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Mechanism of Action

Author: Dr. Edward Group 05/22/2009

7-Keto Thermo imageThermogenesis is a term which describes the creation of heat in mammals. Heat is a form of energy produced when the food we eat is metabolized in the cells of our body. Chemical energy, in the form of adenosine triphosphate (ATP) is also produced in this reaction and is the body’s biologically useful energy. ATP is the “energy currency” of the cell and is used to drive all energy requiring reactions including the synthesis of proteins, carbohydrates and fats. It also causes muscles to contract and nerves to conduct.

ATP, while a good energy packet, is not a good fuel storage molecule, as it is used quickly after being formed. Better storage forms of energy are glycogen and triglycerides. Glycogen is broken down to glucose and triglycerides are broken down to fatty acids, both of which are readily utilized for energy. Of importance is that any food not utilized for energy is subsequently stored for use later, and mostly as fat since it is the most efficient energy storage form at 9 kcal/gm. The synthesis of triglycerides requires glycerol (from carbohydrates), fatty acids and energy from ATP.

The production of energy from glucose and fatty acids occurs at the cellular level with glycolysis (glucose metabolism) occurring in the cytosol of the cell and fatty acid oxidation in the mitochondria of the cell. The mitochondria is often considered the “powerhouse” of the cell, and most cells involved with fatty acid metabolism are in the liver. Acetyl CoA, an essential substrate for energy production, is an end product of both glycolysis and fatty acid metabolism. The enzyme required for the oxidation of fatty acids to acetyl CoA is fatty acyl CoA oxidase.

Acetyl CoA, as a substrate in the Krebs cycle, produces NADH, NADPH and FADH2, which are reducing agents that supply hydrogen atoms or electrons in chemical reactions and are used for ATP production in the mitochondria via a process called oxidative phosphorylation. The oxidation of fatty acids also produces NADH and FADH2. Each mole of NADH produces 3 ATP’s within the confines of the mitochondria. NADH is also produced in the cytosol (outside of the mitochondria) but needs to be transported into the mitochondria in order to be converted to energy. This transport mechanism is called the “glycerol-3-phosphate shuttle” and requires the enzyme glycerol-3-phosphate dehydrogenase to catalyze the reaction. This “shuttle” requires energy and the end result is that cytosolic NADH is only able to produce 2 ATP’s per mole and the rest of the energy is released as heat. This is therefore a more “thermogenic” utilization of NADH (the reaction produces less ATP and more heat, also called “futile cycling”).

For the purpose of this discussion we will also include the reaction which converts malic acid (a Krebs cycle intermediate) to pyruvate and NADPH. This conversion occurs in the cytosol and requires an enzyme called malic enzyme. This reaction is important since it not only produces cytosolic NADPH but also produces heat.

Compounds with thermogenic activity are substances which foster the production of heat relative to the production of ATP. Very often these compounds have the ability to enhance the activity of certain enzymes which drive these thermogenic reactions. The quintessential thermogenic compound is the thyroid hormone, thyroxin (T4). Thyroxin has the ability “uncouple” oxidative phosphorylation (less ATP production and more heat production) by enhancing the activity of glycerol-3-phosphate dehydrogenase and malic enzyme.

Research by Lardy and others has shown that 7-oxo DHEA is able to enhance the activity of three thermogenic enzymes: glycerol-3-phosphate dehydrogenase, malic enzyme and fatty acyl CoA oxidase.

7-keto Mechanism

1. Fatty Acyl CoA Oxidase

The activation of fatty acyl CoA oxidase results in an enhancement of fatty acid breakdown. This reaction results in the production of acetyl CoA, NADH and FADH2. This drives the cell to utilize fatty acids for energy, which in turn promotes the breakdown of triglycerides, the body’s fat storage moiety. The acetyl CoA, NADH and FADH2 produced in this reaction are subsequently converted to ATP and heat, and at a faster rate than normally expected. The end result is an increased production of heat considering the inefficiency of the reaction.

2. Malic Enzyme

The activation of malic enzyme results in the conversion of malic acid to pyruvate and NADPH in the cytosol. This results in an excess of NADPH in the cytosol which is subsequently transported into the mitochondria where it is converted to ATP and heat. This is a thermogenic effect since more heat is produced relative to ATP production due to the cytosolic origin of the reaction.

3. Glycerol-3-phosphate dehydrogenase

The activation of glycerol-3-phosphate dehydrogenase results in an up-regulation of the glycerol-3-phosphate shuttle. This, in turn, favors the conversion of cytosolic NADH to a pathway of less ATP production and more heat production.

All three of these enzyme activations drive energy producing substrates in a direction of less efficient ATP production relative to heat production. This is the biological definition of thermogenesis. In addition, they promote the utilization of fat stores for energy and heat production. Hence 7-Keto’s ability to enhance thermogenesis and through that mechanism accelerate the utilization of fat stores for heat production.

Posted In: 7 Keto DHEA

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