Elsevier

Physiology & Behavior

Volume 139, February 2015, Pages 303-313
Physiology & Behavior

Physically active rats lose more weight during calorie restriction

https://doi.org/10.1016/j.physbeh.2014.11.044Get rights and content

Highlights

  • High intrinsic aerobic fitness is linked to favorable metabolic health.

  • Rats selected for high intrinsic aerobic capacity (HCR) are more physically active.

  • HCR lose more body weight under calorie restriction.

  • HCR also remain more physically active during calorie restriction.

  • Metabolic thriftiness and defense of body weight are linked to low aerobic capacity.

Abstract

Daily physical activity shows substantial inter-individual variation, and low physical activity is associated with obesity and weight gain. Elevated physical activity is also associated with high intrinsic aerobic capacity, which confers considerable metabolic health benefits. Rats artificially selected for high intrinsic aerobic capacity (high-capacity runners, HCR) are more physically active than their low-capacity counterparts (low-capacity runners, LCR). To test the hypothesis that physical activity counters metabolic thriftiness, we measured physical activity and weight loss during three weeks of 50% calorie restriction (CR) in the HCR and LCR rat lines. At baseline, HCR ate more and were more active than LCR; this was seen in male rats, where LCR are considerably heavier than HCR, as well as in a set of female rats where body weight did not differ between the lines, demonstrating that this effect is consistent across sex and not secondary to body weight. We show for the first time that HCR lose more weight than LCR relative to baseline. Physical activity levels declined throughout CR, and this was more pronounced in HCR than in LCR, yet some aspects of activity remained elevated in HCR relative to LCR even during CR. This is consistent with the idea that low physical activity contributes to metabolic thriftiness during food restriction, allowing LCR to defend body mass, particularly lean mass. This has implications for physical activity during diet-induced weight loss, the genetic underpinnings of individual differences in weight loss during a diet, and the potential evolutionary opposition between metabolic thriftiness and aerobic capacity.

Introduction

Weight gain and obesity result from low energy expenditure for the level of energy intake. The negative influence of obesity in a host of medical conditions underscores the need to understand what underlies individual differences in obesity susceptibility. Even in an obesogenic environment, however, about a third of our adult population remains lean [1]. The energy expended in the activities of daily living, also known as non-exercise activity thermogenesis (NEAT), confers protection against fat gain during overfeeding in humans [2]. Daily physical activity and NEAT are biologically regulated, heritable traits [3], [4], [5], but relatively little is known regarding the mechanisms underlying the tendency to be physically active, or how these may change under energetically challenging conditions [reviewed in [4], [6], [7]]. While descriptive accounts have noted that severe energy restriction (~ 50% for 24 weeks) results in lethargy and suppressed physical activity in people [8], varied methodologies have resulted in different answers regarding how food restriction affects physical activity in animals and humans [9], [10], [11], [12].

Physical activity fosters success in weight loss and maintenance of metabolic health, while low activity predicts negative metabolic outcomes [13], [14], [15], [16], [17], [18], [19]. Like obesity, “spontaneous” or daily physical activity has a strong hereditary component [3], [4], [5], [20], [21], [22], [23], [24]. We have found a strong association between levels of daily physical activity and intrinsic aerobic capacity [25], [26], [27]. In both humans and rats, individuals with high exercise capacity are consistently more physically active and resistant to metabolic and cardiovascular disease [25], [26], [27], [28], [29], [30], [31]. Based on the hypothesis that aerobic capacity shapes the vulnerability to complex disease (the aerobic hypothesis), a rat model system was developed through divergent artificial selection for intrinsic aerobic capacity, resulting in high- and low-capacity runners (HCR and LCR) derived from a genetically heterogeneous founder population [32]. For selection based on phenotype, aerobic capacity was assessed in the founder population and subsequent generations by determining maximal treadmill running endurance: the male and female from each litter with the best (i.e., longest) running time were selected for breeding using an algorithm to minimize inbreeding; the same was done for rats with the shortest running time. Aerobic capacity was measured in offspring at 3 months of age, and the phenotype has been continually refined at each generation. The result is rats with intrinsically high and low aerobic capacity, independent of training, with associated differences in cardiovascular and metabolic disease factors [33]. Importantly, in the selection process, low NEAT segregated with low aerobic capacity, and high NEAT with high aerobic capacity [25], [26], [27]. The active rats are also resistant to obesity and metabolic disease [32], [33]. This allows us to investigate the mechanisms underlying high NEAT, specifically to test the hypothesis that obesity or the tendency to become obese is related to an increased “thriftiness” of metabolism [34].

People differ not only in obesity propensity but also in their ability to lose weight on a diet [35], [36]; the same is true for laboratory animals [37]. Apart from the known importance of diet adherence [36], these differences may be attributable to disparities in energy expenditure, reflecting differences in metabolic “thriftiness” during food restriction [10], [35]. Activities of daily living may contribute to differences in energy expenditure and weight loss during calorie restriction (CR) [10], [35], [36]. If the trade-off for elevated intrinsic aerobic capacity is a compromise in fuel efficiency or “thriftiness,” then those with high aerobic capacity and physical activity would lack the metabolic thriftiness necessary to conserve energy and body fat during food scarcity. For example, obese rats lacking leptin receptors are resistant to starvation [38], [39]. To test this hypothesis in relation to physical activity and aerobic capacity, we assessed the ability of alterations in behavior—elevated physical activity—to promote negative energy balance and, therefore, weight loss, as well as the impact of decreased food availability on physical activity levels.

Section snippets

Ethical approval

Animal protocols were approved by the Kent State University Institutional Animal Care and Use Committee.

Diet

Food (5P00 MRH 3000, T.R. Last Co., Inc.) was available ad libitum except during calorie restriction. Prolab RMH 3000 Chow Pellets are comprised of 26% protein, 14% porcine and plant oil fat, and 60% carbohydrate, with a physiological fuel value of 3.46 kcal/g. Consideration of the risk for inadequacy of nutrients is important, especially when macronutrients are varied for specific weight loss

Statistical analyses

A mixed-design (split-plot) analysis of variance (ANOVA) was used to analyze physical activity, with line of rat (HCR vs. LCR) as the between-subjects independent variable, and time of measurement as the within-subjects independent variable. This was used to analyze physical activity (baseline and during CR), body weight, change in body weight or composition (as a proportion of baseline body weight), and body composition (fat mass in grams, lean mass in grams, percent body fat of total mass,

Genetically lean female rats showed elevated levels of daily physical activity

This group of female HCR and LCR did not differ in initial body weight (HCR, 266 ± 7 g; LCR, 284 ± 11 g). Female HCR ate more than female LCR (Fig. 1A), with a group by time interaction where a significant difference arose between phenotypes only by the 5th day of activity measurement. For water intake, one outlier LCR was removed (> 3 SD above the mean due to rat physically disturbing nozzle); water showed a significant interaction resembling food intake, where HCR drank significantly more than LCR

Discussion

High levels of daily “spontaneous” physical activity are consistently coupled with leanness and healthy metabolic outcomes [25], [26], [27], [28], [29], [30], [31], [45]. Here, we demonstrate that highly active rats show enhanced weight loss during food restriction, supporting the assertion that physical activity opposes metabolic thriftiness during food restriction. Obesity-prone LCR lost less weight than HCR and, in females, conserved adiposity. Moreover, the highly physically active HCR

Conclusions

Here we show for the first time that low intrinsic fitness is tightly coupled to metabolic thriftiness and thus to defense of body weight, and that low or suppressed physical activity may aid in energy conservation. Taken together with previous reports [25], [26], [27], [49], these data strongly support the hypothesis that there is an intrinsically lean phenotype associated with high intrinsic aerobic capacity, high daily activity levels, and accelerated weight loss during food restriction.

Competing interests

None of the authors have any conflicts of interest to disclose.

Author contributions

The studies were performed in the laboratory of CMN. Conception and design of experiments: MES, CMN, SLB, and LGK. Collection, analysis and interpretation of data: MES, CMN, and KZB. Drafting of the article or revising it critically for important intellectual content: all authors.

All authors have approved the final version of the manuscript, all authors qualified for authorship, and all those who qualify for authorship are listed.

Funding

This work is supported by NIH R01NS055859, NIH R15DK097644, and AHA GIA 410805 to CMN. The LCR–HCR rat model system was supported by the Office of Research Infrastructure Programs/OD grant R24OD010950 and by grant R01DK099034 (to LGK and SLB) from the National Institutes of Health. SLB was also supported by National Institutes of Health grants R01DK077200 and R01GM104194.

Acknowledgments

We acknowledge the generous assistance from Mark Moser and his staff in the KSU Department of Biological Sciences vivarium, and the expert care of the rat colony provided at the University of Michigan by Molly Kalahar and Lori Heckenkamp. Contact LGK ([email protected]) or SLB ([email protected]) for information on the LCR and HCR rats: these rat models are maintained as an international resource with support from the Department of Anesthesiology at the University of Michigan, Ann Arbor,

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