Orexin activation counteracts decreases in nonexercise activity thermogenesis (NEAT) caused by high-fat diet
Introduction
Overweight and obesity result from imbalance between caloric intake and energy expenditure, including energy expended as part of basal metabolic rate (BMR), the thermic effect of food (TEF), and activity thermogenesis (AT; [1]). Inter-individual variability in total daily energy expenditure among people of similar body weights is primarily explained by variations in AT, which includes both exercise thermogenesis and non-exercise activity thermogenesis, or NEAT [1]. While human exercise is typically thought of as a chosen or purposeful physical activity, there is also non-exercise physical activity, known as spontaneous physical activity, or SPA, which includes all activity not specifically undertaken for chosen exercise [1]. In humans, SPA therefore includes unconscious, nonvolitional movements, such as increased drive to stand and walk, gesticulating, and fidgeting [2]. The NEAT that results from these activities represents EE produced by physical activity excluding exercise, and can vary up to 700 kCal per day [1], [3].
Underlying neural mechanisms for exercise and SPA likely differ, with exercise primarily mediated by higher-level cortical function and SPA by more primitive brain areas such as the hypothalamus. Several neuropeptides have been implicated in mediating changes in SPA, including orexin-A, agouti-gene-related protein (AgRP), ghrelin, and neuromedin U (NmU). For a review of their role in SPA and NEAT, see Kotz et al. 2007 [2]. Extensive research has been conducted to characterize the role of the neuropeptide orexin in facilitating SPA. Located within the lateral, dorsomedial, and perifornical hypothalamic regions, orexin neurons project widely throughout the brain and make synaptic contacts with other systems in brain regions implicated in motor activity, energy expenditure, and arousal [2]. Targeted experiments have demonstrated a specific role for lateral hypothalamic orexin neurons in SPA [4], [5], [6]. We have shown that direct infusions of orexin into the rostral lateral hypothalamus (rLH) produce robust increases in SPA [5], whereas infusions of GABA receptor agonists into this area inhibit the effects of orexin on SPA [7]. Orexin administration into several other orexin target sites also produces SPA [2], and can be blocked with the orexin 1 receptor antagonist, SB334867 [4], [5], [7].
Animal models of SPA typically include measurements of all activity within a dedicated space that allows for complete freedom of movement, such as those used to measure anxiety-like behaviors (i.e., open field testing apparatus), or within a home cage-like environment in which animals can interact with the environment (e.g., bedding, food and water hoppers etc.; [2]). Spontaneous physical activity can then be measured through video recording, telemetry, or infrared beams [2]. To measure changes in BMR and NEAT, simultaneous measurement of physical activity and calorimetry is needed, with BMR calculated at rest and NEAT calculated during activity.
Total physical activity throughout the day, and SPA in particular, may be affected by the type of diet available [8]; however, studies investigating the effects of diet type on changes in SPA have yielded contradictory results. For example, several studies have shown a decrease in physical activity during exposure to high-fat diet (HFD), with others showing the opposite effect, suggesting this relationship may be complex [9], [10], [11], [12], [13], [14]. Similarly, total EE may also be affected by the type of diet available, with studies showing both increases and decreases in energy expenditure in animals with access to HFD compared to chow and low-fat diets [9], [14], [15]. In addition, there have been no studies to date which have assessed the effect of chow-feeding vs. HFD specifically on NEAT, which is important for understanding the diet-based relative contribution of SPA to energy expenditure.
In the present study, we sought to characterize changes in NEAT and SPA in animals with access to HFD, using highly sensitive indirect calorimeters, which simultaneously record energy expenditure, physical activity and interactions with food and water hoppers continuously. These variables were continuously recorded for 10 consecutive days, with breaks in measurement only occurring during body weight collection, manual food intake measurements, and injections (~ 30 min per day). This allowed for a very thorough and precise measurement of energy expenditure and the temporal relationship between changes in total EE and behaviors within the cages, without having to move the animals in and out of their home cages. The potential for orexin to therapeutically enhance NEAT was then investigated by activating orexin neurons using the DREADD approach. This particular technique was used for the precise targeting and activation of the orexin neuronal field [16]. Compared with previous work of targeted infusions of orexin and/or orexin agonists into the brain, the use of DREADDs allows for the sustained activation of these neurons on the order of hours without needing to inject directly into the brain [17], [18]. Instead, activation of orexin neurons occurs following peripheral administration of clozapine-N-oxide (CNO), the designer drug portion of the DREADD, which is otherwise biologically inert. In addition, the DREADD approach allows for a within subjects design, ideal for investigating SPA, which is inherently variable between individuals [19]. We hypothesized that HFD exposure would increase the probability of physical inactivity in a behavioral analysis, while orexin neuron activation would restore the inactivity probability to pre-diet levels.
Section snippets
Animals
Male (n = 16) orexin-cre heterozygous mice with a C57/B6J background, aged 8 weeks, were used in these studies, as described previously [20]. Prior to their use in a different study, these animals were evaluated for baseline differences in SPA, NEAT, and food intake on HFD or chow and their results are presented herein. Also presented are the effects of chronic orexin neuron activation via DREADDs on NEAT in animals on HFD. Prior to their use in the present study, animals were group housed
Probability matrix
Fig. 3 shows the changes in the time spent eating and time inactive among mice consuming chow that were switched to HFD. Inactivity was separated into short (≤ 60 s) and long (> 60 s) bouts. Fig. 3 shows the mean percent time: 1). spent eating (panel A); 2) being inactive for a short bout (panel B); and 3) being inactive for a long bout (panel C) within a 24 h period and presented as a mean for all 10 days of testing for animals on a HFD or chow. There was a significant difference between percent
Discussion
Using continuous metabolic and behavioral phenotyping, the current study demonstrated that the behavioral patterning of food intake, inactivity, and NEAT is dependent on diet (chow vs. HFD). Animals were more likely to be inactive within their home cage and spent less time eating when they were switched from a chow diet to a HFD. In a separate cohort of animals, access to HFD resulted in a decrease in energy expenditure from physical activity, such that the efficiency of energy expenditure
Conclusions
The present study found that animals fed HFD spent less time engaging in feeding behavior and more time in periods of inactivity relative to animals fed chow. In addition, HFD-fed animals had a greater probability of inactivity following a meal compared to animals eating chow. Finally, NEAT was decreased in animals eating a HFD, and was increased to match the levels of that in control (chow fed) animals following CNO activation of orexin neurons. Together these results suggest that consumption
Acknowledgments
This work was supported by the Department of Veterans Affairs (5I01RX000441-04 to CMK and CJB), the National Institute of Health (5R01DK100281-03 to CMK and CJB and the Minnesota Obesity Center, 5R01DK100281-03), and by Award Number T32DK083250 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; to PEB). We are grateful to all the members of the Obesity Neuroscience group at the Minneapolis VA, especially Martha M. Grace and Morgan Little, for their support in
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