Research reportVoluntary wheel-running attenuates insulin and weight gain and affects anxiety-like behaviors in C57BL6/J mice exposed to a high-fat diet
Introduction
Lifestyle, such as in American society where poor diet and lack of exercise is common, can contribute to the promotion of obesity, which leads to an increased risk of developing Type-2 Diabetes Mellitus (T2DM) and in some cases poor mood. T2DM is a polygenic disease that disrupts the ability to regulate blood glucose levels, and can lead to hyperglycemia, hyperinsulinemia, and insulin resistance [1]. Roughly 90% of the total reported cases of diabetes are cases of T2DM and most individuals, but not all, are also obese (American Diabetes Association, 2014). Studies utilizing rat and mouse models have been used to provide information about T2DM. The T2DM-mimicking symptoms in these animal models are produced either through genetic manipulation, such as selective breeding or induced mutations, or through environmental factors such as exposure to a high-fat diet (HFD), which produces obesity and hyperinsulinemia. For example, when given a HFD, the C57BL/6J (B6) mouse model has been shown to develop obesity and exhibit hyperinsulinemia, hyperleptinemia, and decreased glucose tolerance [2].
In addition to producing significant alterations to metabolism and leading to the induction of T2DM, poor diet, obesity, and T2DM have also been linked to alterations in behavior. Consumption of a HFD and obesity has consistently been shown to produce impairments in cognitive performance, as seen in both human [3], [4] and animal studies [5], [6], [7] Consumption of a HFD and obesity also can produce increases in anxiety-like behaviors in animal studies using a variety of tests, including the light-dark box and open field [8], [9], [10], [11]. Human studies have also shown that obesity [12] and T2DM [13] can lead to anxiety by itself. Both animal and human studies show that diets with high levels of unhealthy fats can produce poor cognitive function and increase anxiety in addition to promoting the development of T2DM and overall unhealthy outcomes.
In humans, exercise promotes improved behavioral and physiological outcomes and is considered part of a healthy lifestyle. Physical exercise can alleviate the symptoms of T2DM, including insulin resistance [14], and can be beneficial even without reductions in body weight [15]. As for behavioral outcomes, recent studies show that exercise can reduce both depression symptoms [16], [17], [18]. In the animal literature, there are two main methods that can be employed to mimic exercise in rodent models. One way is through treadmill running (or mechanically rotating running wheel) where the animal is placed onto an already moving device and has to run in order to prevent falling off; this method can mimic a forced exercise program. Another potential method is the use of running-wheel access, where the animal can freely choose to run on the wheel or not. Voluntary wheel-running for rodents is also considered a rewarding behavior and is known to increase dopamine levels in the Ventral Tegmental Area (VTA) [19] and the nucleus accumbens [20], areas associated with the reward pathway. While voluntary wheel-running can also alleviate negative cognitive symptoms associated with HFD intake [21], its effects on anxiety in animal studies are somewhat conflicting, as it has been shown to produce increases and decreases to anxiety depending upon the species and test performed. There are studies which show that voluntary wheel-running may decrease [22], increase [23] or have no [24] effect on anxiety in commonly used assays (including open field, light-dark box, elevated-plus maze) for measuring behavior in laboratory rodents.
While exercise is well known to be part of a healthy lifestyle, its effects on staving off obesity, the development of T2DM, and on anxiety remain somewhat unclear, as evident by the somewhat conflicting evidence in both human and animal studies which can show that moderate exercise may or may not affect those physiological and behavioral parameters. In some cases, moderate exercise can facilitate reductions in anxiety [22], [25], [26], and body weight both animal [27], [28] and human studies [15], [29], but in other instances, exercise has shown to be ineffective for treating anxiety [27], [31] or for weight and diabetes management [32], [33], [34]. Therefore, this study investigated the effects of wheel-running on HFD intake to determine if exercise can alter some of the behavioral and physiological effects of HFD consumption. B6 mice were used due to their high wheel-running locomotor activity phenotype and that they develop T2DM-like symptoms when exposed to a HFD.
Section snippets
Statement on animal care
All animal studies were carried out with the approval from Bridgewater State University’s Institutional Animal Care and Use Committee (IACUC).
Animals and housing conditions
B6 mice were used because of their predisposition for increased levels of locomotor activity on the running-wheel and being a good model for diet induced obesity. Twenty-four 6-week old male B6 mice were purchased from Jackson Laboratories (Bar Harbor, ME) and were maintained in a 12:12 Light-Dark (LD: ∼50 Lux) cycle. Upon arrival, mice were individually
Body mass and wheel-running activity
No differences in body mass were observed among all the groups until aged-week 12, where the HF NW group became significantly heavier than all the other groups for the rest of the experiment (all p < 0.05). For an additional two weeks, the HF W group exhibited similar body masses compared to both regular chow groups, but at aged-week 15 (8 weeks after HF diet access), the HF W group became larger than both RC groups, but were still significantly smaller than the HF NW group for the rest of the
Discussion
These results add to a growing body of evidence which illustrate that exercise can alleviate some, but not all, of the negative physiological consequences associated with a poor diet. This study and other animal studies have shown that voluntary-wheel running can produce reductions in obesity and insulin levels in mice and rats given either a HFD or Western Diet [27], [28], [42]. In addition, mice consuming HFD have shown reductions in leptin resistance [27] and inflammation [43] when given
Competing interest
The authors declare no competing financial interests.
Acknowledgements
This work was supported by Bridgewater State University ATP, CARS, Daniel Smith, and OTL Awards. Brad Carley, Angela Forte, and Josh West facilitated with data collection.
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