Sucrose overconsumption impairs feeding circuit dynamics and promotes palatable food intake

Background

Consuming the right proportion of nutrients is very important to maintain health and avoid disease. Because of that, dietary guidelines were created to recommend the right amount of macronutrients we should ingest on a daily bases. Ideally, adults should consume between 45% and 65% of their total calories from carbohydrates (Trumbo et al., 2002). In mice, 59.5% of the standard diet consists of carbohydrates (Safe Diets, n.d.). Sucrose is the most common type of carbohydrate and is formed by a combination of glucose and fructose (ChEBI, n.d.). Even though glucose is the main source of energy for our cells, when in excess it can lead to metabolic dysfunctions that influence body weight regulation.

Maintenance of a steady body weight throughout life is achieved by a tightly regulated process called energy homeostasis which balances energy intake and expenditure. This regulation occurs through complex mechanisms that involve neuropeptides and signals controlled by the brain, specifically the arcuate nucleus in the hypothalamus. In this location, two types of neurons coexist: the orexigenic AgRP neurons, which promote hunger, and the anorexigenic POMC neurons, which mediate satiety (Schwartz MW et al., 2000). A dysfunction in this area of the brain leads to altered feeding behavior which, consequently, can be a cause of obesity.

Several studies have shown that an energy balance shift toward over-caloric consumption can occur by exposure to specific macronutrients. Consumption of a high-fat diet (HFD) was shown to selectively dampen AgRP neurons’ response to dietary fat, but not glucose and protein (Beutler et al., 2020), and to also shift consumption toward a more palatable diet (with a reduction in chow intake) (Mazzone et al., 2020). Another study showed how cholesterol changes the preference for carbohydrates or fat, a process that involves the melanocortin system (Nelson et al., 2022). Glucose is known to increase dopamine levels, stimulating the reward systems in the brain (Colantuoni et al., 2001; Zhang et al., 2018). These studies suggest that the food we eat might modulate our subsequent food choices.

The influence of specific macronutrients in obesity pathogenesis is still highly debated, but sugar and fat have received the most attention. Understanding the impact of these two macronutrients is essential to understand how to treat obesity and recommend better food choices to people suffering from this disease.

Main findings

In this preprint, Lorch and colleagues (Lorch et al., 2023) discovered that sucrose can impair AgRP signalling in the hypothalamus, deviating food preference towards higher sugary foods.

Changes in diet macronutrient composition and increased caloric intake, body weight, and adiposity with exposure to liquid sucrose

The authors exposed C57BL6/J mice to a 4-week high-sucrose diet (HSD) period, using a liquid sucrose solution (25%) in addition to chow, followed by 4 weeks of regular chow. During the 4-week HSD, mice decreased their caloric intake from chow, due to the consumption of the liquid sucrose solution. This resulted in an increase in total daily caloric intake with a shifted balance toward carbohydrate consumption (from 60% to 80%). Consequently, body weight and fat mass percentage increased significantly in these mice, with more pronounced effects in males.

High-sucrose diet significantly alters hormonal and metabolic parameters and reversibly suppresses fasting-induced hyperphagia

After 4 weeks of sucrose consumption, an increase in leptin levels was observed, which correlated with the body weight gain in these animals. 5 minutes after intraperitoneal administration of glucose, a higher glucose rise was observed in HSD animals, coinciding with impaired glucose tolerance even though changes in insulin levels were not observed. Liver steatosis was also seen in HSD animals, without changes in cholesterol and liver hormone levels.

To understand the feeding behavior of these animals after the 4-week HSD period, the authors challenged the animals to a fasting + re-feeding experiment. After a 6h fasting, mice were presented with 3 types of food with increasing concentrations of sugar (chow pellets, chocolate, and a 25% sucrose solution). They observed a feeding suppression of the lower sugar-containing foods (chow and chocolate) and a stable, or even increased, consumption of the high-sugar sucrose solution (Fig.1). This suggests that sucrose consumption might promote palatable food intake.

 

High-sucrose diet attenuates AgRP neuron-driven feeding and suppresses AgRP neuron responses to glucose

To understand the impact of sucrose at the level of the brain, the authors analyzed neuronal activity in the appetite-controlling region of the hypothalamus, where AgRP neurons are located. It is known that AgRP neurons’ activity can change as a response to several food cues. Since AgRP neurons mediate hunger, their activity decreases with exposure to food (pre-consumption), food consumption, and nutrients’ infusion (p.e. glucose) into the stomach. On the other hand, their activation increases during fasting and strongly promotes feeding.

The authors measured AgRP neurons’ activity by using fiber photometry after the HSD period and observed that the normal AgRP suppression after food exposure was blunted in these animals following exposure to chow. The authors then decided to infuse individual nutrients into the stomach by a gastric catheter. After glucose infusion, a blunted AgRP suppression was observed not only after the 4-week HSD, but also after the “recovery” period (after 8 weeks). However, the same response was not observed for fructose, peptide, or sucrose. This dampened AgRP neurons’ suppression might explain the decreased satiety and increased food intake after sucrose consumption.

To explore how HSD influences food intake after AgRP activation, the authors used optogenetics to activate these neurons and then exposed the mice, in a fed or fasted state, to chow or chocolate. They observed that the 4-week HSD mice attenuated the increased consumption observed with AgRP stimulation at baseline. This suggests that HSD can change the downstream responses of AgRP stimulation and modulate feeding in these animals.

Why I picked this preprint:

I picked this preprint because I’m very interested in understanding feeding behavior and how it is affected by the food we eat. I find it extremely interesting how specific macronutrients modulate food intake and perception of food. Nowadays, we are aware that carbohydrates (such as sucrose) are responsible for dramatic changes in our metabolism, influencing body weight and fat accumulation. However, it is not completely clear how sugar affects the brain and its circuits, defining the behavior towards food and negatively impacting our health. This preprint explores the influence of sucrose on our brain circuits and shows how consumption can be modulated by the type of food we eat. Combining physiological experiments with fiber photometry and optogenetics allowed the authors to explore AGRP neurons’ modulation. These results show that it is relevant to go deeper into molecular brain mechanisms to unveil their crucial role in feeding behavior.

Questions for the authors:

1. In addition to the exposure to the 3 types of food (chow pellets, chocolate, and a 25% sucrose solution), did you also challenge mice with both chow and HFD to measure their food intake? What do you think would be their response toward HFD?
2. Do you have an explanation for the fact that sucrose overconsumption did not diminish AgRP neuron responses to fructose or sucrose, but dampened the AgRP inhibition as a response to glucose?

References

Beutler, L. R., Corpuz, T. V., Ahn, J. S., Kosar, S., Song, W., Chen, Y., & Knight, Z. A. (2020). Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat. ELife, 9, e55909. https://doi.org/10.7554/eLife.55909

ChEBI. (n.d.). CHEBI:17992—Sucrose. Retrieved 7 May 2023, from https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:17992

Colantuoni, C., Schwenker, J., McCarthy, J., Rada, P., Ladenheim, B., Cadet, J.-L., Schwartz, G. J., Moran, T. H., & Hoebel, B. G. (2001). Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain. NeuroReport, 12(16), 3549.

Lorch, C. M., Hayes, N. W., Xia, J. L., Fleps, S. W., McMorrow, H. E., Province, H. S., Frydman, J. A., Parker, J. G., & Beutler, L. R. (2023). Sucrose overconsumption impairs feeding circuit dynamics and promotes palatable food intake (p. 2023.06.15.545110). bioRxiv. https://doi.org/10.1101/2023.06.15.545110

Mazzone, C. M., Liang-Guallpa, J., Li, C., Wolcott, N. S., Boone, M. H., Southern, M., Kobzar, N. P., Salgado, I. de A., Reddy, D. M., Sun, F., Zhang, Y., Li, Y., Cui, G., & Krashes, M. J. (2020). High-fat food biases hypothalamic and mesolimbic expression of consummatory drives. Nature Neuroscience, 23(10), 1253–1266. https://doi.org/10.1038/s41593-020-0684-9

Nelson, N. G., Wu, L., Maier, M. T., Lam, D., Cheang, R., Alba, D., Huang, A., Neumann, D. A., Hill, T., Vagena, E., Barsh, G. S., Medina, M. W., Krauss, R. M., Koliwad, S. K., & Xu, A. W. (2022). A gene–diet interaction controlling relative intake of dietary carbohydrates and fats. Molecular Metabolism, 58. https://doi.org/10.1016/j.molmet.2022.101442

Safe Diets. (n.d.). Premium Scientific Diets RODENTS – BREEDING. Retrieved 7 May 2023, from www.safe-diets.com

Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, & Baskin DG. (2000). Central nervous system control of food intake. Nature, 404, 661–671. https://doi.org/10.1038/35007534

Trumbo, P., Schlicker, S., Yates, A. A., Poos, M., & Food and Nutrition Board of the Institute of Medicine, The National Academies. (2002). Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. Journal of the American Dietetic Association, 102(11), 1621–1630. https://doi.org/10.1016/s0002-8223(02)90346-9

Zhang, L., Han, W., Lin, C., Li, F., & de Araujo, I. E. (2018). Sugar Metabolism Regulates Flavor Preferences and Portal Glucose Sensing. Frontiers in Integrative Neuroscience, 12, 57. https://doi.org/10.3389/fnint.2018.00057

doi: https://doi.org/10.1101/2023.06.15.545110

Tags: agrp neurons, energy homeostasis, feeding, hunger, palatable food, sucrose

doi: https://doi.org/10.1242/prelights.35004

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