Wheel running leads to sex-specific effects on Western diet-associated glucose homeostasis and brain insulin signaling without altering food-related impulsive choice.

OBJECTIVES: There is a clear association between obesity and impulsivity. While exercise can suppress weight gain and decrease impulsive choice (IC), the relationship between impulsivity, the consumption of palatable, energy dense diets, and exercise is unclear. We examined IC before and after Western diet (WD) exposure in rats of both sexes and whether exercise would rescue any diet-mediated increases in IC. Our hypotheses were twofold: first, increased impulsivity would be associated with higher WD preference in a positive feedback loop and second, increased WD consumption would impair both peripheral and central insulin signaling, both of which exercise would attenuate. METHODS: Following baseline assessment of IC through a delay discounting task, rats were divided into naïve, sedentary (Sed), or wheel running (WR) groups for a 5-week WR and two-diet choice period after which rats underwent an oral glucose (OGTT) and insulin tolerance test (ITT) in addition to a re-test of IC. Insulin induced Akt-GSK3ß signaling in the brain was examined using western blot. RESULTS: All Sed rats preferred the WD diet, and all WR rats initially avoided the WD but subsequently reversed their avoidance to preference with females reversing earlier than males. Exercise suppressed weight gain and adiposity to a greater extent in males than females. Only WR males showed improved glucose clearance during OGTT, but both male and female WR rats had a faster recovery of hypoglycemia during ITT. Furthermore, WR rescued WD-induced deficits in hypothalamic Akt-GSK3ß signaling in males but not females. In the prefrontal cortex, however, WD and WR both reduced Akt-GSK3ß signaling in males but not females. There were no sex differences in IC at baseline, and all rats made more impulsive choices during the re-test independent of diet, sex, or exercise. DISCUSSION: The results suggest that while exercise may have a greater efficacy at attenuating diet-mediated metabolic dysregulation in males, it has some beneficial effects for females and highlights the need to develop sex-specific interventions for restoring energy balance.

Sex-Dependent Wheel Running Effects on High Fat Diet Preference, Metabolic Outcomes, and Performance on the Barnes Maze in Rats.

Excessive and prolonged intake of highly palatable, high fat (HF) foods contributes to the pathogenesis of obesity, metabolic syndrome, and cognitive impairment. Exercise can restore energy homeostasis and suppress HF diet preference in rats. However, it is unclear if exercise confers similar protection against the detrimental outcomes associated with a chronic HF diet preference and feeding in both sexes. We used our wheel running (WR) and two-diet choice (chow vs. HF) paradigm to investigate the efficacy of exercise in reversing HF diet-associated metabolic and cognitive dysregulation in rats, hypothesizing that beneficial effects of exercise would be more pronounced in males. All WR rats showed HF diet avoidance upon running initiation, and males, but not females, had a prolonged reduction in HF diet preference. Moreover, exercise only improved glucose tolerance and insulin profile in males. Compared to sedentary controls, all WR rats improved learning to escape on the Barnes maze. Only WR females increased errors made during subsequent reversal learning trials, indicating a sex-dependent effect of exercise on behavioral flexibility. Taken together, our results suggest that exercise is more effective at attenuating HF-associated metabolic deficits in males, and highlights the importance of developing sex-specific treatment interventions for obesity and cognitive dysfunction.

Role of glucocorticoid signaling in exercise-associated changes in high-fat diet preference in rats.

The simultaneous introduction of wheel running (WR) and diet choice (high-carbohydrate chow vs. high-fat diet) results in sex-specific diet choice patterns in rats. WR induces a high-fat (HF) diet avoidance, and such avoidance persists in the majority of males, but not females, throughout a 2-wk period. Exercise is a physiological stressor that activates the hypothalamic-pituitary-adrenal (HPA) axis and stimulates glucocorticoid (GC) release, which can alter dietary preferences. Here, we examined the role of the HPA axis and GC signaling in mediating exercise-induced changes in diet preference and the associated neurobiological adaptations that may underlie sex differences in diet choice patterns. Experiment 1 revealed that adrenalectomy did not significantly alter the initiation and persistence of running-induced HF diet avoidance in male rats. Experiment 2 showed that acute WR resulted in greater neural activation than chronic WR in the medial prefrontal (mPFC) and insular cortices (IC) in male rats. Experiment 3 revealed sex differences in the molecular adaptation to exercise and diet preference. First, exercise increased gene expression of fkbp5 in the mPFC, IC, and hippocampus of WR females but had limited influence in males. Second, male and female WR rats that reversed or maintained HF diet avoidance showed distinct sex- and HF diet preference-dependent expression profiles of genes involved in cortical GC signaling (e.g., nr3c1, nr3c2, and src1). Taken together, our results suggest sex differences in region-specific neural adaptations may underlie sex differences in diet preference and the health benefits from exercise.

Sex and individual differences in meal patterns mediate the persistency of running-associated high-fat diet avoidance in rats.

The modern environment is characterized by convenient access to a variety of high-fat (HF) foods and encourages excess energy intake, which leads to weight gain. While healthier diets and exercise are common interventions that facilitate energy balance, meal patterns also influence body weight and energy metabolism. The current study characterized the association among exercise, diet choice, and meal patterns in rats. Unlike sedentary rats, which prefer a HF to a chow diet, wheel-running rats initially avoid the HF diet. Subsequently, the running-induced HF diet avoidance persists longer in males than in females. We hypothesized that differences in meal patterns contribute to sex differences in the prevalence and persistency of HF diet avoidance. During two-diet choice, rats did not mix chow and HF diet within a meal and consumed discrete meals of each diet. Exercise decreased chow meal size in both sexes (4.5 vs. 5.7 kcal) but decreased total meal frequency only in male rats. Analyses of individual differences revealed WR rats that maintained HF diet avoidance (HF avoiders) had larger chow than HF meals (5.2 vs. 1.3 kcal) upon initial 3 days of diet choice. When compared with rats that reversed HF avoidance (HF eaters), HF avoiders had shorter latency to consume their first meal of HF diet (2.6 vs. 98.9 min) upon initial running and diet choice. Taken together, these results suggest that both sex and individual differences in meal patterns contribute to differences in the persistency of exercise-associated HF diet avoidance.

Ovarian hormones mediate running-induced changes in high fat diet choice patterns in female rats.

Physical inactivity and increased consumption of energy dense, high fat (HF) foods often leads to a state of positive energy balance. Regular exercise can facilitate the maintenance of a healthy body weight and mediate changes in dietary selection. Past studies using a two-diet choice (chow vs. HF) and voluntary wheel running paradigm found that when a novel HF diet and wheel running are simultaneously introduced, male rats show complete and persistent HF diet avoidance whereas the majority of females show HF diet avoidance for a few days, but then revert to HF diet preference. Ovariectomy (OVX) appears to decrease preference for the HF diet bringing it closer to that of males. Given that estradiol but not progesterone mediates changes in food intake and energy balance, we hypothesized that estradiol signaling is required for the reversal of HF diet avoidance in female rats. Accordingly, Experiment 1 compared the persistency of running-induced HF diet avoidance in males, sham-operated females, and OVX rats with replacement of oil vehicle, estradiol benzoate (E), progesterone (P), or both (E + P). The number of wheel running rats that either avoided or preferred the HF diet varied with hormone treatment. The reversal of HF diet avoidance in running females and OVX E + P rats occurred more rapidly and frequently than male running rats. E + P but not E or P replaced OVX wheel running rats significantly reversed HF diet avoidance. OVX oil rats avoided HF diet to the same extent as male rats for the first 11 days of diet choice and then rapidly increased HF diet intake and began preferring it. This incomplete elimination of sex differences suggests that developmental factors or androgens might play a role in sustaining running-induced HF diet avoidance. Subsequently, Experiment 2 aimed to determine the role of androgens in the persistency of running-associated HF diet avoidance with sham-operated and orchiectomized (GDX) male rats. Both intact and GDX male running rats persistently avoided the HF diet to the same extent. Taken together, these results suggest that activational effects of ovarian hormones play a role in female specific running-induced changes in diet choice patterns. Furthermore, the activational effects of androgens are not required for the expression of HF diet avoidance in males.