am facut topicul sticky, o sa postez deasemeni pasaje esentiale pentru ca e foarte bine explicat, imo.
Chapter one on leptin……..
Ok so you have heard me talk a lot about leptin. Why is it so important? It is a hormone that controls all of energy metabolism in the body. Not only that it controls all the other hormones in the body as well. So if it is not working well you can bet that the rest of your hormones are going to show clinical problems as well. I can’t tell you how many people think they have thyroid issues when all the time they have been leptin resistant. One becomes leptin resistant when the brain no longer recognizes the leptin signal sent from our fat cells. Testing leptin is easy to do but rarely done in medicine today. The easiest way is to look in the mirror. If you’re way too fat or way too thin guess what? You are leptin resistant, most likely. Biochemically we can also assess it with a test called a reverse T3 level. This is rarely ordered because many docs don’t know about the test and because it is not covered by insurance. Reverse T3 is a competitive inhibitor to T3 and T4. Those are your thyroid hormones. So yes, leptin resistance completely turns off your thyroid gland! That does not allow you to burn fat in your muscles because it down regulates your basal metabolic rate. Now you know what controls your metabolism too! That process is called peripheral (muscle) leptin resistance. That is why some fat people can not burn fat with exercise. That is why your thyroid test are close to worthless clinically in leptin resistance. I bet many of you just had an epiphany!
The brain has to get information on the energy status on 20 trillion cells in your body at all times. Due to constraints of space ( your skull size ) it does not monitor every single cell in the body with a nerve cell connection to complete that task. It uses the endocrine system to do that. That is the system that hormones come from. Leptin is made from your white fat cells in your body. But you first get leptin from your mother when she first breast feeds you. So if you were not breast fed you may have started life off on the wrong foot from an energy metabolism stand point. In fact the latest research is showing that not getting leptin from your mothers colostrum has huge implications right away for your DNA. It effects a chemical process that alters your DNA called methylation. That information is transmitted directly to your DNA and causes a change that leads to epigenetic signals. This is one way we know obesity can be transmitted across generations. There are others.
Leptin enters the brain through some complex signaling that occurs at the hypothalamus. Once it enters the brain it begins to set off a group of neurons that will modulate your energy status for the remainder of your life. This part of your brain is about the size of pea and it sits right over your nerves that go to your eyes. Imagine a hole drilled between your eyes straight back about 5 inches. That is where all the action happens. The hypothalamus links the brain to all your endocrine system in the body. The endocrine system includes every hormone you have heard of. The hypothalamus also modulates many of the most important centers in the brain. Without energy no animal could live or carry out any complex tasks. Think about your car for a minute. How far could you go if you never knew how much gas you had? The only way to go anywhere and feel safe is if you just filled up and went. But then again you’d never know when it was time to fill up again either would you? That is precisely what happens to a human when they are leptin resistant. The brain can’t tell what the energy status is in the body. The energy status is your fat cells. Leptin is that connection from fat to the brain. It controls everything to do with energy. Without energy everything fails.
Some of the organ systems in the body that rely on energy the most are also tied to leptin status. Once such tissue is bone. Bone is incredibly active as it constantly remodels to stresses it is placed under. To allow a system that wide range of change it requires massive energy sources. That is why leptin is important in bone physiology. Leptin resistance always pre-dates the development of osteoporosis. Leptin also controls the ability of women to get pregnant. That is called fecundity. If a women is leptin resistant she will have a lot of difficulty getting pregnant. We see this in PCOS (polycystic ovarian syndrome), in anorexia, or over training. Having a baby requires a lot of energy for growth. Leptin is the key for that process to occur smoothly.
Leptin also controls and modulates the immune system in the brain too. It is chemically very similar to an inflammatory chemical called IL-6 (interleukin 6) and in people with high leptin levels (fat people) we see high levels of white blood cells. It also modulates all the inflammatory cytokines associated with visceral fat. Generally when someone is leptin resistant they also have low vitamin D levels. I also use this as a proxy to assess leptin status in working up patients. Visceral fat is the fat below your “six pack” muscle in your abdominal cavity. This is one of the worse places to get fat because it is highly inflammatory. That is also the fat seen in type two diabetics that fills their liver cells. That is called metabolic syndrome or non alcoholic fatty liver disease. Elevated leptin is also the first sign seen before high blood pressure shows up and causes a cascade of further physiologic problems. The reason for this is that high levels of leptin will destroy another protein secreted in your beta cells of your pancreas called amylin. The beta cells in the pancreas make insulin. So you now know why high levels of leptin (fat) cause type 2 diabetes. The high leptin fries the amylin in the beta cells and causes them to stop making insulin eventually. If it takes a long time it can cause type two diabetes.
If that process happens fast, for example, because of an auto immune response surrounding a pregnancy or a leaky gut then you can get an autoimmune diabetes often called type 1.5 diabetes. The only difference between type 2 and type 1.5 is the time is shorter and the immune response much greater. Again, all mediated by leptin resistance. The chronic leptin elevation leads to eventual leptin resistance and usually occurs 5-7 years before someone becomes insulin resistant! (Type 2 DM) Today’s medicine focuses in on insulin to treat diabetes. In my view this is completely off target. It makes no sense to treat insulin resistance after it has occurred. It makes more sense to target leptin resistance because it occurs 5-7 years before insulin resistance occurs!!! It is now clear that obesity is a disease of inflammation. But we know obesity has several causes. Obesity is not a disease of excess calories. Why? Because the body has several built in ways of dealing with calorie excess without you ever getting fat if leptin is working properly in your liver and your muscles.
[...] Leptin resistance always precedes the development of insulin resistance…….(minus traumatic pancreatic loss) once both occurring long enough it leads to adrenal resistance. And adrenal resistance means you have a problem with CORTISOL. Don’t forget this point…..it’s that important. WHEN INSULIN AND CORTISOL are raised simultaneously and chronically this is how cancer and chronic diseases humans occur by effecting the p53 gene (oncogenesis levee). They all start with leptin problems……not insulin.
Many people are under the assumption that the thyroid is the real key to metabolism. I can’t tell you how many meetings I have been to and heard this nonsense. It happened today while I was speaking to a dietician and nutritionist in a hospital. It’s just not correct. The liver is the engine of our body’s Ferrari! The thyroid is best described as the gas pedal for the engine and leptin is the electronic chip that controls the entire process. So we need to discuss some biochemistry now. Rub your head a few times before we start to increase your blood flow!
When humans eat a meal about 60% of the calories wind up in the liver to deliver energy to tissues between meals to sustain normal energy production. Another hormone mediates this release of fuel. (Glucagon) The remainder of the energy (40%) is sent packing to the the peripheral tissues and the muscles where insulin allows the energy to enter the cells. If those cells are leptin sensitive they use all 40% of the calories with nothing left over. If they are leptin resistant the excess calories go directly back to the liver to be placed into fat storage (or stuck inside the liver cell) in fat cells because of the high insulin levels. The more fat that gets deposited the higher leptin levels go over time. If the fat gets stuck in the liver it causes a large immune reaction driving up more inflammatory chemicals. When it gets to a critical level (different body fat levels for all people) the fat begins to make the bad stuff. (IL6 and TNF alpha)
At the liver level something new happens though. Because muscles (muscle leptin resistance) can no longer use the calories partitioned to them they return to the liver. Leptin resistance at the liver also down regulates the LDL receptor in the liver. This allows the LDL particle to stay in the blood longer making it more susceptible to oxidation and disease. The liver responds by packaging this fuel into LDL particles to get rid of it. If the meal is high in carbs it makes small dense LDL. (SdLDL) If the calories are high in fat or protein the LDL is intermediate or large fluffy LDL.(ILDL or VLDL) SdLDL is the particle that causes many chronic diseases when it is present in excess chronically. It correlates best with heart disease and stroke risk. This is the most important thing to take away from a lipid panel. You want this number as close to zero as possible. sdLDL also causes high blood pressure and atherosclerosis because it damages the vascular endothelium (lining of artery) and the LDL particle is small and dense so it fits between the endothelial cells and deposited in the arterial wall to make it a lead pipe. Before it gets into the artery wall it usually becomes oxidized (rusted) because it is chemically very sensitive to chemicals that cause oxidation. (IL6, TNF alpha, and ROS are some of these) The large fluffy VLDL are not a problem because they can not fit in vessel walls so most go to our fat under the control of LPL and hormone sensitive lipase. (Estrogen and testosterone levels determine where on the body this fat goes and stays!) This is the real reason why andropause and menopause cause weight gain in specific parts of your body as you age. Your sex steroid status varies with the amount of inflammation present at the cellular level. Understand that the inflammatory chemicals from the fat are what cause this to happen over time.
Having your liver make a ton of SdLDL is a huge problem for health. Eating carbs results in high sdLDL and not fat or protein. Fructose is a special carb that makes more sdLDL than another sugar we have because of how the liver has to handle it biochemically. The large amounts of these particles causes the liver to make a ton of triglyceride particles to store all the sdLDL’s for storage in the bad places like are arteries, viscera, heart or liver. KEY POINT: Hepatic insulin resistance occurs when the liver decides all excess calories must be packaged and stored as fat which fuels the obesity. OK, reference point. When the liver is working well and not leptin resistant what does it do? Remember the 60/40 split of calories from a meal we spoke of earlier? The liver should use the stored 60% of those calories to feed the body fuel when we are not eating like during a fast or during sleep. This is done by raising the hormone glucagon to make fuel from the energy depots in the liver. This is how the body works to supply fuel it needs when we can’t eat or won’t eat. The liver is a fuel bank account for use in a rainy day when we are leptin sensitive. This pathway way does not work well at all when we are leptin resistant because the liver is spewing out excess fuel for storage instead of use.
When we are leptin resistant the end result is to package calories to fat in some form of LDL’s. That delivery has to leave the liver because there is a physical limit to how much fat can stay in the liver. If this process of LDL construction is chronic and overwhelms the liver, fat builds up inside the liver cell and causes extreme reactive oxygen species (ROS). Remember THE QUILT’s levee number seven? These are the inflammatory chemicals that insidiously kill cells and are at the heart of all chronic diseases you know of. This process is called development of fatty liver or the Metabolic Syndrome. If the liver continues to be clogged with fat it physically grows and your waist size grows with it. This is why physicians are so concerned about your waist size. It also correlates with your blood test called an ultra sensitive CRP! As your waist grows your cardiac CRP goes higher too. But if you are paying attention to the 30,000 foot view here, the growth of your waist size is a very late development in your disease process. If your waist is large, you have been asking your liver work like mad to store this excess fuel for a long time. The end result for the patient is a sign of feeling of chronic fatigue. You also report a loss of energy if you are asked and it occurs slowly over time and nothing the doctor or you do seem to help. All your basal metabolic studies look fine. Your thyroid panel is unremarkable and you tell the doctor no matter how little you eat or as much as you exercise nothing seems to help the process. Does this sound familiar to anyone reading this? This is classic LEPTIN RESISTANCE AT THE LIVER LEVEL!
[...] When leptin was discovered in 1994 no one really had a clue as to its many functions. One of those functions that was particularly murky was how did the brain control peripheral energy utilization and optimize it. It is awfully hard to realize that the hypothalamus (size of a pea) can control 20 trillion cells in the human body need for fuel. Well, in the last few years scientists found out about uncoupling proteins. (UCP) So far five have been discovered in mammals. The one we will discuss today is UCP3. This protein allows leptin to work inside of peripheral cells like the muscle cell. For UCP3 to work optimally, it requires optimal functioning of leptin and thyroid hormone simultaneously. In muscle cells, UCP3 is the dominant UCP in humans. So it is vital to exercise and energy use to maximize efficiency. What UCP3 allows the muscle to do is shift out of regular oxidative energy production done at the mitochondria and making energy in the form of ATP and into making pure heat without generating ATP. This biochemical action decreases ROS (levee 3) at the mitochondrial level, decreasing cellular stress and the energy is dissipated as mostly heat. UCP1 is dedicated to doing this same action when it is activated 100% of the time.
UCP3 functions in this manner as an alternative pathway to deal with excess energy (calories). [...] calories do not matter when you are leptin sensitive. They matter big time to folks who are leptin resistant because they cannot utilize this pathway at all. This is the primary pathway that fat burning occurs peripherally in the human body. If it is not working well or at all the excess calories are sent packing to visceral stores or to organ depots that generate their own set of problems when it occurs chronically.
Let us think about what this means for the muscle cell. If you are Anthony Colpo or Robb Wolf, you can burn whatever fuel you see because your UCP3 is optimal. The fuel source is immaterial, even if the source is high in carbs or high in fats. But lets say you’re Oprah, and you cannot do this, then the muscle cell has to make a choice. Since her UCP3 is not optimal when fuel is delivered to the muscle it cannot be used quickly and builds up. The cell tries to activate UCP3 to dissipate the excess but it requires leptin sensitivity and good T3 and T4 function. We know looking at Oprah she is not optimal. (the mirror test) With exercise Oprah tires quickly and her muscles fatigue faster than Robb’s. WHY? She cannot utilize the fuel. So the excess is sent off to depots, while her muscles are still energy starved, send a signal via the gut to eat more to give the cells fuel. That is precisely what she does over and over again. The problem is the muscles never get the correct amount of fuel in them to meet demands.
Chronically this excess energy is stored in her fat and no matter how much she works out; she finds it difficult to lose the weight she wants. Sound familiar yet? The cure for her is to stop listening to Dr Oz crazy diet recommendations instead focus in on regaining her leptin sensitivity to make the muscles burn more efficiently.
When her muscles see excess calories consistently, it clogs them with ALE’s from fat and AGE’s from sugars. These are two more levees in THE QUILT. Think about what maple syrup looks like if you left it on your counter top for weeks! It becomes concrete like. That is precisely what happens to a muscles in a type two diabetic chronically because UCP3 is shot. Moreover, the longer it goes on the worse it gets. That condition then begins to effect the nerves that go to the muscles that innervate them and cause pain and sensory dysfunction. This is how fibromyalgia and peripheral neuropathy develops. It begins with a defect in energy metabolism at the muscle level due to peripheral leptin resistance.
So when you think about exercise and performance (Cross fit/Wolf/Colpo) folks one must understand about the CONTEXT your muscles are in when you begin to optimize yourself. This contextual problem is why we have so many competing ideas of how we should advocate exercise for all people. Exercise for Robb or Anthony do not equate with Oprah because their biochemistries are not similar. Here is the best part. Oprah can become equal to them if she has somebody explain this to her. Dr Oz certainly has not for over decade! Her goal is to focus on becoming leptin sensitive by being required by eating 50 grams of protein at breakfast everyday within 30 minutes of rising, eliminating all snacking especially past 730 PM, eating three meals a day, and limiting her carb intake below fifty grams per day for about 6-8 weeks. In my practice, over the last 5 years that is about the bell curve I have seen for most patients to require their regain their signaling back. I check leptin sensitivity by asking a few questions or by ordering a reverse T3 level.
Here are my questions for assessing a patients leptin status…….. Do you notice you sweat more and have less muscle fatigue when you do exercise now? Have your carb cravings gone away? Is your hunger under control now? And are you waking up more refreshed? When these questions are all yes then I push the button and tell them to start exercising more with intensity and duration first using weights and never using aerobics. The reason for weight lifting first is it is generates less ROS in the muscle at the mitochondrial level and more importantly stimulates the release of growth hormone to fire up muscle activity via the neuro endocrine system. It also more quickly reestablishes leptin sensitivity of the furnaces that our muscles contain to burn the fat we want to get rid of. As they improve, more weight comes off and the exercise plan increases. So far this plan has not failed me because it is not based upon my opinion; it is based upon our biochemistry that is 2 million years old! Most of my neurosurgical patients get this treatment before I will operate on them because outcomes are better when the patient is fit metabolically for recovery. If you are a patient who is leptin resistant, and work too hard too quick exercising as you drop weight, the risk is generating too much ROS and depleting their stem cell supply. The short term effect will be weight loss and a good result but the long term effect may be faster aging and decrease longevity!
[source: http://jackkruse.com/why-is-oprah-still ... in-part-3/
I have been asked by many to put a short post out about how I reverse leptin resistance in my own clinic for my patients. [...]
1. First make sure you really are leptin resistant to begin with
The easiest way to do so if your heavy is to look in the mirror. If your overweight you definitely are leptin resistant. If you still have a large appetite and crave carbohydrates especially at night these are also signs that you likely are LR. If you are fit or in decent shape and not sure based upon the above symptoms I would tell you to go get a blood test and check your reverse T3. It will be elevated. I also recommend simultaneously checking a salivary cortisol level. With LR will always see higher cortisol levels later in the day.
2. To regain LS follow a strict paleolithic diet as outlined in The Paleo Solution or the Primal Blueprint.
The type of fuel is important in eliminating the foods that cause leptin receptors to become non functional. These two books clearly outline a solid reference point to achieve this.
A. Try to eat as soon as possible upon rising in the AM. Make sure that breakfast has little to no carbs and has a lot of protein and fat. I use as a general rule 50-75 grams of protein with most patients. Some patients can use less and some need more. The key point of knowing how much for you is your hunger later in the day. If you remain ravenous you need to eat more protein in the AM. If you can hold off eating until dinner you probably are at homeostasis for you. If you can skip both meals your likely are overdoing it at breakfast. As for sources I suggest pastured or organic eggs first [...]
B. Try to limit carb intake to 25 grams if your are overweight but greater than 30 lbs. If you are fit and have a small amount of weight to loss (less than 30 lbs) you can titrate up your carb loads. Even then I do not advocate potatoes or rice as some paleo diets allow for. You will be able to eat them eventually but try to avoid starches until you have mastered your cravings and hunger. Do not count calories. It is not needed at this point. Any time I eat carbs I use liberal amounts of butter, heavy cream, coconut or palm oil. I do not recommend other oils initially like olive oils or industrial seed oils. I would also avoid nut oils at the initial stages. My personal favorite is coconut oil because of the great metabolic effects of MCT and how it helps heal the guts of LR folks.
3. How you eat that fuel is MORE IMPORTANT than any other factor including the food itself.
A. Never snack at all. This is meant initially and forever. Snacking completely stresses the liver’s metabolism and is just not recommended. Your liver needs to relearn how to use gluconeogenesis normally again when you sleep and awake. Snacking just destroys timing and circadian clocks that work in unison with leptin.
B. Try to eat three meals a day initially but as your hunger and cravings fade you can adapt to two a day.
C. Try to eat breakfast as early as possible from rising.
D. Do not work out before or after breakfast.
E. Try to allow 4-5 hours between dinner and sleep time
F. If you decide to incorporate working out do it after 5 PM.
G. Within an hour of sunset try to make your surroundings as dark as possible.
H. If you have trouble falling asleep I suggest 3-5 minutes of of body weight exercises right before bed (push ups or air squats are fine) (avoid this if your PM cortisol are high)
I. If your inclined too try becoming mindful when you first lay down. I use transcendental meditation techniques to help me clear my mind and concentrate on improving my thinking. (Optional but is awesome if your PM cortisol are high)
4. Most people will notice a change in their cravings and hunger within 4-6 weeks. Other changes I as of my patients is to supplement prescription grade fish oils. The dose depends upon their HS CRP and salivary cortisol levels.
5. Signs that you are becoming leptin Sensitive (LS) again……men will notice quick weight loss. Women will notice mood changes first (calmer/sleepy) and their sleep will improve. Their clothes will fit differently but weight may not change drastically initially because of effects on the pituitary. This will change too if they continue moving forward. You will notice a change in your sweating pattern. You will also notice you have better recovery from exercise and your energy levels seem to have risen. Your hunger is gone and so are your cravings. And when you awaken you will feel very refreshed like you slept well. Generally when the signs are all present I then really push HIIT exercise with heavy weights.
1. Body temperature is controlled by the hypothalamus in the brain ……and it also controls leptin status and sensitivity centrally via the hypocretin neurons (HCN). The HCN also help modulate our sleep by keeping the stages in order and working optimally.
2. So you ever wonder why we “like” to wear blankets when we sleep? Well, the reason is simple. Melatonin is made from our brain’s pineal gland from stored serotonin after four continuous hours of total darkness (the reason you need to avoid light after sunset). One of melatonin’s functions during sleep is to lower our body temperature. Why do you guess the brain would want to do this when we sleep you ask?
3. After the 4 hours of darkness, melatonin secretion increases and this allows plasma leptin to enter the hypothalamus if we are sensitive to its receptor. If we are resistant this process can no longer occur. Once leptin enters and binds to its receptors, it effects the lateral hypothalamic tracts to immediately send a second messenger signal to the thyroid to signal it to upregulate thyroid function and efficiency. This specifically is how we can raise our basal metabolic rate when we are leptin sensitive. These coupled events, matched with leptin’s actions peripherally in muscles, occur at the UCP3 sites……to burn fat as we sleep at a higher basal metabolic rate. This means electron chain transport does not make ATP as usual. When leptin allows this uncoupling to occur we make heat and not energy from normal metabolism. This means we will burn off our excess calories as pure heat. This is one reason why calories in and calories out argument makes no biologic sense once you understand how leptin works. Humans are built to burn fat at night as we sleep to loose excess weight we don’t need. The timing of the leptin action is also critical. It usually occurs between 12-2 AM and is tied to when you last ate and how much darkness your eyes have seen. This generally occurs soon after our hypothalamus releases another hormone called prolactin from our pituitary gland in the brain. The prolactin surge does not happen if the patient has sleep apnea or ate some carbs to close to bedtime. If you eat any carbs and protein within 4 hours of sleep you will never see the prolactin surge because any spike in insulin turns off this critical release. Ok you must be asking why is this prolactin hormone so important? Is not prolactin just a hormone to secrete human milk doc? That is not the only action of prolactin. Immediately after prolactin is released at this time, another signal is sent to the anterior pituitary to release Growth Hormone (GH). GH is stimulated only during autophagic sleep cycles in stage 3 and 4…..to increase protein synthesis for muscle growth……all while your disapating heat. This is the major release of GH in humans post puberty. The implications here are huge. If you are LR and have sleep apnea you will have an altered body composition because of a low GH level. It means as you age you have higher body fat and lower muscle mass. This is precisely what we see in humans as they age and invariably their sleep is also poor.
The reduced temperature induced by melatonin in sleep is needed for Central Nervous System autophagic repair for another less well known reason. The lowered temperature sets the stage for the biologic quantum effects to be optimal on neuron microtubules that facilitate learning and neuronal spouting that occur brain wide. This is why if you don’t sleep well you feel badly and your performance suffers the next few days on tasks. Research also shows your learning is severely impaired. This is why we monitor truck drivers and airline pilots sleep and wake cycles by law! Moreover, in hospitalized patients or the elderly when this occurs, it sets the stage for the appearance of acute onset delirium. We see this often in hospitilized patients who can not sleep well in ICU’s. Acute delirium states very much look the same as chronic sleep deprivation patients we see clinically as well.
4. Simultaneously, while sleep is rebuilding our cellular terroir (think levee one), the immune system is also undergoing autophagic repair……that is another reason why the temperature has to fall. Usually, temperature rises causes immune function to increase in response and duration in fever, stress and infections. This turning on depletes our immune system of its reserves. Dropping our temperature as we sleep allows us to repair it. During sleep this is when the body re tools our immunity to function optimally the next day. What controls this entire orchestra of hormonal regulation? Its all leptin mediated……..and the brain is the master receptive organ to its function.