Effects of body weight and alcohol consumption on insulin sensitivity

Abstract

Background: Obesity is a risk factor for the development of insulin resistance, which can eventually lead to type-2 diabetes. Alcohol consumption is a protective factor against insulin resistance, and thus protects against the development of type-2 diabetes. The mechanism by which alcohol protects against the development of type-2 diabetes is not well known. To determine the mechanism by which alcohol improves insulin sensitivity, we fed water or alcohol to lean, control, and obese mice. The aim of this study was to determine whether alcohol consumption and body weights affect overlapping metabolic pathways and to identify specific target genes that are regulated in these pathways.

Method: Adipose tissue dysfunction has been associated with the development of type-2 diabetes. We assessed possible gene expression alterations in epididymal white adipose tissue (WAT). We obtained WAT from mice fed a calorie restricted (CR), low fat (LF Control) or high fat (HF) diets and either water or 20% ethanol in the drinking water. We screened the expression of genes related to the regulation of energy homeostasis and insulin regulation using a gene array composed of 384 genes.

Results: Obesity induced insulin resistance and calorie restriction and alcohol improved insulin sensitivity. The insulin resistance in obese mice was associated with the increased expression of inflammatory markers Cd68, Il-6 and Il-1alpha; in contrast, most of these genes were down-regulated in CR mice. Anti-inflammatory factors such as Il-10 and adrenergic beta receptor kinase 1 (Adrbk1) were decreased in obese mice and increased by CR and alcohol. Also, we report a direct correlation between body weight and the expression of the following genes: Kcnj11 (potassium inwardly-rectifying channel, subfamily J, member 11), Lpin2 (lipin2), and Dusp9 (dual-specificity MAP kinase phosphatase 9).

Conclusion: We show that alcohol consumption increased insulin sensitivity. Additionally, alterations in insulin sensitivity related with obesity were coupled with alterations in inflammatory genes. We provide evidence that alcohol may improve insulin sensitivity by up-regulating anti-inflammatory genes. Moreover, we have indentified potential gene targets in energy metabolic pathways and signal transducers that may contribute to obesity-related insulin resistance as well as calorie restriction and alcohol-induced insulin sensitivity.

Figure 1

Body weight and percent body fat in mice consuming water and alcohol. Panel A: Body weight in animals consuming the CR, LF, and HF diets and drinking water or 20% alcohol. Panel B: Percent body fat levels in the various groups of mice.

Figure 2

Leptin mRNA and protein levels. Panel A: Serum leptin levels. Panel B: Adipose tissue leptin mRNA levels measured by StellARray. Panel C: Adipose tissue leptin mRNA levels measured by qRT-PCR. The data in this Fig is the relative mRNA change in selected genes in the adipose tissue of CR, LF, and HF mice consuming water or 20% alcohol relative to LF mice consuming water. If the ratio is higher than 1, the mRNA content for that gene was amplified; if the ratio is below 1, the mRNA content decreased. The ratio for the LF mice consuming water is 1 because the mRNA level for that gene was the control group.

Figure 3

Adiponectin and markers of insulin sensitivity. Panel A: Adipose tissue adiponectin mRNA levels measured by qRT-PCR. Panel B: GTT area under the curve. Panel C: ITT area under the curve.

Figure 4

Adipose tissue inflammation-related factors. Panel A: Il-6 levels. Panel B: Il-10 levels. Panel C: Il-1α levels. Panel D: Adrbk1 levels. The data is fold change in mRNA of gene relative to LF mice consuming water. *Significant difference compared to the water-consuming Control group, p < 0.05.

Figure 5

Adipose tissue Cd68 and Il-18 mRNA expression levels. Panel A: Cd68 levels. Panel B: Il-18 levels. The data represent the expression of mRNA relative to LF mice consuming water. *Significant difference compared to the water-consuming Control group, p < 0.05.

Figure 6

Panel A: Adipose tissue mRNA Ptgds levels. Panel B: KCNJ11 levels. The data represent the expression of mRNA relative to LF mice consuming water. *Significant difference compared to the water-consuming Control group, p < 0.05.

Figure 7

Hormones and enzymes related to obesity-induced insulin resistance. Panel A: Lpin2 levels. Panel B: Rbp4 levels. Panel C: Lpin3 levels. Panel D: Angptl6 levels. The data represent the expression of mRNA relative to LF mice consuming water. *Significant difference compared to the water-consuming Control group, p < 0.05.

Figure 8

Expression levels of phosphatases associated with the insulin signaling pathway. Panel A: Levels of Dusp-9/Mkp-4. Panel B: Ptpra mRNA levels. The data represent the expression of mRNA relative to LF mice consuming water. *Significant difference compared to the water-consuming Control group, p < 0.05.