Physiology of Prolonged Fasting

If you have ever wondered what happens to your body when you consume no food for several days in a row, then this is the article for you. In this article, we will delve into the metabolic and hormonal changes that occur with extended periods of not consuming food.

What is considered Prolonged Fasting?

We will define prolonged fasting as several (2-3 days) of consuming nothing containing energy – merely water.

Changes with Prolonged Fasting
Metabolic

Resting metabolic rate does not change after a 16 hour fast; however, after 3 days, resting metabolic rate does decrease [3][4]. As the fast continues, blood glucose levels decrease between 10-20% (in most cases), before leveling out, yet still remaining more elevated in men than women [1]. Predictably, glucose oxidation is also elevated in men compared to women, yet dampened relative to a fed state [2]. Lipid oxidation is also increased, likely to due to increases in circulating fatty acids, after 3 days of fasting, yet no differences between men and women present [2][3]. Predictably, ketones, B-hydroxybutyrate and acetoacetate, also increase over time, with higher levels in women [1][3].

In addition, lactate and pyruvate levels do not change drastically – both decreasing quickly (within 12 hours of fasting) and then remaining stable over time – especially pyruvate [1]. In terms of amino acids, gluconeogenic amino acids threonine, glycine, serine, and phenylalanine move up and down in a non-specific manner, with some differences between men and women [1]. However, plasma leucine levels skyrocket by the 3 day fast time point [1].

Endocrinology

Insulin levels are, predictably, lower and lower as fasting continues; also predictably, glucagon levels increase as fasting extends longer, although the increase is modest [1][3]. Cortisol levels increase diurnally, leading to high levels in the morning and lower levels in the evening, although this effect could be seen independent of fasting; however, overall cortisol concentrations increase as the fast runs past 72 hours [1]. Growth hormone levels increase and decrease with night time and day time, respectively [1].

Adipocyte centric hormones like adiponectin remain stable over the course of a three day fast, but remain significantly higher in women [2][3][5]. As for leptin levels, they drop significantly over a 3 day fast [3][5].

Understanding the physiology

As usual, understanding the reasoning for why these changes occur is paramount – so, let’s get into the weeds.

An eventual decrease in metabolic rate is likely attributable to a series of adaptations seen via the litany of hormonal changes. For example, decreases in leptin lead to changes in the brain’s hypothalamus – which controls significant aspects of metabolic rate, like spontaneous movement.

Blood glucose levels decrease over time, as the supply of bodily glucose is substantially smaller than the supply of fatty acids; so, the body shifts from a glucose centric metabolism to a fatty acid centric metabolism – likely majorly due to decreases in insulin and increases in glucagon. This is further substantiated by decreases in glucose oxidation and increases in fat oxidation. Increases in fatty acid concentrations are also indicative of greater lipolysis from the adipocytes (fat cells) as the adipocytes feed the system with the majority of its lipid content. Again, further evidenced by rises in ketones as the liver takes this heightened concentration of blood lipids and converts them to ketones B-hydroxybutyrate and acetoacetate.

Finally, discussing the amino acids, there is substantial variability, so diagnosing each amino acid is pointless in this overarching article; however, leucine increases are intriguing and likely an indication of some protein catabolism occurring over time – especially as leucine is a ketogenic amino acid.

As for the endocrinological changes, they are also numerous but expected – insulin, as there is decreased glucose, decreases from a lack of pancreatic stimulation – closing the channels for its escape and release into the blood stream. Concurrently, with decreased insulin signaling, glucagon is released to maintain blood glucose levels while also stimulating lipid release from adipocytes. Cortisol increases are likely due to greater need for stimulus for catabolism as glycogen stores run low, as well as the simple strenuous nature of fasting for such a long time – this likely contributes to the release of leucine and greater protein breakdown during this period, as well. Growth hormone also falls in line with cortisol production as growth hormone stimulates cortisol release, as well as impacts lipid metabolism.

Finally, the lack of change in adiponectin is a bit surprising, but could be unchanged as it may regulate even further fasting adaptations and 3 day fasts may not be long enough to see changes. Normally, adiponectin would regulate glucose and fatty acid breakdown. However, we do see changes in leptin, which, in low concentrations, releases the break on lipolysis from the adipocytes.

 

Summary

Prolonged (3 day) fasting leads to decreases in blood glucose, increases in fatty acids, ketones, leucine, as well as a switch from glucose centric metabolism to fatty acid centric metabolism. This switch is likely mediated by lowered insulin, leptin, and increased cortisol and glucagon.

Writer: Nicolas Verhoeven

References

[1] Haymond, M. W., Karl, I. E., Clarke, W. L., Pagliara, A. S., & Santiago, J. V. (1982). Differences in circulating gluconeogenic substrates during short-term fasting in men, women, and children. Metabolism, 31(1), 33-42. doi:10.1016/0026-0495(82)90024-5

[2] Soeters, M. R., Sauerwein, H. P., Groener, J. E., Aerts, J. M., Ackermans, M. T., Glatz, J. F., … Serlie, M. J. (2007). Gender-Related Differences in the Metabolic Response to Fasting. The Journal of Clinical Endocrinology & Metabolism, 92(9), 3646-3652. doi:10.1210/jc.2007-0552

[3] Bak, A. M., Vendelbo, M. H., Christensen, B., Viggers, R., Bibby, B. M., Rungby, J., … Jessen, N. (2018). Prolonged fasting-induced metabolic signatures in human skeletal muscle of lean and obese men. PLOS ONE, 13(9), e0200817. doi:10.1371/journal.pone.0200817

[4] Tatiana, M. (2016). Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males. Journal of Translational Medicine, 14(290). doi:10.1186/s12967-016-1044-0

 

[5] Merl, V. (2005). Serum adiponectin concentrations during a 72-hour fast in over- and normal-weight humans. International Journal of Obesity, 29, 998–1001. Retrieved from https://www.nature.com/articles/0802971
 

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