In a recent study published in the journal Nature Neuroscience, researchers investigate the role of hypocretin/orexin neurons (HONs) in temptation-resistant voluntary exercise (TRVE).

Study: Orexin neurons mediate temptation-resistant voluntary exercise. Image Credit: ViDI Studio / Shutterstock.com

The neurology of obesity

Obesity is a major public health issue worldwide, with many individuals under-exercising and overconsuming highly palatable foods (HPF). The neurological mechanisms that may be involved in the exercise-HPF consumption association remain unclear despite chronic HPF overconsumption being shown to adversely influence cognitive and neural measures.

The lateral hypothalamic region is involved in motivation; however, its involvement in controlling food intake and calorie balance is unknown. Lateral hypothalamic HONs release neurotransmitters called orexins/hypocretins, which activate particular G-protein-based receptor molecules throughout the brain.

About the study

In the current study, researchers use murine models to investigate the role of orexin and HONs on the decision to exercise or eat. The influence of pharmacological or optogenetic interruption of HON activity on exercise or HPF intake was also examined in multiple-choice settings.

Voluntary-type wheel running was used to model human health-promoting exercise. During ten-minute trials, mice were offered eight alternatives, including a wheel to run on and a “milkshake bar” with a strawberry-flavored milkshake. Several groups of mice were subjected to these tests, including control mice and those with suppressed orexin systems due to almorexant (ALMO) treatment or genetic alteration.

The appetitive and consummatory stages of food consumption and exercise were investigated by providing mechanistic and neuroeconomic explanations of exercise choice. To this end, mice were placed in eight-arm mazes with options such as moving wheels, novel objects, water, light and dark zones, and food. One arm was left vacant or held very appealing food. Ten-minute sessions were used to assess initial decision-making processes while minimizing fatigue and satisfaction effects.

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

Decision-making processes involved in TRVE, specifically murine engagement in wheel running or HPF consumption from a neutral zone, were also studied. To better understand the impact of HONs on HPF usage, mice were housed in a cage containing both alternatives to reduce appetitive place p.

Real-time fiber photometry recordings from the lateral hypothalamus allowed the researchers to investigate the fast dynamics of HONs during TRVE. Linear mixed-effects models (LMEM) were used with HON signaling as response variables and HPF licking, wheel run, and non-wheel locomotive activities as input variables. To investigate the significance of normal HON activity variations, persistent HON-selective optostimulation was used to create an artificially elevated state.

Study findings

with a blocked orexin system were more likely to choose HPF over exercise, whereas mice with intact orexin systems spent twice as much time running on the wheel and half the time eating food.

These findings indicate that orexin does not control the time spent in physical activity or eating; however, it is crucial for selecting between activity and eating when both options are available. Without orexin, mice abandoned exercising in favor of the strawberry milkshake.

Limiting meal selections to regular chow meals showed that mice spent time between spinning the wheel and eating. After introducing HPF to the choices, mice spent significantly less time eating chow, whereas running wheel usage and occupation remained the same. Reduced running wheel use in mice treated with ALMO was associated with increased time spent in the highly palatable food area and HPF consumption. ALMO treatment significantly limited the occupancy and utilization of both running wheel areas when they were available. Thus, orexin likely mediates between eating and running without altering appetitive or consummatory urges towards either activity.

HON signals significantly changed in mice moving through a labyrinth, with HON activity negatively associated with licking and positively associated with wheel and non-wheel running speed. Optostimulation decreased measurements of activities typically associated with low HON activity, thus indicating that HON activity variations are critical for preferring exercise over eating.

a, Mice (n = 71) explored an eight-arm maze containing distinct alternatives at the end of each arm. Mouse location was video-tracked over a 10-min period. b, Heatmaps of an example mouse displaying a shift in time spent in the chow arm (left) toward the HPF, when available (right). c, In the maze version lacking the HPF option (black), mice spent the most time in the wheel and chow arms. In the maze version with the HPF option available (teal), mice spent the most time in the wheel and HPF arms. The lines represent the means; the shaded regions represent the s.e.m. of n = 71 mice. d, Total time spent in the wheel arm in the absence and presence of the HPF option (paired t-test: t₇₀ = −0.683, P = 0.497, n = 71 mice). e, Total distance traveled on the wheel in the absence and presence of the HPF option (paired t-test: t₇₀ = 1.514, P = 0.134, n = 71 mice). f, Total distance run in the xy plane of the maze outside the wheel in the absence and presence of the HPF option (paired t-test: t₇₀ = −1.147, P = 0.256, n = 71 mice). NS, not significant. Box plots: the center line is the median, the box edges are the top and bottom quartiles, the whiskers are minimum and maximum.

Implications

HONs are required for voluntary activity when highly palatable meal options are available, thus indicating that the HON system is crucial for determining exercise motivation. These observations may support individuals requiring exercise motivation and the development of new techniques to promote physical activity.

Future studies are needed to examine the role of orexin in humans, particularly people with genetic limitations or those who use medications that inhibit orexin. Understanding this neurological function may also aid in the development of solutions for combatting obesity and metabolic disorders.