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31. Gluconeogenesis as a Stress Response: Regulation by Cortisol

Lesson 31 of Masterclass With Masterjohn: Energy Metabolism

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The last lesson covered how insulin, glucagon, and allosteric regulators from within the liver ensure that the liver only engages in gluconeogenesis when it can and when it needs to. This lesson focuses on an additional layer of regulation: cortisol.

Cortisol is the principal glucocorticoid in humans. Glucocorticoids are steroid hormones produced by the adrenal cortex that increase blood glucose. Cortisol has multiple actions on the liver, muscle, adipose, and pancreas that all converge on making glucose more available to the brain.

Among them, it increases movement of fatty acids from adipose to the liver, which provide the energy for gluconeogenesis, and the movement of amino acids from skeletal muscle to the liver, which provide the building blocks for gluconeogenesis. Cortisol serves both to antagonize insulin, thereby acutely increasing gluconeogenesis, and to increase the synthesis of gluconeogenic enzymes, which amplifies all other pro-gluconeogenic signaling and increases the total capacity for gluconeogenesis. In fact, even the day-to-day regulation of gluconeogenesis by glucagon is strongly dependent on normal healthy levels of cortisol in the background.

Since gluconeogenesis is an extremely expensive investment with a negative return, it makes sense that the body would regulate it as a stress response, and thus place it under control by cortisol. This raises the question of whether carbohydrate restriction increases cortisol. Several studies are reviewed in this lesson that indicate that 1) there may be an extreme level of carbohydrate restriction that always increases cortisol, and 2) carbohydrate restriction definitely increases cortisol in some people. It may be the case that other stressors in a person’s “stress bucket” determine whether and how strongly the person reacts to carbohydrate restriction with elevated cortisol.

The audio and video of the first three lessons of this course are available to everyone for preview, but lessons 4-39 are for Masterpass members only. Start a preview from the beginning here. To learn more about the Masterpass, click here.

The full video is for paid subscribers

Harnessing the Power of Nutrients
Masterclass With Masterjohn: Energy Metabolism
This is a course with 39 lessons on the biochemistry of how we burn carbohydrate and fat for fuel.
Chris Masterjohn, PhD