Orexin activation counteracts decreases in nonexercise activity thermogenesis (NEAT) caused by high-fat diet

P. E. Bunney, A. N. Zink, A. A. Holm, C. J. Billington, C. M. Kotz

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144 Scopus citations


Overweight and obesity result from an imbalance between caloric intake and energy expenditure, including expenditure from spontaneous physical activity (SPA). Changes in SPA and resulting changes in non-exercise activity thermogenesis (NEAT) likely interact with diet to influence risk for obesity. However, previous research on the relationship between diet, physical activity, and energy expenditure has been mixed. The neuropeptide orexin is a driver of SPA, and orexin neuron activity can be manipulated using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). We hypothesized that HFD decreases SPA and NEAT, and that DREADD-mediated activation of orexin neuron signaling would abolish this decrease and produce an increase in NEAT instead. To test these ideas, we characterized behaviors to determine the extent to which access to a high-fat diet (HFD) influences the proportion and probability of engaging in food intake and activity. We then measured NEAT following access to HFD and following a DREADD intervention targeting orexin neurons. Two cohorts of orexin-cre male mice were injected with an excitatory DREADD virus into the caudal hypothalamus, where orexin neurons are concentrated. Mice were then housed in continuous metabolic phenotyping cages (Sable Promethion). Food intake, indirect calorimetry, and SPA were automatically measured every second. For cohort 1 (n = 8), animals were given access to chow, then switched to HFD. For cohort 2 (n = 4/group), half of the animals were given access to HFD, the other access to chow. Then, among animals on HFD, orexin neurons were activated following injections of clozapine n-oxide (CNO). Mice on HFD spent significantly less time eating (p < 0.01) and more time inactive compared to mice on chow (p < 0.01). Following a meal, mice on HFD were significantly more likely to engage in periods of inactivity compared to those on chow (p < 0.05). NEAT was decreased in animals on HFD, and was increased to the NEAT level of control animals following activation of orexin neurons with DREADDs. Food intake (kilocalories) was not significantly different between mice on chow and HFD, yet mice on chow expended more energy per unit of SPA, relative to that in mice consuming HFD. These results suggest that HFD consumption reduces SPA and NEAT, and increases inactivity following a meal. Together, the data suggest a change in the efficiency of energy expenditure based upon diet, such that SPA during HFD burns fewer calories compared to SPA on a standard chow diet.

Original languageEnglish (US)
Pages (from-to)139-148
Number of pages10
JournalPhysiology and Behavior
StatePublished - Jul 1 2017

Bibliographical note

Funding Information:
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 establishing the working protocols used within these experiments and productive discussions and constructive comments they provided on the project and manuscript.

Publisher Copyright:
© 2017 Elsevier Inc.

Copyright 2017 Elsevier B.V., All rights reserved.


  • Designer receptors exclusively activated by designer drugs (DREADDs)
  • High-fat diet
  • Non-exercise activity thermogenesis (NEAT)
  • Orexin
  • Spontaneous physical activity (SPA)

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