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

Abstract

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.

Neuromodulation of orexin neurons reduces diet-induced adiposity

“…1; (20)). Adult male orexin-cre (Cre) or wildtype (Wt) mice (n = 3/group) received injections of a DREADD virus (hM3Dq) at one site per hemisphere aimed at caudal lateral LH (Fig.…”

Hypothalamic leptin sensitivity and health benefits of time‐restricted feeding are dependent on the time of day in male mice

“…As part of experiment 3, we examined whether TRF causes changes in energy metabolism and behavior. Therefore, mice were monitored in a multichannel respirometry system (3721 mouse cages, Promethion; Sable Systems International, Las Vegas, NV, USA) for 3 d. It was previously shown that a change of housing conditions to metabolic cages of the Sable Systems Promethion Line does not induce novelty-induced increase in spontaneous activity within the first several days of housing, suggesting the absence of a housing acclimation effect (35). Nonetheless, in our study mice were given 12 h adaptation time, after which we did not observe differences in activity for each group throughout the experiment.…”

Spontaneous Physical Activity Defends Against Obesity

“…When considering the influence of SPA on obesity, measuring NEAT and not SPA should be the ultimate goal, yet only recently technological advances have been able to provide accurate quantification of NEAT in rodents using specialized equipment [45, 46], which helps explain why SPA is more commonly measured as compared to NEAT. Currently, NEAT is determined by analyzing overall energy expenditure (i.e.…”