Chronic administration of palmitoleic acid reduces insulin resistance and hepatic lipid accumulation in KK-Ay Mice with genetic type 2 diabetes

Abstract

Background: Studies have demonstrated the beneficial effect of palmitoleic acid (C16:1 n-7) on reducing muscle insulin resistance and preventing beta-cell apoptosis. However, the effect of palmitoleic acid on diabetes remains to be elucidated. The aim of this study was to examine the antidiabetic effect of palmitoleic acid in KK-Ay mice, a spontaneous model for studies of obese type 2 diabetes with low insulin sensitivity.

Methods: KK-Ay mice were orally administered vehicle, 300 mg/kg of palmitoleic acid, or 300 mg/kg of palmitic acid (C16:0) on a daily basis for 4 weeks.

Results: Palmitoleic acid reduced body weight increase, ameliorated the development of hyperglycemia and hypertriglyceridemia, and improved insulin sensitivity. In addition, hepatic characteristics were significantly affected, as weight of the liver and hepatic triglyceride levels were lower in the palmitoleic acid group when compared to the control (vehicle and palmitic acid groups). Oil red O staining clearly indicated reduced hepatic lipid accumulation in response to palmitoleic acid. Furthermore, palmitoleic acid down-regulated mRNA expressions of proinflammatory adipocytokine genes (TNFα and resistin) in white adipose tissue and lipogenic genes (SREBP-1, FAS, and SCD-1) in liver.

Conclusions: These results suggest that palmitoleic acid improves hyperglycemia and hypertriglyceridemia by increasing insulin sensitivity, in part owing to suppressing proinflammatory gene expressions and improving hepatic lipid metabolism in diabetic mice.

Figure 1

Effect of palmitoleic acid on plasma glucose concentrations in KK-A^y mice. Animals were orally administered vehicle (control), 300 mg/kg of palmitic acid, or 300 mg/kg palmitoleic acid on a daily basis for 4 weeks. Values are means ± SE, n = 10. *p < 0.05 compared with the control group. C16:0, palmitic acid; C16:1, palmitoleic acid.

Figure 2

Effect of palmitoleic acid on insulin resistance in KK-A^y mice. Animals were orally administered vehicle (control), 300 mg/kg of palmitic acid, or 300 mg/kg palmitoleic acid on a daily basis for 4 weeks. (A) Plasma glucose levels in an insulin tolerance test. The insulin tolerance test was carried out on day 22 of the 4-week experiment. Animals were deprived of food for 5 h before administration of the insulin. Blood samples were collected immediately before the insulin injection (0 min) and 30, 60, and 120 min later. Values are means ± SE, n = 10. p < 0.1 and *p < 0.05 compared with the control group. (B) Plasma insulin levels. Blood samples were collected at the end of 4-week experiment after over-night fasting. Means in a row with superscripts without common letter are different, p < 0.05. C16:0, palmitic acid; C16:1, palmitoleic acid.

Figure 3

Effect of palmitoleic acid on hepatic steatosis in KK-A^y mice. Animals were orally administered vehicle (control), 300 mg/kg of palmitic acid, or 300 mg/kg palmitoleic acid on a daily basis for 4 weeks. Graphs depicting neutral lipid accumulation in liver tissue are shown. (A) Hepatic triglyceride concentration. Values are means ± SE, n = 10. Means in a row with superscripts without common letter are different, p < 0.05. C16:0, palmitic acid; C16:1, palmitoleic acid. (B) Oil red O staining of liver sections from control (I), palmitic acid (II), and palmitoleic acid (III) groups of KK-A^ymice. Images are shown at 20× magnification. Scale bar = 100 μm.

Figure 4

Effect of palmitoleic acid on lipogenic gene expression in liver in KK-A^y mice. Animals were orally administered vehicle (control), 300 mg/kg of palmitic acid, or 300 mg/kg palmitoleic acid on a daily basis. (A) Relative mRNA expression levels of SREBP-1; (B) Relative mRNA expression levels of FAS; (C) Relative mRNA expression levels of SCD-1. Each value is the mean ± SE, n = 10. Means in a row with superscripts without common letter are different, p < 0.05. C16:0, palmitic acid; C16:1, palmitoleic acid; SREBP-1, sterol regulatory element binding protein 1; SCD-1, stearoyl-coenzyme A desaturase 1; FAS, fatty acid synthase.

Figure 5

Effect of palmitoleic acid on adipocytokine mRNA levels in adipose tissue in KK-A^y mice. Animals were orally administered vehicle (control), 300 mg/kg of palmitic acid, or 300 mg/kg palmitoleic acid on a daily basis. (A) Relative mRNA expression levels of TNFα; (B) Relative mRNA expression levels of resistin; (C) Relative mRNA expression levels of adiponectin. Each value is the mean ± SE, n = 10. Means in a row with superscripts without common letter are different, p < 0.05. C16:0, palmitic acid; C16:1, palmitoleic acid; TNFα, Tumor necrosis factor alpha.