tissue, as well as changes in the expression of adipocytokines that play a central role in the regulation of insulin sensitivity, we hypothesized that chronic ethanol-induced insulin resistance would be associated with increased macrophage infiltration into adipose tissue and changes in the expression of adipocytokines by adipose tissue.


METHODS
Male Wistar rats were fed a liquid diet containing ethanol as 36% of calories or pair-fed a control diet for 4 weeks. The effects of chronic ethanol feeding on insulin-stimulated glucose utilization were studied using the hyperinsulinemic-euglycemic clamp technique, coupled with the use of isotopic tracers. Further, macrophage infiltration into adipose tissue and expression of adipocytokines were also assessed after chronic ethanol feeding.


RESULTS
Hyperinsulinemic-euglycemic clamp studies revealed that chronic ethanol feeding to rats decreased whole-body glucose utilization and decreased insulin-mediated suppression of hepatic glucose production. Chronic ethanol feeding decreased glucose uptake in epididymal, subcutaneous, and omental adipose tissue during the hyperinsulinemic-euglycemic clamp, but had no effect on glucose disposal in skeletal muscle. Chronic ethanol feeding increased the infiltration of macrophages into epididymal adipose tissue and changed the expression of mRNA for adipocytokines: expression of mRNA for monocyte chemoattractant protein 1, tumor necrosis factor alpha, and interleukin-6 were increased, while expression of mRNA for retinol binding protein 4 and adiponectin were decreased in epididymal adipose tissue.


CONCLUSIONS
These data demonstrate that chronic ethanol feeding results in the development of insulin resistance, associated with impaired insulin-mediated suppression of hepatic glucose production and decreased insulin-stimulated glucose uptake into adipose tissue. Chronic ethanol-induced insulin resistance was associated with increased macrophage infiltration into adipose tissue, as well as changes in the expression of adipocytokines by adipose tissue.
Kang
Li
L
Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA.
Sebastian
Becky M
BM
Pritchard
Michele T
MT
Pratt
Brian T
BT
Previs
Stephen F
SF
Nagy
Laura E
LE
D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D000437:Alcoholism / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002492:Central Nervous System Depressants / Q000009:adverse effects / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D007333:Insulin Resistance / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012177:Retinol-Binding Proteins / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D052242:Adiponectin; C491768:Ccl2 protein, mouse; D002492:Central Nervous System Depressants; D018932:Chemokine CCL2; D016207:Cytokines; D015850:Interleukin-6; C502487:Rbp4 protein, mouse; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D005947:Glucose