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 makin...
Oct 09, 2017•10 min
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 also regulates glycolysis and gluconeogenesis according to whether amino acids are available to supply ...
Oct 08, 2017•14 min
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 details of the reactions as well as the rationale for investing so much energy. One of the most perva...
Oct 07, 2017•10 min
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 versatility. Since glucose can only be stored in small amounts and since it is the most versatile of the macro...
Oct 06, 2017•8 min
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 sugars, used structurally in DNA, RNA, and energy carriers like ATP, coenzyme A, NADH, NADPH, and FAD...
Oct 05, 2017•11 min
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 bodybuilding competition. No one knew she had a rare genetic disorder that would make the breakdown of pro...
Oct 04, 2017•1 hr 7 min
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 the uptake of glucose in skeletal muscle over adipose tissue and will promote the oxidation of gluco...
Oct 04, 2017•12 min
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 adipose tissue, it prevents the release of free fatty acids from adipose tissue into the blood. At th...
Oct 03, 2017•8 min
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 cell membrane and hexokinase 2 locks the glucose into the cell, making sure that glucose travels inwar...
Oct 02, 2017•6 min
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 availability. What can explain this discrepancy? In this lesson, we explore the possibility that it is th...
Oct 01, 2017•13 min
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 synthesis in the cytosol but a regulator of fatty acid transport in the mitochondrion. Thus, there ...
Sep 30, 2017•9 min
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 allows the production of 5-carbon sugars and antioxidant defense if needed, or stores it as glycogen if...
Sep 29, 2017•12 min
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 that fatty acids are not hydrates of carbons like sugars are, which is where the name carbo hydrate co...
Sep 27, 2017•10 min
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 relative differences in water consumption and carbon dioxide generation between fat and carbohydrate. As w...
Sep 27, 2017•15 min
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 full episode, go to chrismasterjohnphd.com/mwm/2/18 Sign up for MWM Pro for early access to content, en...
Sep 26, 2017•12 min
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 maximal intensity always depends on carbs if the intensity and duration are sufficient to deplete phos...
Sep 25, 2017•12 min
"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 substrate. During carbohydrate restriction, protein takes over. Fat is the least anaplerotic of the m...
Sep 18, 2017•10 min
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 of peak energy needed during stressful situations that include high-intensity exercise. The biochemi...
Sep 12, 2017•12 min
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 outbreaks of thiamin deficiency among wildlife attributed to poorly characterized thiamin antagonist...
Sep 10, 2017•10 min
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 analogous to the alpha-ketoglutarate dehydrogenase complex, sharing all the same cofactors and catal...
Sep 09, 2017•10 min
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 delivery of oxygen to tissues during exercise. In our first glimpse into glycolysis and beta-oxidat...
Sep 07, 2017•9 min
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 deficiency. For the full lesson go to chrismasterjohnphd.com/mwm/2/11 Sign up for MWM Pro for early acce...
Sep 06, 2017•11 min
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, relates to a number of health endpoints such as the functions of vitamin K and biotin, delivery of oxyge...
Sep 05, 2017•12 min
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 appearance of CoA allows us to harness energy released during the decarboxylation of alpha-ketoglutarate to form A...
Sep 04, 2017•9 min
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, and how to recognize markers of these processes in blood or urine. We make the subtle yet critical di...
Sep 03, 2017•10 min
The alpha-ketoglutarate dehydrogenase complex is marvelously complex and incredibly rich in details that are relevant to the big picture of metabolism and to many issues of health and disease. Today, we break down what actually happens so that we can spend all of Wednesday's lesson discussing the rich array of relevant principles it brings to light. For the full video, go to chrismasterjohnphd.com/mwm/2/7 Sign up for MWM Pro for early access to content, enhanced keyword searching, self-pacing to...
Sep 02, 2017•8 min
Are you interested in working with me one-on-one so I can help you better meet your health goals? Good news! I'm now accepting new clients for both hourly consultations and health and wellness packages . Here are the core things I'm best at that I would love to do for you: Help you develop actionable priorities and an overall strategy for improving your health. Discuss your experiences with you and suggest useful tests that you could ask your doctor about. Analyze the results of genetic tests, d...
Sep 01, 2017•7 min
If you develop dry skin on a low-fat diet, especially if you're eating egg whites and throwing out the yolks, it could be a biotin deficiency. Or, it could be an essential fatty acid deficiency. Either way, egg yolks and liver come to the rescue. To get these episodes free of ads, with transcripts, and weeks or sometimes even months before they are released to the public, along with access to monthly live Q&A sessions, sign up for the CMJ Masterpass at https://chrismasterjohnphd.com/masterpa...
Sep 01, 2017•4 min
This lesson looks at the third step of the citric acid cycle in much more detail, digging into the organic chemistry concepts involved in the conversion of isocitrate to α-ketoglutarate. We dive deep into this because it's the only way to explain why this step parts ways with most other decarboxylation reactions in that it does not require thiamin (vitamin B1). This, in turn, provides a basis for understanding why burning carbohydrate for fuel requires twice as much thiamin than burning fat, and...
Aug 31, 2017•11 min
Do you get dry skin when you put on muscle mass? It could be a zinc deficiency. Here's how to take care of it. To get these episodes free of ads, with transcripts, and weeks or sometimes even months before they are released to the public, along with access to monthly live Q&A sessions, sign up for the CMJ Masterpass at https://chrismasterjohnphd.com/masterpass . Use the code LITE10 to get 10% off. To make it easier to get the discount, use this link, which has the coupon already activated: h...
Aug 30, 2017•4 min
