Voluntary exercise improves insulin sensitivity and adipose tissue inflammation in diet-induced obese mice

Abstract

Exercise promotes weight loss and improves insulin sensitivity. However, the molecular mechanisms mediating its beneficial effects are not fully understood. Obesity correlates with increased production of inflammatory cytokines, which in turn, contributes to systemic insulin resistance. To test the hypothesis that exercise mitigates this inflammatory response, thereby improving insulin sensitivity, we developed a model of voluntary exercise in mice made obese by feeding of a high fat/high sucrose diet (HFD). Over four wk, mice fed chow gained 2.3 +/- 0.3 g, while HFD mice gained 6.8 +/- 0.5 g. After 4 wk, mice were subdivided into four groups: chow-no exercise, chow-exercise, HFD-no exercise, HFD-exercise and monitored for an additional 6 wk. Chow-no exercise and HFD-no exercise mice gained an additional 1.2 +/- 0.3 g and 3.3 +/- 0.5 g respectively. Exercising mice had higher food consumption, but did not gain additional weight. As expected, GTT and ITT showed impaired glucose tolerance and insulin resistance in HFD-no exercise mice. However, glucose tolerance improved significantly and insulin sensitivity was completely normalized in HFD-exercise animals. Furthermore, expression of TNF-alpha, MCP-1, PAI-1 and IKKbeta was increased in adipose tissue from HFD mice compared with chow mice, whereas exercise reversed the increased expression of these inflammatory cytokines. In contrast, expression of these cytokines in liver was unchanged among the four groups. These results suggest that exercise partially reduces adiposity, reverses insulin resistance and decreases adipose tissue inflammation in diet-induced obese mice, despite continued consumption of HFD.

Fig. 1.

Body weights of Chow vs. high-fat diet (HFD) mice. A: 12-wk-old male C57BL/6 were fed either chow (n = 13) or HFD (n = 16) for 4 wk and body weights were recorded. B: Chow and HFD mice were subsequently subdivided into 4 groups: chow-no exercise (n = 6), chow-exercise (n = 7), HFD-no exercise (n = 8), and HFD-exercise (n = 8), and body weights were monitored for an additional 6 wk. Mice were housed individually, and running wheels were provided for exercise groups. #P < 0.05 vs. Chow; *P < 0.05 vs. HFD-Exercise; +P < 0.05 vs. Chow-Exercise.

Fig. 2.

Lean and fat body mass composition (A) and cumulative food intake (B) of chow-no exercise, chow-exercise, HFD-no exercise, and HFD-exercise mice, respectively, after 6 wk of chow vs. HFD with and without exercise paradigm. DEXA scanning was used to measure body composition. +P < 0.05 vs. Chow-exercise; ++P < 0.05 vs. Chow-no exercise; **P < 0.05 vs. HFD-no exercise.

Fig. 3.

A: glucose tolerance test (GTT) of chow-no exercise, chow-exercise, HFD-no exercise, and HFD-exercise mice, respectively, after 6-wk exercise period. Dashed lines represent HFD mice. Animals were fasted overnight (1700-0800). Chow-exercise mice had slightly better glucose tolerance (6% decrease in glucose AUC) than chow-no exercise mice. By comparison, HFD-no exercise mice had significantly worse glucose tolerance than chow-no exercise mice (25% increase in glucose AUC), whereas HFD-exercise mice showed a significant improvement in glucose tolerance (20% reduction in glucose AUC) compared with HFD-no exercise mice. B: fasting plasma insulin levels. Blood was collected just prior to starting GTT. +P < 0.05 vs. chow-exercise; ++P < 0.05 vs. chow-no exercise; **P < 0.05 vs. HFD-no exercise. C: insulin tolerance test (ITT) was performed after 6-wk exercise period. Fed mice were injected between 1400 and 1500 with regular insulin (0.75 U/kg body wt). Chow-exercise and HFD-exercise mice displayed similar insulin sensitivity, and both these groups were significantly more insulin sensitive (P < 0.05) than either chow-no exercise or HFD-no exercise mice.

Fig. 4.

Plasma leptin (A) and adiponectin (B) levels in chow-no exercise, chow-exercise, HFD-no exercise, and HFD-exercise mice, respectively, after 6-wk exercise period. +P < 0.05 vs. chow-exercise; ++P < 0.05 vs. chow-no exercise; **P < 0.05 vs. HFD-no exercise.

Fig. 5.

Effect of 6-wk exercise period on tumor necrosis factor-α (TNF-α; A), IκB kinase-β (IKKβ; B), monocyte chemoattractant protein-1 (MCP-1; C), and plasminogen activator inhibitor-1 (PAI-1; D) gene expression (A-D) in perigonadal fat from Chow vs. HFD mice. +P < 0.05 vs. chow-exercise; ++P < 0.05 vs. chow-no exercise; **P < 0.05 vs. HFD-no exercise.

Fig. 6.

PAI-1 and MCP-1 gene expression are increased by HFD and reduced by exercise in mesenteric fat from chow-no exercise, chow-exercise, HFD-no exercise, and HFD-exercise mice. +P < 0.05 vs. chow-exercise; ++P < 0.05 vs. chow-no exercise; **P < 0.05 vs. HFD-no exercise.

Fig. 7.

TNF-α, IKKβ, MCP-1, and PAI-1 gene expression in liver are not significantly different among chow-no exercise, chow-exercise, HFD-no exercise, and HFD-exercise mice.