Study reveals key brain cells that resist food temptation and encourage exercise

A recent study published in the journal Nature Neuroscience, Researchers are investigating the role of hypocretin/orexin neurons (HONs) in temptation-resistant locomotor activity (TRVE).

study: Orexin neurons mediate voluntary movements that resist temptation. Image credit: ViDI Studio / Shutterstock.com

The neurology of obesity

Obesity has become a major public health problem worldwide, with many people being physically inactive and consuming excessive amounts of high-palatability foods (HPF). Although chronic HPF overconsumption has been shown to have adverse effects on cognitive and neurological function, the possible neurological mechanisms involved in the association between exercise and HPF consumption remain unclear.

The lateral hypothalamic region is involved in motivation, but its involvement in the control of food intake and caloric balance is unknown. The lateral hypothalamic HON releases neurotransmitters called orexins/hypocretins, which activate specific G protein-based receptor molecules throughout the brain.

About the Research

In the current study, the researchers used mouse models to investigate the role of orexin and HON in exercise and dietary decisions, and also examined the effects of pharmacological or optogenetic disruption of HON activity on exercise or HPF intake in a multiple-choice setting.

Voluntary wheel running was used as a model of health-promoting exercise in humans. During the 10-minute test, the mice were given eight choices, including a wheel to run on and a “milkshake bar” filled with strawberry-flavored milkshakes. Multiple groups of mice underwent these tests, including control mice and mice whose orexin system had been suppressed through almorexant (ALMO) treatment or genetic modification.

The appetitive and consummatory phases of food intake and exercise were investigated, providing a mechanistic and neuroeconomic explanation for exercise choice. For this purpose, mice were placed in an eight-arm maze with a choice between a moving wheel, a novel object, water, light and dark zones, and food. One arm was left empty or was filled with highly attractive food. A 10-min session was used to assess early decision-making processes while minimizing the effects of fatigue and satiation.

The behavioral and microstructural processes of orexin-based TRVE were examined by assessing the frequency and duration of running and eating bouts.

The decision-making processes involved in TRVE, specifically mice's involvement in wheel running or HPF consumption from a neutral zone, were also studied. To better understand the impact of HON on HPF use, mice were housed in cages containing both options, reducing appetitive place preference.

Real-time fiber-optic photometric recordings from the lateral hypothalamus allowed the researchers to investigate the fast dynamics of HON during TRVE. Linear mixed-effects models (LMEMs) were used with HON signaling as the response variable and HPF licking, wheel running, and non-wheel locomotor activity as input variables. To investigate the significance of changes in normal HON activity, sustained HON-selective light stimulation was used to create an artificially elevated state.

research result

Mice with their orexin system blocked were more likely to choose HPF over exercise, whereas mice with normal orexin systems doubled the time they spent running on the wheel and halved the time they spent eating.

These findings indicate that orexin does not control the time spent on physical activity or eating, but is important for choosing between activity and eating when both options are available. In the absence of orexin, the mice abandoned exercise in favor of a strawberry milkshake.

We found that when food options were restricted to regular food, mice spent time between spinning the wheel and eating. After introducing HPF into the options, mice spent significantly less time eating, whereas running wheel use and occupancy remained the same. Decreased running wheel use in ALMO-treated mice was associated with increased time spent in the highly palatable food area and increased HPF consumption. ALMO treatment significantly restricted occupancy and use of both areas when the running wheel area was available. Thus, orexin appears to mediate between eating and running without altering appetite or the drive to complete either activity.

Mice navigating the maze underwent significant changes in HON signals, and HON activity was negatively correlated with licking behavior and positively correlated with wheeled and unwheeled running speed. Light stimulation reduced activity measures normally associated with low HON activity, indicating that changes in HON activity are important for preferring exercise over food.

OneMice (n = 71) explored an eight-arm maze with a different option at the end of each arm, and their location was video tracked over a 10-min period. bHeatmap of a sample mouse showing the time spent in the baited arm (left) shifted towards the HPF (when available) (right). cIn the maze version without the HPF option (black), mice spent the most time in the wheel and food arms. In the maze version with the HPF option available (teal), mice spent the most time in the wheel and HPF arms. Lines represent means and shaded areas represent sem for n = 71 mice. dthe total time spent in the wheel arm with and without the HPF option (paired t-test: t₇₀= −0.683, P = 0.497, n = 71 mice). ethe total distance traveled on the wheel with and without the HPF option (paired t-test: t₇₀= 1.514, P = 0.134, n = 71 mice). debtthe total distance traveled in the xy plane of the maze outside the wheel with and without the HPF option (paired t-test: t₇₀= −1.147, P = 0.256, n = 71 mice). NS, not significant. Box plots: center line is median, box edges are upper and lower quartiles, whiskers are minimum and maximum values.

Implications

“In the presence of highly palatable food options, HON is required for spontaneous activity, suggesting that the HON system is important in determining motivation to exercise. These observations may be useful for individuals in need of exercise motivation and for the development of new techniques to promote physical activity.”

Future studies are needed to investigate the role of orexin in humans, especially in those with genetic limitations or those taking orexin-blocking medications. Understanding this neuronal function may also help develop solutions to combat obesity and metabolic disorders.