Permethrin alters glucose metabolism in conjunction with high fat diet by potentiating insulin resistance and decreases voluntary activities in female C57BL/6J mice

Abstract

Permethrin, a type 1 pyrethroid insecticide, was previously reported to promote adipogenesis in 3T3-L1 adipocytes and insulin resistance in C2C12 muscle cells; however, the effects of permethrin exposure on glucose and lipid metabolisms in vivo remain unknown. The purpose of this study was to investigate the effects of permethrin exposure on glucose and lipid homeostasis as well as voluntary movement in female mice in response to dietary fat. We tested three doses of permethrin (50, 500, & 5000 μg/kg body weight/day) in low fat diet-fed (4% w/w of diet) and high fat diet-fed (20% w/w of diet) female C57BL/6 J mice for twelve weeks. Our results demonstrated that permethrin treatment potentiated high fat diet-induced insulin resistance as indicated by insulin tolerance tests, glucose tolerance tests, and homeostasis model assessment - insulin resistance (HOMA-IR) without altering weight or fat mass. Permethrin treatment significantly decreased voluntary movement and elevated blood glucose and insulin levels. Western blot results further showed that permethrin impaired insulin signaling via the Akt signaling pathway in the gastrocnemius muscle. Taken together, these results suggest that oral administration of permethrin potentiated high fat diet-induced insulin resistance, possibly increasing the risk of type 2 diabetes without altering weight gain in female C57BL/6 J mice.

Keywords: Glucose metabolism; Insecticide; Permethrin; Voluntary activities.

Figure 1

Effects of permethrin treatment on body weight in female C57BL/6J mice. Low fat or high fat diets, without or with permethrin [50, 500, or 5000 μg/kg body weight (BW)/day] were given to mice ad libitum for 12 weeks. Open symbols, low fat diet-fed mice; Filled symbols, high fat diet-fed mice: Circles, control; Up-triangles, 50 μg/kg BW/day; Down-triangles 500 μg/kg BW/day; and Squares, 5000 μg/kg BW/day. Values represent means ± S.E. (n= 5–6).

Figure 2

Effects of permethrin on voluntary movements (non-exercise physical activity test) in female C57BL/6J mice. Low fat or high fat diets, without or with permethrin [50, 500, or 5000 μg/kg body weight (BW)/day] were given to mice ad libitum for 12 weeks. Voluntary movement was measured in week 1 (A) and week 8 (B) from 8:00 pm to 4:00 am. Travel distance change (C) was calculated based on the difference of travel distance in week 8 and week 1 of individual mice. Diet and water (HydroGel, Portland, ME, USA) were provided ad libitum to mice during the measurement. Total travel distances (m) were recorded by an infrared camera with LoliTrack Quatro Video Tracking Software Version 1.0 (Loligo Systems, Tjele, Denmark). Values represents means ±S.E. (n=5–6).

Figure 3

Effects of permethrin treatments on insulin responsiveness in female C57BL/6J mice. Low fat or high fat diets, without or with permethrin [50, 500, or 5000 μg/kg body weight (BW)/day] were given to mice ad libitum for 12 weeks. Insulin tolerance test (ITT, Figure 3A–C), glucose tolerance test (GTT, Figure 3D–F), and insulin level during GTT (Figure 3G–I). Values represent means ± S.E. (n= 4–6). Means with different letters are significantly different (P<0.05).

Figure 4

Effects of permethrin on homeostasis model assessment-insulin resistance (HOMA-IR) score in female C57BL/6J mice. Low fat or high fat diets, without or with permethrin [50, 500, or 5000 μg/kg body weight (BW)/day] were given to mice ad libitum for 12 weeks. HOMA-IR score was calculated during adaptation period, weeks 6, 11, and 12 with HOMA-IR calculator. Values represent means ± S.E. (n= 4–6). Means with different letters are significantly different (P<0.05).

Figure 5

Effects of permethrin treatments on molecular targets involved in Akt signaling pathway in gastrocnemius skeletal muscle of female C57BL/6J mice. Low fat or high fat diets, without or with permethrin [50, 500, or 5000 μg/kg body weight (BW)/day] were given to mice ad libitum for 12 weeks. (A) Protein levels of phosphorylated Akt (pAkt) Thr308; (B) pAkt Ser473; (C) Akt; (D) pAkt Thr308 to Akt ratio; (E) pAkt Ser473 to Akt ratio; (F) phosphorylated phosphoinositide-dependent kinase-1 (PDK1); and (G) Glucose transporter 4 (GLUT4). Values represent means ± S.E. (n= 4–6). Means with different letters are significantly different (P<0.05).