Mastering Nutrition

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....

Since gluconeogenesis is extremely expensive, it has to be tightly regulated so that it only occurs when both of two conditions are met: 1) the liver has enough energy to invest a portion into synthesizing glucose, and 2) the rest of the body is in need of that glucose. Since the liver is the metabolic hub of the body that also plays a major role in anabolic synthesis and nitrogen disposal, it als...

Gluconeogenesis is extremely expensive. Three steps of glycolysis are so energetically favorable that they are irreversible. Getting around them requires four gluconeogenesis-specific enzymes and the investment of a much larger amount of energy. Overall, six ATP worth of energy are invested to yield glucose, a molecule that only yields 2 ATP when broken down in glycolysis. This lesson covers the d...

Insulin is commonly seen as a response to blood glucose whose primary role is to keep blood glucose within a narrow range. This view of insulin fails to account for its many roles outside of energy metabolism that govern long-term investments in health. The biochemistry and physiology of insulin secretion suggest, rather, that insulin is a gauge of short-term energy status and energetic versatilit...

The pentose phosphate pathway provides a deep look into a stunning array of essential roles for glucose. In it, glucose becomes the source of NADPH, used for antioxidant defense, detoxification, recycling of nutrients like vitamin K and folate, and the anabolic synthesis of fatty acids, cholesterol, neurotransmitters, and nucleotides. At the same time, glucose also becomes the source of 5-carbon s...

In August of this year, 25-year-old bodybuilding mom Meegan Hefford was found unconscious in her apartment, brought to the hospital where she was declared brain-dead, and died soon after. The cause? "Too much protein before competition," according to the New York Post. She had recently doubled her gym routine, started dieting, and begun slamming protein shakes in preparation for an upcoming bodybu...

Although insulin promotes storage of fat in adipose tissue, this occurs in the context of multiple layers of regulation where energy balance is the final determinant of how much fat we store. In a caloric deficit, the low energy status of muscle and heart will lead them to take up fat rather than adipose tissue, even in the presence of insulin. Insulin combined with low energy status will promote...

Insulin prevents fat-burning in part by locking fat in adipose tissue and in part by shutting down transport of fatty acids into the mitochondrion inside cells. By downregulating lipoprotein lipase (LPL) at heart and skeletal muscle and upregulating it at adipose tissue, insulin shifts dietary fat away from heart and muscle and toward adipose tissue. By downregulating hormone-sensitive lipase in a...

Most people interested in health and nutrition know that insulin clears glucose from the blood into cells, but it is much less widely appreciated that insulin also makes you burn that glucose for energy. Insulin stimulates the translocation of GLUT4 to the membrane of skeletal muscle, heart, and adipose cells, and activates hexokinase 2. GLUT 4 increases the rate of glucose transport across the ce...

Insulin secretion. Remarkably, we know from dietary studies that we get the most insulin from eating carbohydrate, yet we know from molecular and cellular studies that insulin secretion is primarily triggered by the ratio of ATP to ADP inside the pancreatic beta-cell. The former implies that insulin is a response to glucose, while the latter implies that insulin is a response to total energy avail...

This lesson covers the regulation of beta-oxidation. The primary regulation of beta-oxidation occurs at the mitochondrial membrane, where fatty acids are transported into the mitochondrion. Acetyl CoA carboxylase governs both the formation of fatty acids from non-carbohydrate precursors and the transport of fatty acids into the mitochondrion. Its product, malonyl CoA, is a substrate for fatty acid...

This lesson covers the regulation of glycolysis. The principle regulation occurs at phosphofructokinase, which guards the gate to the first irreversible, committed step to burn glucose for energy. What governs it? Energy. If you need more ATP, you burn more glucose; if you don't, you don't. If the cell has glucose beyond its needs for energy, it uses it for the pentose phosphate pathway, which all...

In this lesson, we examine the beta-oxidation in its simplest form: the breakdown of a long-chain, saturated fatty acid. We see once again the principle that the oxygen content of a molecule determines how much water its metabolism consumes and how much carbon dioxide its metabolism releases. In beta-oxidation, we consume one water per round and release no carbon dioxide. This reflects the fact th...

In this lesson, we examine the entire glycolytic pathway. We use as our theme the transfer of oxygen from phosphate to newly generated water. This explains why the standard stoichiometry of glycolysis found in textbooks show it generating two water molecules, and ties the information together with the analogous principles from substrate-level phosphorylation in the citric acid cycle and the relati...

Can fat fuel intensity in a competitive athlete? This lesson takes a critical look at the commonly cited evidence in favor of a neutral or beneficial effect of low-carbohydrate or ketogenic diets on sports performance, as well as key pieces of conflicting evidence. Bottom line? Fat can fuel duration, but probably can never fuel your peak intensity, just as the physiology would predict. For the ful...

Can athletes fat-adapt their workouts? This lesson lays down the principles of exercise biochemistry and physiology needed to understand the importance of the three energy systems supporting energy metabolism in skeletal muscle: the phosphagen system (ATP and creatine), anaerobic glycolysis (dependent on carbs), and oxidative phosphorylation (dependent on carbs, fat, or protein). We discuss why ma...

"Anaplerosis" means "to fill up" and refers to substrates and reactions that fill up a metabolic pathway as its own substrates leak out for other purposes. The citric acid cycle is a central example of this because its intermediates are often used to synthesize other components the cell needs. On a mixed diet where carbohydrate provides much of the energy, pyruvate serves as the main anaplerotic s...

One of the advantages of carbohydrate over fat is the ability to support the production of lactate. This is so important that carbohydrate is physiologically essential to red blood cells and certain brain cells known as astrocytes. For the same reason, it plays an important role in supporting the energy requirements of the lens and cornea, kidney medulla, and testes, and supports the quick boosts...

Did you realize that thiamin deficiency can be caused by your environment? In the old days, beriberi was associated with the consumption of white rice. Nowadays, refined foods are an unlikely cause of thiamin deficiency because they are fortified. We associate deficiency syndromes such as Wernicke's encephalopathy and Korsakoff's psychosis primarily with chronic alcoholism. Yet there are regional...

The pyruvate dehydrogenase complex catalyzes the one decarboxylation step that carbohydrate undergoes to generate acetyl CoA, which accounts for the one carbon dioxide molecule produced in carbohydrate metabolism that is not produced during the metabolism of fat. It also accounts for why burning carbs requires twice as much thiamin as fat. In fact, the pyruvate dehydrogenase complex is remarkably...

Since carbs are richer in oxygen than fat, they consume less water in their metabolism and release more carbon dioxide. Carbon dioxide puts stress on the lungs and its generation should be restricted in the case of lung injury to allow healing. This calls for a low-carbohydrate, high-fat diet. On the other hand, carbon dioxide is needed to support the action of vitamin K and biotin, and to promote...

Now we take it clinical: how do we use what we've learned so far to interpret the section of a urinary organic acids test that reports the citric acid cycle metabolites? We begin by looking at the underlying chemistry to explain the curious absence of oxaloacetate on these tests. We conclude by mastering the ability to spot three unique patterns: energy overload, oxidative stress, and thiamin defi...

This lesson looks at the fundamental principle that atomic oxygen is the limiting factor for the release of carbon dioxide in metabolism, and when we don't have enough we take it from water. This will become very relevant when we cover fats versus carbohydrates, because they consume different amounts of water and release different amounts of carbon dioxide for this very reason. That, in turn, rela...

This lesson addresses the curious case of why  CoA  makes a brief cameo in the citric acid cycle during the formation of succinyl  CoA  only to leave again in the next step. We dig into the chemistry underlying the high-energy thioester bond that  CoA  forms with acyl groups, which explains more broadly one of the key roles of sulfur in energy metabolism. We conclude by looking at how the appearan...

This complex is  so rich  in biochemical concepts and relevance to health and disease. Having done the dirty work of looking at its organic chemistry mechanisms in the last lesson, here we explore broadly applicable biochemistry principles like energetic coupling and substrate channeling. We look at how thiamin deficiency, oxidative stress, arsenic, and heavy metal poisoning can affect metabolism,...