Lyle McDonald - The Stubborn Fat Solution Patch 1.1

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The Stubborn Fat Solution Patch 1.1

A Pharmacological Approach to Manipulating Atrial Natriuretic

Peptide for Ultimate Fat Loss

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This book is not intended for the treatment or prevention of disease, nor as a substitute for medical treatment, nor as an alternative to medical advice. It is a review of scientific evidence presented for information purposes only. Use of the guidelines herein is at the sole choice and risk of the reader.

Copyright: First Edition © 2015 All Rights Reserved

This book or any part thereof, may not be reproduced or recorded in any form without permission in writing from the publisher, except for brief quotations embodied in critical articles or reviews.

For information contact: Lyle McDonald Publishing 1200 Hatteras Drive Austin, Tx 78753

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Table of Contents|

Foreword

Introduction

Chapter 1: Fat Cell Physiology

Chapter 2: Natriuretic Peptides and Lipolysis

Chapter 3: Natriuretic Peptides and Brown/Beige Fat

Chapter 4: Natriuretic Peptides and Appetite/Hunger

Chapter 5: Beta-Blockers for Fat Loss

Chapter 6: Beta-blocker Effects Chapter

7: Putting it All Together

Selected References

My Other Books

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Foreword

As everyone was taught in high school, history has a tendency to repeat itself. My writing career certainly seems to work this way. Way back in 1996, I finished my first book, a tediouslytechnical book called The Ketogenic Diet that

was

THE comprehensive be-all, end-all book on low-carbohydrate diets. While many people raved about it, I was never really happy with it. That's not relevant but what few know is that finishing that book nearly killed me, it was not the right project to start my career and it was a nightmare at the end to actually complete.

Over the next two years, I would attempt to start new projects but anxiety over the nightmare that was finishing the first book would stop me in my tracks. I'd get 75% of the way through the new project and start to have issues and go start something else. I have folders of partially finished stuff from that time period.

Finally, in 1998, I published an odd little booklet called Bromocriptine: A New Use for an Old Drug. Probably my least well-known and least successful project, it was a weird little drug booklet that mostly dealt with the topic of body weight regulation; it just turned out that this 30 year old drug seemed to fix a certain problem that I had been working on. But given that I'm known for training and nutrition, a drug solution to anything just wasn't really consistent with 99% of what I wrote about.

Time passed and I wrote more books but, apparently at the 10 year mark it was time for my next nightmare project. Around 2006, I was working on another monstrously tedious technical book called The Protein Book. It was THE comprehensive be-all, end-all book on the topic of dietary protein for athletes. As with The Ketogenic Diet, it was a horror to finish, months of writers block and a complete inability to complete the damn thing were just another horrible chapter in my writing career; finally, I finished it.

In 2008, I published The Stubborn Fat Solution. And going by my rough history, I should have started my next little drug

booklet shortly thereafter. And I actually did. But, as I'll talk about in the introduction below, I sort of abandoned it for a while (about 6 years) only coming back to it as part of research for another recent project. No, it is not the Super Secret Project (TM) I've been talking about for about the same amount of time. As the title suggests, it sort of follows up on The Stubborn Fat Solution and a topic that I discussed but couldn't elaborate on at the time.

This is another weird little side project for me, another drug booklet that is really outside of what I usually write about. But it's just so damn cool. Enjoy.

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Introduction

If you're at all interested in the topic of fat loss (and outside of that small percentage who stay perpetually lean without much effort, everyone is), odds are you've read my other books on the topic. In all likelihood, this includes my last book

The Stubborn Fat Solution (or SFS as it's usually abbreviated).

The SFS was the culmination of a decade long project examining the topic of stubborn body fat loss. Men's abs and low back and especially women's thighs are more stubborn than other areas to get rid of. There are a myriad number of reasons for this and, as is my way, I covered all of them in SFS. I spent chapters detailing everything there is to know about body fat including what makes certain fat cells more stubborn than others to empty and get rid of.

Of course, I provided solutions in the form of the SFS protocols, 4 different targeted protocols that can be integrated with other diets to get rid of stubborn body fat. Some specific supplements were mentioned as well. Although I didn't talk about specific diets, I did discuss how the protocols would best fit with certain types of diets (e.g. low- vs. high- carbohydrate). In that book, I had a chapter discussing the impact of hormones on body fat and such and in that chapter, almost as an afterthought, I mentioned a relatively 'new' fat mobilizing hormone called Atrial Natriuretic Peptide (ANP) that might have promise in terms of fixing the stubborn fat problem in a bit less effort intensive way than than the SFS protocols.

At the time I had some of the data on what ANP did and it certainly looked promising; I'll discuss that in a later chapter. But there was no meaningful way to manipulate it that I had come across. The only things I was aware of just wasn't terribly applicable. It was interesting but ultimately a dead end.

But, as is so often the case, a few months later I came across some fascinating research, a pharmaceutical way of

manipulating ANP in a useful fashion. Yes, a drug. I guess I could have revised SFS with that new information but, frankly, it tends to be a losing battle.

Not only do I kind of not like to revisit projects (I'd rather learn about/write about something new), drug discussion is polarizing. The people who are interested in such topics (either intellectually or practically) are generally far overwhelmed by the people for whom drug discussion turns them away. Whether it's the general public (who are often selectively anti- drug) or athletes who compete drug-free, it's just often a problem.

In my experience, when you talk about drugs in a non-drug oriented book, you tend to lose a lot of readers; this is just reality. The guys willing to use any and all drugs aren't happy because there isn't more drug information and the anti-drug people aren't interested at all. By trying to be all things to all people, you end up making everybody unhappy. So even if I had been aware of what this book talks about, I wouldn't have included it in SFS.

Admittedly, what I'm going to talk about in this book really isn't anything that problematic from a legality standpoint. You will need to combine it with some other compounds but with the exception of a couple, they are all either mostly legal (depending on where you live) or at least in that gray-market area.

Now, I originally started this book when I found the original research, probably in 2009. Then for reasons I am not entirely clear on, I got distracted. I don't know if I lost interest or had more problems to solve but I just put it away, partially written. But then, in 2015, I started researching a new book project. And in doing so came across more literature relating to Atrial Natriuretic Peptide. Exciting literature that simply did not exist when I started the project in 2009 or whenever I gave up. So here was a place where my disorganization and probably laziness benefitted me. Basically I'm glad that I didn't finish this back when I did.

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Chapter 1: Fat Cell Physiology

Ah the fat cell. Originally thought to be nothing more than an inert storage depot for excess energy, we now know that it is highly active, contributing immensely to overall human physiology. With dozens and dozens of chemicals that it produces (such as leptin and adiponectin), it is truly an enormous player in the human body. You'll have to forgive me for waxing a bit poetic, I've written a lot about the fat cell and have to keep myself interested.

But the interesting physiology of the fat cell doesn't change the fact that it's kind of a pain in the ass. Whether for lean dieters trying to get very lean or even the obese carrying too much of it, finding ways to get rid of (ideally permanently) fat has been a goal for years.

Liposuction has been around for a while but does some weird things. A new approach called Cryo-Lipolysis looks

promising, it may actually cause fat cells to die (with the application of extreme cold). Both tend to be limited in how much fat they can realistically remove anyhow. And while I'm not suggesting that this book will allow one to get rid of fat cells forever (I gave up on the fat cell apoptosis/death project years ago) it does represent an entirely new way of stripping fat off the body. Yes, new. But to understand why this is new, I have to look at what has been thought up until this point and look at the basics of fat cell metabolism, with a focus on fat mobilization.

The Basics of the Fat Cell

Fat cell number varies enormously in humans as does their size. Big and small fat cells actually turn out to have somewhat different physiologies (it's harder to get fat out of the small ones) and people with more but smaller fat cells are at a disadvantage in terms of fat loss. Of course even bigger fat cells shrink on a diet which is part of why getting rid of the last of them becomes more problematic (trust me there are a LOT more reasons than just this).

The primary component fat cells is lipid, also called triglyceride (TG). This is the combination of three fatty acid chains bound to a glycerol backbone ("tri" means three and "glyceride" refers to the glycerol). Fatty acids chains vary in structure in both their length (short, medium, long) and saturation (just accept that this is an organic chemistry thing).

When people talk about saturated, monounsaturated and polyunsaturated fats, they are really talking about the structure of the fatty acid chains. There are actually some differences in how readily the different types of fat are stored or mobilized. Saturated fats and longer chains are harder to get out of fat cells, for example (trivia: stubborn fat tends to store more saturated fats, another reason they are stubborn).

Somewhere between 85-90% of a fat cell is composed of TG. One pound of fat is 454 grams, if 85-90% of that is TG that's roughly 400 grams of fat or so. When burned each gram of fat provides 9 calories of energy and that's 3600 calories. That's where that old value of 3,500 calories to lose one pound of fat comes from. It doesn't work quite that cleanly for reasons I won't discuss here.

The other 10-15% of the fat cell is water and the cellular machinery that does all of the things that a fat cell does. Producing leptin, adiponectin, the other dozens of chemical messengers. Of course, there are enzymes and such involved in both the storage and mobilization of fat within the cell. Let's talk about those.

Lipoprotein Lipase (LPL) and Hormone Sensitive Lipase (HSL)

The key players in fat storage and mobilization are LPL and HSL, two enzymes that, respectively store fat and mobilize it. There is also another molecule in the fat cell called Acylation Stimulation Protein that is hugely important for fat storage. Discovered in the 80's, it's actually more important for fat storage than LPL. And, a fact ignored by most, ASP activity can be turned on simply by fat in the bloodstream, without the hormone insulin present or increased. Take that Gary Taubes. But since we're talking about fat loss, let's focus on HSL. HSL is regulated predominantly by something called cyclical Adenosine Monophosphate (or cAMP) in the fat cell. When cAMP is low, HSL activity is low; when cAMP activity is high HSL activity is high.

Burning Fat

The process of "burning fat" can get as complicated as you want to make it but I tend to focus on three primary steps: mobilization, transport and oxidation (burning). I discussed all three in some detail in The Stubborn Fat Solution but will only focus on mobilization in this book.

Mobilization is the step we're concerned with here. When HSL is activated, stored TG in the fat cell is broken down and the fatty acids are released into the bloodstream as is the glycerol backbone (sometimes scientists just measure glycerol release with the assumption that fatty acids are being released in a ratio of 3:1). This process is called lipolysis ("lipo" = fat, "lysis" = breakdown).

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These fatty acids can actually then just be stored again (a process called re-esterification) but if blood flow is sufficient, they get carried away (transported) elsewhere in the body. Eventually they run into a tissue such as skeletal muscle or liver or heart where they are oxidized (burned) for energy. That's ultimately what the process of losing fat is:

mobilize the fatty acids, transport them away from the fat cell, burn them off for energy. I discuss the above in excruciating detail in The Stubborn Fat Solution but for now that's all you really need to know.

And as I mentioned above, the hormone HSL is the key to fat mobilization and HSL activity is increased when cellular cAMP goes up. So we want to raise cAMP. Some readers may remember the supplement forskolin that was popular years ago. It was shown to raise cAMP in cells (at least when done in a petri dish or infused) but it more or less crapped out as an oral supplement.

So what, you ask, controls cAMP in the fat cell?

A Tale of Two Hormones: Insulin and the Catecholamines

Before talking about the key hormones involved in fat cell metabolism, I should mention that others play important but ultimately secondary roles. Testosterone, progesterone, estrogen, thyroid, cortisol, growth hormone, leptin and others all impact on fat cell metabolism.

GH and small cortisol pulses help to mobilize fatty acids for example. In contrast, chronically elevated cortisol, especially in conjunction with elevated insulin levels can cause fat storage. Thyroid affects overall metabolism and the drop in thyroid on a diet is part of why metabolism slows down; note that too much thyroid can burn off muscle tissue and cause other

problems.

Testosterone can impact on the levels of HSL and LPL (not so much the activity) and impacts on something called adrenoceptors that I'll discuss below. The female hormones, estrogen and progesterone are too schizy to get into: in some parts of the body, they help fat loss, in others they hurt and they interact in a complex way (that changes throughout the menstrual cycle).

But the two key hormones when it comes to fat mobilization have been, for decades, considered to be primarily insulin and the catecholamines. Since insulin is simpler, and I suspect most readers know what it is, let's talk about it first to get it out of the way.

Insulin is the primary inactivator of HSL (it is also part of what turns on fat storage), inhibiting fatty acid mobilization from fat cells. Insulin goes up in response to both protein and carbohydrate consumption and is usually thought of as "bad" when it comes to fat loss. Certainly there is some truth to this.

As above, it's very incorrect as thinking that insulin is the only thing that affects fat storage (as many are now claiming), ASP that I mentioned above works just fine without it when fat is consumed even if insulin levels don't go up (that is, fat stimulates it's own storage). But for now you can think of insulin as the "bad guy" for fat mobilization (and thus loss). Insulin acts, by binding to insulin receptors on the surface of the fat cell, to decrease cAMP. This insulin inhibits fat mobilization.

But what about the catecholamines. Known as adrenaline/noradrenaline or epinephrine/norepinephrine depending on what part of the world you live in (I'll use adrenaline/noradrenaline), the catecholamines are key players all around the body with a lot of different functions.

For the record, adrenaline is released from the adrenal gland into the bloodstream and it tends to act very globally in the body, affecting most tissues. In contrast, noradrenaline is released from nerve terminals and tends to only affect the tissue that the nerves are close to (innervates in anatomical terms).

And, just as insulin was thought to be the only player in fat storage (it's not), the catecholamines were thought to be the only mobilizers of fat from the fat cell (they aren't). Before expanding on that, let's talk about how these hormones work. To understand that, I need to talk about something called adrenoceptors (or adrenoreceptors).

All About Adrenoceptors

Just as insulin has it's own receptor on the surface of cells (and actually every hormone has it's own specific receptor), the catecholamines have their own receptors called adrenoceptors. There are two primary classes of adrenoceptor called alpha and beta and each one has a number of subtypes. The ones we are concerned with here are alpha-1 receptors (that kind of don't matter for fat cell metabolism), alpha-2 receptors (which matter hugely), beta-1 receptors (not critical for fat cell metabolism), beta-2 receptors (hugely important) and beta-3 receptors.

Let me talk about the beta-3 receptor briefly. Originally found in animals, in something called Brown Adipose Tissue, beta-3 receptors were hoped for a while to be the key to obesity treatment. In animals, beta-3 activating drugs caused massive fat

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loss and it was just awesome. Obesity was cured.

But as so often happens when trying to go from animal research to humans, it didn't pan out. When beta-3 activator drugs were tried in humans they had either a very small or pretty much no effect (the reasons why aren't relevant). They were abandoned and keep that in mind when you hear of some supplement company that claims to have a beta-3 product that works. When companies with potential multi-billion dollar profits stop researching something or can't make it work, the idea that a supplement company has figured it out is about nil.

So what about the other adrenoceptors? Again I'll focus on alpha-2 and beta-2 for the time being since they are key players in the fat cell. You can think of alpha-2 receptors as a "brake" on fat cell mobilization. Despite being activated by the catecholamines, they lower cAMP and inhibit fat mobilization. Think of beta-2 receptors as "accelerators", when activated they raise cAMP levels and stimulate fat mobilization. Alpha-2 receptors bad, beta-2 receptors good.

Some of the hormones I mentioned above can impact on alpha-2 and beta-2 receptor density. Testosterone often lowers alpha-2 receptor number, helping with fat loss. Estrogen can raise alpha-2 receptor number, hurting it (again, estrogen is way more complicated than this).

So why does this matter? As it turns out, different depots of fat in the body can have vastly different ratios of alpha-2 and beta-2 receptors. Women's hip and thigh fat, for example, has a very high ratio of alpha-2 receptors to beta-2 receptors and this is a big part of why it's so difficult to mobilize and get rid of. Men's ab/low back fat isn't quite as bad but can still be stubborn and as you sort of move up the body, things get a lot easier. Visceral fat, found surrounding the organs is very easy to mobilize due to it's adrenoceptor ratios and incredibly high blood flow.

This actually explains the "order" in which people lean out. If they are carrying visceral fat, they lose that first. They don't look much better outside of a flatter stomach but they feel leaner. Then fat loss is sort of top down. Upper body leans out first, women and men get ripped, veiny delts and chest long before anything else.

The abs come in next (and even upper and lower abdominals come in at different rates). For women, who often carry a lot of lower bodyfat, abs often get ripped fairly early in the process and end up with a ripped upper body and relatively fat hips and thighs. Lower body fat is simply always the last place people lose fat. Men, who generally do not have a lot of fat in their lower bodies have abs and low back as the typical problem areas. Some men do have a more "female" bodyfat patterning and they have the same problems with lower body fat as women do.

There are actually some solutions to the 2 adrenoceptor issue. The supplement yohimbe/yohimbine is a natural alpha-2 blocker; it takes the "brake" off of fat loss. Very low-carbohydrate diets for a few days also naturally inhibit alpha-alpha-2 receptors as well. I imagine most know about ephedrine or clenbuterol both of which hit the beta-2 receptors (ephedrine actually activates both beta-1 and beta-2 receptors but that is neither here nor there for now). Exercise causes the release of hormones that may or may not mobilize fat depending on the area you're looking at.

There are also ways to modulate exercise to work around the problems above, I outlined all of them, diet, supplement and training in

The Stubborn Fat Solution

and won't detail them again here since that's not what this book is about. But so far none of the above is really that exciting if you've read much in recent years (or any of my books). Insulin is bad, the catecholamines have variable effects, you can lower carbs, exercise or take some supplements to try and fix the issue. I should mention in closing that insulin pretty much always "wins" against the catecholamines in the battle for fat cell metabolic control. When insulin is high, it's anti-fat mobilization effects will suppress the fat mobilization effects of adrenaline/noradrenaline. Do realize that it's somewhat unusual to have high levels of both at the same time. Generally when insulin is high, catecholamines are low and vice versa.

But clearly I wouldn't be writing this book if I was just going to repeat the same tired information. This book is about something new and exciting. Because above I made it sound like insulin and the catecholamines are the only players in fat cell mobilization, certainly this was thought for decades.

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Chapter 2: Natriuretic Peptides and Lipolysis

So now you have the basics of fat cell mobilization as well as why stubborn fat is stubborn: a preponderance of alpha- receptors compared to beta-receptors make fat cell mobilization more difficult. There are other issues related to things like insulin sensitivity, blood flow, etc. that I'm not going to get into here.

For now let's just focus on the beta/alpha adrenoceptor issue that I talked about last chapter. Just remember that insulin is bad, catecholamines are variable and a high alpha to beta receptor density makes fat mobilization more hard. It can be worked around but what if there was another way. A New Hope perhaps (sorry).

The New Millennium

In the year 2000, society did not collapse due to Y2K and programmers not realizing that years need to have 4 digits. It's a shame since I was running a big credit card debt and was hoping it would get wiped out when all of the computers crashed. Ah well. Neither did the Messiah return and for the most part, the whole thing was nothing more exciting than watching the numbers change; kind of like watching the odometer of your car turn over from 99,999 to 100,000. Whoop de doo.

However, something cool did happen, at least if you define cool relative to being a big nerd on the fat loss front. Which I do. Because in 2000, a nifty little review paper came out titled “Millennium fat-cell lipolysis reveals unsuspected novel tracks.” that described an entirely new fat mobilizing pathway.

As I mentioned in the last chapter, for the previous decades, insulin and the catecholamines were the primary hormones directly affecting lipolysis, there were a bunch of secondary hormones but that was basically it. And that limited what could be manipulated. Drop carbs, hit the beta receptors with exercise of drugs, take yohimbine or use a low-carb diet.

But this paper discussed an entirely new pathway to mobilizing fat, that worked outside of or at least around the classical insulin/catecholamine pathway. Recall from last chapter that both insulin and the catecholamines work to mobilize (or inhibit) mobilization of stored fat by affecting cAMP levels (which affects HSL activity). Low cAMP and you get sluggish fat mobilization, high cAMP and it increases.

When insulin or the catecholamines bind to their receptors, they ultimately affect cAMP through something called downstream signalling. Basically the hormones bind, something happens, something else happens and 6 other somethings happen and finally something useful or important happens. Sometimes it's good (increased cAMP in this case) and sometimes it's not (decreased cAMP in this case).

The Natriuretic Peptides

ANP stands for atrial natriuretic peptide and is actually one of a class of natriuretic peptides. There is also b-type (or brain) natriuretic peptide and a c-type natriuretic peptide. Respectively they are called ANP, BNP and CNP. In this book I will predominantly focus on ANP although BNP plays a role that is actually fairly important during dieting.

All three of these compounds are released from the heart and the original purpose of them was thought to be mainly related to water balance in the body (natriuretic is a fancy word referring to something that causes natriuresis which is the loss of minerals and the urine; this pulls water out of the body).

As people get sick or obese, they often start holding a lot of water and this tends to increase blood pressure (and other things). The body, being very smart, then releases a host of compounds including the NPs in an attempt to get things back to normal. The natriuretic peptides are a big part of that.

So when people are in heart failure or suffering from massive hypertension (again, often secondary to obesity), NP levels go up in an attempt to get blood pressure back down and things back to normal. It's actually more complicated than that, of course but the details are not particularly relevant here.

But here's an interesting tidbit, ANP turns out to have another major role in the body, one that might not have been

predicted. It mobilizes fat. If you think about it, it makes a certain weird kind of sense in evolutionary terms. If obesity and fat gain are causing some negatives to occur (such as high blood pressure), ANP increases could be part of what helps to burn the fat off. There are a host of other adaptations as well, leptin goes up, fat cells become insulin resistant, etc. This happens due to becoming obese in a (generally futile) attempt to reverse the situation.

Clearly, mind you, it doesn't work that well or there wouldn't be any issues with obesity or high blood pressure. It actually turns out that obese people often have lower ANP levels than leaner people; it appears that their bodies degrade ANP more effectively or excrete it through the kidneys. So a pathway that should rightfully work to help with fat loss seems to have become dysfunctional for whatever reason. This is also not unusual in obesity: systems that are meant to work at lower levels or be very effective go screwy as people get obese.

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In any case, ANP levels often go up when blood pressure or what have you occur and in addition to its other effects, ANP stimulates fat mobilization. But of far more interest to this book and the issue of stubborn body fat, not only does ANP mobilize fat, it works through a completely different pathway than insulin and the catecholamines. Like those other hormones, ANP has it's own receptor on the fat cell but when ANP binds, it does something different.

Because while insulin and the catecholamines work by modulating cAMP, atrial natriuretic peptide works through a cGMP mechanism (cGMP stands for cyclical guanadine monophosphate which those of you who remember high school or college chemistry may be familiar with). In the same way that cAMP is a downstream signalling molecule, cGMP is too.

This has a number of consequences not the least of which is that ANP's effects are not impacted directly by insulin or catecholamine levels. They are working completely separately. Let me say that again: ANP mediated effects on fat mobilization are not impacted by insulin or the catecholamines; they don't actually interact at all. So while insulin and the catecholamines may be "fighting it out" for the control of fat cell metabolism (with insulin usually winning), ANP just does an end-run and works through a completely different pathway.

Quite in fact, ANP is even more interesting in that it can simulate lipolysis even when insulin is high which is something that the catecholamines can't do. I'll come back to this later in the book in terms of practical applications.

As I mentioned above, like all hormones, ANP has it's own specific receptor to bind to and very preliminary research (not much has been done) suggests that ANP doesn't show the same density differences in different areas of the body. So in addition to working when insulin is high, ANP may get around the whole alpha/beta receptor issue that makes some types of fat so damn hard to get rid of.

On that note, however, it has been shown that fat mobilization in females may be mediated more by ANP levels than in men, in premise, some of what I'm going to discuss in this book may help women more than men in terms of getting rid of stubborn body fat. It's really about time; women are screwed in terms every other aspect of fat loss. Finally, something may be going their way.

So now you're thinking, I'm sold, bring on the ANP and I'll watch the fat (stubborn and otherwise) melt right off. As usual there is a catch.

So What's the Problem?

Mind you, when I wrote The Stubborn Fat Solution I already knew most of the above and I expressed that in the short section of that book on ANP. The problem was that I hadn't found any useful way to raise ANP levels and I stated that clearly. Clearly getting high blood pressure is out of the question, and I would have found it difficult to sell heart failure as a way of getting ripped (bodybuilders would have done it).

In most of the research at that time, when they examined ANP it was with infusion. Since ANP is a protein based hormone, you can't take it orally, it will simply get digested in the gut. And I doubted bodybuilders, crazy as they are, would infuse ANP during morning cardio. They might, mind you but it didn't seem terribly practical for most.

Most of what I had seen to raise ANP that wasn't the above involved massive hyper-hydration. But not just "drinking extra water". It was gallons of water with a saline infusion and hormones like cortisol and aldosterone to make the body retain fluids Hardly practical. I would note that at least one contest prep guru has been suggesting very high sodium intakes during diet prep and I do wonder if this isn't affecting ANP levels by causing body water to go up. Maybe.

Another approach was to use something called a tilt table. This is a table that takes people from lying flat to a head down position; this spikes blood pressure and this causes ANP to go up at least acutely. Exercise in the prone position (laying down) seemed to raise ANP as well. While I can imagine some creative cardio machines that flip you upside down every five minutes to raise ANP, it didn't seem that useful either. One study found that ANP went up more in response to exercise in the water but it didn't affect fat mobilization more than doing the same exercise on land.

Doing exercise under hypoxic conditions (no, NOT training masks, we're talking the inhalation of hypoxic air) also had a profound impact on raising ANP but that's hardly practical.

I would note that exercise per se does increase ANP and this is part of the overall fat mobilizing process; as I mentioned above this effect seems to be more pronounced in women. Intensity may be a key to this. One study found that ANP went up (in women more than men) after sprint exercise for example.

I do wonder, in hindsight, if part of the benefit of the stubborn fat protocols aren't related to this (since they involve high intensity intervals to start or finish the exercise bout). But perhaps this whole inane fascination with high intensity aerobic activity for fat loss isn't totally misguided. If you’re wondering about resistance training and ANP release, there is almost literally no research on it. I’ve found one study and it showed no ANP response so this looks to be a cardio thing only.

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One study found that performing two bouts of exercise an hour apart saw a big increase in ANP levels during the second bout. Perhaps this lends some credibility to the idea that cardio morning and evening is better than a single session; I don't know if the effect is still seen with 12 hours between sessions but maybe the bodybuilders weren't nuts to do it this way. But for the most part, none of this was really as useful as I wanted it to be. It's generally bad idea to do high-intensity exercise daily (your legs tend to fall off) especially on a diet. The hyper-hydration thing is interesting but there's still no real indication that anything but the most extreme levels reliably impact on ANP levels. And raising blood pressure deliberately doesn't seem like a good idea.

Again, I knew all of the above when I wrote The Stubborn Fat Solution but just sort of left it sitting there. As I mentioned in the foreword I found another approach and started writing this book before getting bored and doing something else. And in hindsight I'm glad I did because as it turns out, there's way more interesting stuff coming out of the ANP literature now and this book gets to be a lot cooler because of my inability to get it finished in the first place.

So before I tell you about the method I'm going to suggest to jack up ANP and take advantage of the fat mobilizing effect, let me tell you about some other things ANP (in conjunction with other things) appear to be able to accomplish.

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Chapter 3: Natriuretic Peptides and Brown/Beige Fat

In the first chapter of this book, I mentioned b-3 receptors and how they worked amazingly in animals but seemed to not do much in humans. This chapter will address part of why that was. Now part of the reason is simple, when receptors are activated they often get downregulated, that is they decrease in number.

Humans don't have a huge number of b-3 receptors to begin with and what we do have is downregulated very quickly in response to stimulation. So even if b-3 drugs worked for a little while, they quickly stopped working. The drug clenbuterol (a beta-2 agonist) often stops working for the same reason, the constant stimulation of the beta-2 receptors causes them to decrease in number and clen loses it's effectiveness.

Ephedrine, which also activates the beta-2 (and beta-1) receptors doesn't do this since it doesn't hit the receptors as hard. You also don't take it 24 hours/day (clen stays in the system for 36 hours after a dose) so the b-2 receptors get a "rest" at night. One study even suggested that chronic ephedrine use could increase it's effects. But the general problem with b-3 receptors wasn't just due to this. Rather it was due to a fairly fundamental difference between rats/mice and humans.

WAT and BAT

In addition to the different areas of fat I talked about a little bit last time (i.e. visceral, abdominal, hip/thigh) there are actually two (and now three) actual types of fat in humans. The type I was talking about earlier in this book is called White Adipose Tissue or WAT. It's the primary type of fat in humans and one of it's major purposes is energy storage. It has a lot of stored triglyceride, a bit of cellular machinery and, of relevance to this chapter, has few mitochondria.

Mitochondria (aka the powerhouse of the cell) are found all over the body and burn both fat and glucose for energy (and they burn mostly fat). In doing this, they produce energy for the body to use (strictly speaking, ATP or adenosine triphosphate which is the "currency" the body uses for energy); a side effect is that mitochondria also throw off heat. And while WAT has very few mitochondria (making it fairly bad at burning fat for energy), a different type of fat called Brown Adipose Tissue (BAT) is effectively the opposite. It contains very little stored TG and has lots of mitochondria. And it's primary role, as you might imagine, is burning fat for fuel. And it generates a lot of heat doing this.

In small animals (mice and rats for example), in which BAT was first found, this helps with thermoregulation. That is, by generating heat, BAT helps to keep animals warm. And because of the crucial role of BAT in those animals, b-3 receptors were critically important (their activation turned on the BAT). So why didn't this pan out in humans?

For years, it's been felt that adult humans didn't have much BAT (babies, who are bad at regulating their body temperature have a good bit of BAT but it was always thought to go away as they got older). What little adult humans was found between the shoulder blades and in the neck but there didn't seem to be much of it and what we did have didn't seem to do much. For years nobody was quite sure why. This was thought to be another reason that b-3 activator drugs crapped out in humans. If their primary role was to activate BAT and humans didn't much BAT, it made sense that the drugs that activated BAT wouldn't do much. Which they didn't.

And this stance, that humans don't have enough BAT to worry about, was held for years, I've echoed it in some of my earlier books. But in the last 10 years or so, there has been essentially revolution and renewed interest in BAT. Almost purely by accident (i.e. they were looking for tumors in a PET scanner), researchers managed to find that some people had quite a bit of BAT. There was a huge variability in how much though. It also turned out that the amount of BAT present was related to how easily or not people kept lean; more BAT, relatively is correlated with a lower bodyweight.

So why hadn't earlier studies found BAT? Or, rather, why did the new research find it? It turns out that cold exposure is one of the primary activators of BAT and the earlier studies were always looking at normal room temperatures. The only way to really study BAT or even to see how much humans had was to look at it in the cold. I'm not talking about freezing here, temperatures around 19°C (around 66° F).

For many, that's fairly chilly (and this also causes shivering which burns calories) but it's still enough to get BAT, if it's there to perk up activity wise. In that vein, it's been suggested that the fact that humans avoid both cold and hot temperatures (we have central heat and air and clothes) may be contributing to obesity as both cold exposure and heat exposure can raise energy expenditure. But since most don't like being too hot or too cold, we use clothes and technology to stay in a more midrange zone for comfort.

In any case, when studied under colder conditions, it turns out that some people have quite a bit of BAT but the amount can vary about tenfold between people (and we're talking gram levels here, maybe 36 to 360 grams of total BAT so not even a pound of the stuff). It's currently unclear how relevant this really is in the big picture.

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value being a pretty enormous estimation and probably way too high. It would tend to require constant cold exposure (and it's interesting to note that lumberjacks who do undergo chronic cold exposure had been found to have more BAT than others) and you have to compensate for the hunger that occurs.

In one study for example cold exposure did increase energy expenditure by like 150 calories per day. But the folks, allowed to eat without control, ate more than that. So it's a double edged sword. Certainly if food intake is controlled, cold exposure has potential to burn some extra calories and certainly there has been some interest on the Internet for using cold packs or cold exposure for this. But it only works if calories are controlled.

In any case, BAT is back and appears ready to stay. And interest in finding ways to increase and/or activate BAT has been equally renewed. Preferably pharmaceutical means given that most will simply not put up with the inconvenience and discomfort or being cold all the time.

But even more recently, the whole BAT thing has become more complicated. By another tissue that should also be called BAT.

Enter Beige Adipose Tissue

One of the reasons that I'm glad I didn't finish this booklet in 2008 is that I wouldn't have been able to talk about this topic: beige fat (also called "brite fat" in the research). Like most of this it was first discovered in animal models (rats and mice). It's thermogenic like BAT and is thought to be somewhere between regular white fat (WAT) and classic BAT in terms of what it does (as well as in it's color, hence beige fat).

And it's now thought that most of what was considered BAT in adult humans is actually what is being called beige fat in animals. Basically while human children have true BAT, which is then lost; some adults appear to have beige fat in the areas that were once thought to be true brown adipose tissue. That is, adult human brown adipose tissue isn't really brown, it's the beige fat. Confused yet?

This might also help to explain why the drugs that activated brown adipose tissue in animals crapped out in humans. Our brown adipose tissue was really beige (on top of the difference in b-3 receptor function) and was presumably responding to a different stimulus.

From here on out, let's forget about brown adipose tissue and use BAT to refer to beige adipose tissue. Mind you, the end result is basically the same but this is more accurate. It's also thought that research on animal beige fat may actually transfer over to human beige fat since they seem to be an identical tissue. Time will tell and maybe this will be one of the few times where mouse/rat physiology actually translates into something useful for humans.

Where Does BAT Come From?

Since it's clear that we lose brown adipose tissue after babyhood, a question is then were beige adipose tissue comes from. Without getting into excruciating details, realize that there are precursor cells in the body, think of them as baby cells that have to get a signal to mature and turn into adult cells.

For a while it's been wondered if cells could be "transformed" from one type to another. That is, there was brief interest in "turning" white fat cells into brown fat cells, again with the hopes of treating obesity. It's not as if there aren't enough of them. Researchers call this the "browning" of white tissue. Basically turning them more into beige fat cells.

But it looks like this doesn't really happen. And while there was some early question about whether beige fat came from white fat precursor cells (which got a different message when they were told to mature), it looks like there are actually beige precursor cells that, given the right stimulus can mature into beige adipose tissue.

So in premise, given the right stimulus, there should be some way to increase the amount of beige fat. If so, in premise it can be activated and burn off extra fat calories like the original brown adipose tissue was supposed to. At least one of these is already known: chronic cold exposure.

Cold has its effects in the body by generating a sympathetic nervous system response and the beta receptor activation seems to be part and parcel of how it activates beige fat either acutely or to cause it to increase. In this vein, increased beige fat has been found in people suffering from a pheochromocytoma, a type of tumor that chronically produces adrenaline and noradrenaline. Essentially they have a chronic hormonal condition that is just like cold exposure.

Of course, exercise, ephedrine and clenbuterol all do the same and it was suggested early on that chronic use might cause increases in human brown adipose tissue. But without a good way to measure BAT (remember: you have to look for it in the cold), it was never proven.

But we know this: beta-receptor activation increases fat mobilization. Under certain conditions to make beige fat more active as well. And may have the ability to get the body to produce more beige fat. All this was known and still relevant.

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Early on it looked like a compound released by muscle, called irisin, might play a role in all of this. But the significant results in mice/rats were rather inconsistently replicated in humans. Most studies in humans showed no increase in irisin with exercise (and the ones that did found only a small increase). Of some interest, one study of sprint training (4-8 sets of 30" all out) for 3 weeks found that women saw an increase in irisin but men a decrease. The reason for this gender difference is unknown as are the real world effects.

Related to this, an early study found that sprint training caused a significant increase in ANP at the end of 10 maximal sprints and that the effects were also greater in women. I might suggest that the high-intensity protocols in my own

Stubborn Fat Solution

are working partially through this mechanism.

Another compound called BAIBA (beta-amino butyric acid), released from skeletal muscle may hold more promise. It not only appears to be involved in the "browning" of white fat but the single study done to date shows that 20 weeks of endurance training increases BAIBA levels by 17% but at the current time no more is known about what regulates BAIBA. What role this actually plays in terms of the acute stimulus of beige-fat recruitment/activation is unknown but, going forwards this may represent another pathway of interest to "turn on" or "make more" beige fat". I include it only for completeness.

Thyroid hormone is also key here. Not only does it increase energy expenditure and thermogenesis but may be involved in the overall recruitment and cell program that produces beige cells. There are a few other activators of beige fat but I won't get into them: for now they aren't modifiable in any way I am aware of. But it turns out that there are other compounds that appear to not only activate beige fat but possibly increase the amount of it. Compounds that we can actually control. Can you guess why I'm talking about this?

The Return of ANP

Knowing the above, that beta-receptor activation has the effects above and stimulates lipolysis, and knowing (as per the last chapter) that ANP stimulates lipolysis, a seemingly logical question/leap was whether or not ANP (or the natriuretic peptides in general) could either activate or get the body to make more beige fat. That is, if they share the effect of increased

lipolysis, might they also share the effect on beige fat.

And the answer seems to be yes although the research is preliminary. In both animals and humans, exposure of isolated fat cells to ANP (for 6 hours) led to significant increases in the genes responsible for fuel use, mitochondrial biogenesis and activation of the cell program that causes beige fat cells to mature from their precursors. Yet, it was in vitro (in a test tube), and looked mostly at genes.

But the researchers also found an increase in mitochondrial content (meaning the fat cells could burn more fatty acids for fuel). They also found that ANP raised oxygen consumption in the cells (indicative of fuel use) by 250%. These results were similar to that caused by a generic beta-activating compound. In this vein, ANP has been shown to improve the oxidative capacity (essentially the ability to burn fat for fuel) of skeletal muscle.

Following that, the researchers wanted to see if the combination of beta-activation followed by ANP had the same, less or a greater effect than either activator alone. In this case, not only did the beta-activating drug raise oxygen consumption, etc. when ANP was then added, the effect was increased further (and went higher than either compound alone).

Finally, the combination of a beta-activator and ANP was shown to induce the program that "browns" fat. That is, it appeared to turn on the mechanism for making more beige fat. It's important to realize that both compounds worked at concentrations that are found under normal circumstances. Often studies of this sort use concentrations that are impossible to achieve outside of the test-tube. That is not the case here: this occurred at levels of the hormones that can occur in the body.

And irrespective of the irisin issue above, it's interesting to postulate that regular exercise (which raises levels of both the catecholamines and ANP) could be increasing beige fat cell number and activity. This hasn't been studied to my knowledge but is interesting to consider if long-term exercise isn't having an effect on beige fat (possibly making it easier to stay leaner in the long-term).

Regardless of that, a few things are clear:

1. Like beta-receptor activation, ANP by itself seems to activate a lot of good things in terms of energy expenditure, mitochondrial content and may be able to both activate and make more beige fat.

2. Beta-receptor activation does the same by itself.

3. The combination of the two, beta-activation and an increase in ANP has a greater effect than either by itself. 4. A newly found compound called BAIBA released from skeletal muscle appears to brown white fat.

5. Thyroid hormone appears to play a role in the overall production and activation of beige fat.

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Chapter 4: Natriuretic Peptides and Appetite/Hunger

I know readers are waiting for me to get to the point but I have one more brief topic to cover. Once again, had I written this booklet back in 2008, this research wouldn't have existed. That said, please note that what I'm going to talk about in this chapter is fairly preliminary with studies showing some often contradictory results (some of this is probably due to differences between human and animals models) and is probably the least important part of this book. But I'm still going to talk about it.

Now, a population that is known to have elevated levels of natriuretic peptides is individuals in the midst of heart failure. You'll actually hear more about them in the next chapter. Along with this comes a cachexia, essentially weight loss and "wasting" that occurs in these patients.

Some readers may be familiar with the term "cancer cachexia" which refers to the fact that people fighting cancer often find their weight dropping with an inability to eat (this is one therapeutic use of marijuana by the way, stimulating appetite in these folks). The hormone TNF-alpha (an inflammatory hormone that goes up under certain conditions) was originally called "cachexin" as one of its roles is to blunt hunger in the brain.

But the fact that folks in the midst of progressive heart failure start to waste away raises a question of what is causing this. Certainly some of the effect is probably mediated by what I talked about in the previous chapters: increases in energy expenditure, thermogenesis, etc. But is there more?

As it turns out, some preliminary research suggests that the natriuretic peptides, and especially the b-type (BNP) may be key players in regulating hunger and appetite, decreasing both. Once again, the research on this is fairly new but, in the

aggregate it appears that they are playing a role in reducing hunger. This ties into something I talked about in an earlier chapter, the body often undergoes a variety of adaptations in response to obesity or other disease states that look like they are trying to fix the problem.

An increase in BNP with obesity might be an attempt by the body to reduce food intake to bring things back to normal though why this would occur in heart failure is obscure to me. Once again, clearly it doesn't work so well and there is, again, evidence that the obese may have a malfunctioning system, or just clear the natriuretic peptides to a greater degree. One study for example, found that infusion of BNP both decreased subjective ratings of hunger (cutting them to one third) and reduced levels of ghrelin. Ghrelin is the gut hormone responsible for inducing hunger, going up before meals as well as when individuals lose fat. It has other metabolic effects but keeping ghrelin from going up as high, or from going up on a diet, would be very beneficial to keep hunger from going off the rails.

In confusing contrast, another study found that natriuretic peptides reduced leptin levels in the brain which would be expected to make overall hunger worse (primarily by making other hormones involved in hunger regulation work less well). But none of that changes the overall effect of reduced hunger and weight loss in heart patients and the suggestion that raising natriuretic peptides (specifically BNP) seems to blunt hunger.

Natriuretic peptides also have been shown to impact on the metabolic effects to eating a meal. One study looked at the effects of the NPs on metabolism after a high-fat meal and found that both lipolysis and fat oxidation were maintained to some degree during the meal. Importantly, this occurred despite the increase in insulin (which usually shuts off both processes) which typically "wins" the battle over fat metabolism as I mentioned before.

The researchers noted that this isn't automatically a good thing. The increase in fat oxidation was less than the increase in fat mobilization which means that there might have been excessive fatty acids floating around in the bloodstream. This can cause problems, sometimes these rogue fatty acids are put somewhere they don't belong like the liver or pancreas (this is called ectopic fat storage). Mind you this shouldn't be an issue if someone is on a calorie restricted diet (and avoiding very high-fat meals in the first place).

The main point of this is that ANP may help to keep fat burning and mobilization going during a period (right after eating) when it tends to be shut down. For someone on a diet, this might give potentially the best of all worlds: eaten calories go into muscle, body burns off fat (dietary or bodyfat) for fuel. Double win.

And finally with all of that out of the way, it's time to get to the punch line and tell you how I suggest manipulating the NP's to enhance fat loss. And understand going to this that it will initially make no sense.

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Chapter 5: Beta-Blockers for Fat Loss

Ok, this chapter is going to be very short since it's basically a bridge between the stuff I bored you with in the previous several chapters and the stuff that you're really interested in. To get to the main thrust of this book, I'm going to quickly walk through everything I've discussed so far.

In Chapter 1 I talked about some basic fat cell physiology along with the two primary hormones long thought to have the only real impact on whether fat was mobilized well or not. Those two were insulin which inhibits fat mobilization (lipolysis). I also talked about the issue of alpha and beta adrenoceptors and how their different densities/numbers in different areas of the body make it relatively harder or easier to mobilize fat when they are stimulated by the catecholamines.

This led into a discussion in Chapter 2 of an entirely "new" (as of the year 2000 or so) fat mobilizing pathway that works completely independently of insulin and the catecholamines. This pathway was activated by a hormone called Atrial Natriuretic Peptide (ANP, one of three natriuretic peptides) and it worked through an entirely different mechanism than the other hormones.

ANP was released in folks with high blood pressure and in obesity, presumably in an attempt to drop body water and potentially reduce bodyfat. Exercise reliably released ANP as does hyper-hydration (involving gallons of water and hormone infusion) and some of the previously made observations regarding multiple exercise bouts or even high intensity exercise may be explained by increases in ANP.

In Chapter 3, I talked about brown adipose tissue first. Brown adipose tissue mainly exists to burn calories for heat and is involved heavily in thermoregulation. Previously thought to be found in small or insignificant amounts in adult humans, recent research has suggested that brown adipose tissue may be more relevant to human physiology.

But more recently, a midway type of fat cell called beige (or "brite") fat has also been identified and it actually appears that the supposed brown fat in humans is this beige fat. Mind you, beige fat is still thermogenic, burning off calories and fat for heat and is probably what the early studies of brown adipose tissue were looking at. Until recently, the primary activator of beige fat was cold exposure, primarily through the hormonal effect that it has on adrenaline and noradrenaline. Individuals who overproduce those hormones chronically have elevated levels of beige fat so this all fits so far.

Unfortunately none of this was terribly useful information for most people. It's difficult to increase levels of

adrenaline/noradrenaline around the clock because it makes it so you can't sleep. As well, in modern society, most prefer comfort to being chilly all the time; we use clothing and technology to stay in what's called The Thermoneutral Zone. Most are unlikely to put up with being chilly all the time though if you gradually acclimate (by moving the thermostat down a little bit at a time), it's not too awful.

But it also looks like beige adipose tissue can both be activated by and possibly increasing the amount by ANP for even short periods (6 hours). Beta activation increases this effect by ANP and the combination of the two (as might be seen with exercise) is more potent than either in combination. Thyroid hormone also seems to play a key in this, being involved in both thermogenesis and gene expression. Thyroid can't be easily manipulated without drugs, though.

Finally, Chapter 4, I briefly looked at the possibility that the natriuretic peptides, especially BNP may be involved in hunger and appetite control in the brain. Individuals with elevated NP levels often show a wasting (called cachexia) possibly driven by increases in thermogeneis but also related to decreased food intake.

While the research is preliminary as hell, infusions of BNP lower subjective hunger and decrease ghrelin release. Acutely, ANP has been shown to maintain both fat burning and mobilization even in the face of increased insulin when a high-fat meal. This alone shows how ANP is working via a different pathway for all of this; normally insulin wins in the battle to control fat mobilization (stopping it). But ANP stimulated lipolysis and fat oxidation was unaffected by insulin.

Let's Back Up and Talk about Receptor Antagonism

In the first chapter of this book I talked about the catecholamines and how they activate their own receptors (the adrenoceptors). In technical terms, this is called receptor agonism. This simply refers to when a hormone or compound binds to a receptor and causes it to do whatever it normally does.

But there is another class of compounds called a receptor antagonist. As you might imagine, this compound either blocks or stops the normal behavior of the receptor. I told you about one already, yohimbe/yohimbine.

An alpha-2 receptor antagonist, yohimbine blocks the normal effect of the alpha-2 receptor (which is to slow fat

mobilization). It's effect is thus to increase fat mobilization. It's a double negative essentially: inhibiting the inhibitor has the end result of increasing whatever is supposed to happen.

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But let's follow that train of logic and think about what a beta-antagonist (also called a beta-blocker) would do. So first, recall that beta-agonist drugs like clenbuterol and ephedrine tend to increase fat mobilization, etc. and they do this by acting as agonists at the beta-receptor (they raise heart rate and blood pressure as well).

But what if you wanted to lower blood pressure, as in someone with hypertension? You might guess that you could use a drug that was an antagonist to the beta-receptor. That is, if beta-agonism raises blood pressure, beta-antagonism would lower it. And this class of drugs exists and does exactly that, they are called beta-blockers.

Beta-blockers reduce heart rate and blood pressure and are often used by people before a big performance or speech to help folks keep from spazzing out. Athletes such as archers and pistol shooters use beta-blockers too to slow their heart rate; they actually try to fire between heart beats so that their aim is less twitchy.

But what else might a blocker do in the body? If we know that activation stimulates lipolysis, we'd expect a beta-antagonist/blocker to shut down lipolysis. Which should be a distinctly bad thing. So why am I talking about this at such length?

How Was the ANP Pathway Discovered?

Earlier in this book I mentioned that researchers had somehow (you probably assumed magic) discovered this brand spanking new fat mobilizing pathway involving ANP but I didn't explain what even stimulated them to go looking for such. Or how they found it. Because that would have ruined the punchline of this chapter which some of you may have already guessed.

Because the ANP pathway was originally discovered, or at least suggested to exist in studies of, drum roll, heart failure/hypertensive patients taking beta-blockers. Wait, what?

As I discussed above, beta-blockers should more or less eliminate fat mobilization by blocking the primary (and at the time, sole discovered) pathway that stimulated it. But it was seen in these subjects that while fat mobilization was certainly reduced, it was not eliminated completely. But as above, a beta-blocker if it's the only pathway of relevance should block lipolysis. Yet there was still some going on.

Now after nearly 100 years of data, researchers figured that they had the fat metabolism and lipolytic pathways pretty well figured out. And yet here was this weird-assed observation that didn't make sense: how could the body maintain fat breakdown in the face of complete beta-receptor blockade? So they went looking for an explanation.

And what they discovered was this: not only do these patients have already raised levels of ANP but many of the beta- blocker drugs that these patients are given further raise ANP. And they looked further into it they found not only natriuretic peptide receptors on the fat cell but were able to figure out that ANP binding stimulated lipolysis by a previously

undiscovered, non-catecholamine related, non-insulin related, non-cAMP related pathway. And that through this ANP pathway, could stimulate fat breakdown.

Mind you, when I wrote The Stubborn Fat Solution, I only had half of the picture on all of this. I knew what ANP was, what the pathway was but outside of exercise and the fluid stuff I talked about, I hadn't found any meaningful way to raise ANP levels. But as I mentioned in the introduction, a few months later I'd come across the research that filled in the missing pieces: beta-blockers raised levels of ANP (and the other NPs) and gave it some potential to utilize this pathway. I spent a while looking into it, started this booklet and then walked away from it.

Again, I'm kind of glad given the new research into beige fat, appetite and everything else I've discussed. Because after several chapters of introduction, I'm going to discuss is the use of beta-blockers, a drug that should pretty much do nothing but bad for fat loss, and how they can help on a diet. By increasing lipolysis, by possibly increasing beige fat, by helping to control hunger and appetite (maybe).

Am I nuts? Possibly but read on, in the next chapter I'll discuss some of the issues and problems that exist and how, by being crafty, we can side step them completely and do some nifty things.

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Chapter 6: Beta-Blocker Effects

Ok, last chapter seems to have taken quite the left turn from what I first described in this book. Somehow I reached the conclusion that a beta-blocker a drug that should hurt fat loss can actually be useful, by raising ANP (and BNP) levels in the body and cause a number of good things to happen.

So boom, everyone will run out and get a beta-blocker and lose fat, right? Women will be able to lose lower body fat easily (because ANP receptors don't appear to be related to fat depots meaning that we can side step the normal problems with lower body fat) and all will be good with the world. Well, not exactly.

There's usually a catch with this stuff and that's the topic of this chapter. Because if it were as simple as taking beta- blockers for fat loss, then you'd expect all of those hypertension and heart failure patients to be super lean and that's generally not the case. Sure there is the weird cachexia/wasting that occurs in heart failure patients but that could just as easily be due to decreased food intake.

If anything, patients on chronic beta-blocker therapy tend to have problems losing fat and issues with slight weight gain; yet another reason that what I'm proposing in this book seems to make so little sense. And now I'm going to explain the reason to you and how we can work around it.

More About Beta-Blockers

As a general rule, to eliminate variables, researchers tend to only look at drugs in isolation (although in disease states, often they are stacked for therapeutic reasons) and beta-blockers by themselves clearly do NOT cause fat loss.

While lipolysis is maintained to some degree with beta-blockers, it is still lower than what is seen without them so this is not surprising. As I mentioned, the patients would certainly mobilize more fatty acids without the beta-blockers than they do using the drugs in isolation.

Given the role of beta-receptors in overall metabolism, there is also often a small reduction in metabolic rate with chronic beta-blocker use. It's not huge, one study found 2.7% decrease in 24 hour energy expenditure while on the drugs (other studies suggest a larger effect). For someone with a maintenance level of 2700 calories per day, that's about 70 calories which you can burn with 10 minutes on the treadmill. It's not a huge amount of course but it all adds up in the long term. Things that slow metabolic rate are, by and large, not a good thing when the goal is fat loss/you are dieting.

In that vein, there is often a small long-term weight gain for patients on long-term beta-locker therapy. In any case, the weight gain is small, perhaps 2-3 kg (4-6 pounds or so) over about 5 years. Hardly anything to worry about on a short-term diet but it does point out that these drugs lower metabolic rate and have a generally negative impact.

Confusingly, the effect depends a lot on which beta-blocker is being looked at (there are two primary classes of beta- receptors). Like most drugs in the same class, there are different kinds of beta-blocker drugs. Certainly these effects don't seem to fit well with the rest of this book where I crowed on about how awesome ANP appears to be.

There is also some indication that beta-blockers may negatively affect protein synthesis which could lead to muscle loss. Sufficient protein and an exercise program have both been suggested and, once again, this is only an issue when the drugs are used long-term by themselves.

Ultimately, using beta-blockers to improve any aspect of fat loss or whatever seems insane and you may be wondering if I've lost it. And it would be absolutely true if all you were looking at was using beta-blockers by themselves. In isolation, beta-blockers would be expected to hurt things, ANP be damned. But the key to that sentence is the phrase "In isolation." Because a key aspect of making what I'm going to describe work is realizing that beta-blockers have to be taken with at least one other compound (and I'll describe some stacks from mild to wild in the last part of this book) to be effective. Let me put that more directly: if you go get ahold of some beta-blockers and start taking them and them alone, they

might actually make you gain fat or at least slow your diet results. And if you don't get anything else out of this booklet, please read that sentence 5 or 6 more times and let it sink in. I really don't want emails from people that they took beta- blockers by themselves and it hurt their diet efforts.

But to understand how to make blockers work through ANP, I need to get into a bit more detail on the issue of beta-receptors an talk about some of the details I skirted in earlier chapters.

Beta-Adrenoceptor Redux

As I mentioned earlier in the book, there are actually three primary subtypes of beta-receptors, beta-1, beta-2, and beta-3. Beta-3 aren't that relevant in humans, we don't have many and the ones we do seem to go away quickly when stimulated.

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Now, from a physiological standpoint, part of the reason the body has different types of receptors is so that the same hormone (or hormones) can do different things in different places in the body. A good example is the brain chemical serotonin as there are about 15 different types of serotonin receptors. So serotonin can have vastly different effects in different parts of the body depending which receptor type (or types) is present, in what ratios they are present, etc. This is really just an efficiency thing for the body: rather than having 15 different hormones, it has one hormone and 15 different kinds of receptors.

Beta-receptors are the same way, by having different types in different parts of the body, it allows a chemical (or in this case two related chemicals: adrenaline and noradrenaline) to have different effects at different places. I already mentioned how the ratio of beta-2 to alpha-2 receptors impact enormously on whether or not fat is easy or difficult to mobilize and the same thing is seen elsewhere in the body.

Thankfully, compared to serotonin receptor subtypes, beta receptors aren't nearly as complicated as there are really only two we need to worry about: beta-1 and beta-2 receptors (as above, the beta-3 receptor isn't that relevant to human physiology). And although they have nothing to do with beta-receptor agonism or antagonism, we only have to worry about alpha-2 receptors in terms of fat cell metabolism.

Receptor Affinity: A Primer

As I noted above, the body has an efficient way of getting things done by using the same hormone or chemical to do different things in the body based on what kind and how many of of specific receptor subtypes there are. Beta-receptors are no different and beta-1 and beta-2 receptors are found in differing amounts in different parts of the body.

In addition to giving the body itself more precise control over various processes, this has one more important implication: it allows us more control in how we manipulate different processes.

As it turns out, certain drugs can have relatively more or less affinity (a scientific term referring to how well or poorly a given compound binds to a receptor) for one or the other receptor. So, for example, ephedrine is a general beta-agonist, it hits beta-1 and 2 receptors pretty evenly; in contrast, the drug clenbuterol is much more specific for the beta-2 receptors. Clenbuterol is said to have higher affinity for the beta-2 receptors.

I'd note that beta-blockers can also be relatively more or less specific for one or the other beta-receptors. I mentioned above that there are multiple classes of beta-blockers; in this case there are two specific types: general beta-blockers (which affect both beta-1 and beta-2 receptors) and specific beta-1 blockers. There are no beta-2 blocker drugs in use for some reason. And, As you'll see, choice of drug to make this work is important to make sure we are hitting the right receptors with the right compounds to achieve the desired results.

Specifically, by being creative, we can use this type of selectivity to get the benefits of certain compounds without the drawbacks. This will make more sense shortly.

Back to Beta-1 and Beta-2 Receptors

Relevant to this book, the heart has both beta-1 and beta-2 receptors but, relatively speaking, beta-1 receptors are more prevalent and more relevant to heart function. In contrast, fat cells tend to have more beta-2 receptors (there are beta-1 receptors too). This actually explains the difference between ephedrine and clenbuterol in terms of both good and bad effects.

Since ephedrine activates both beta-1 and beta-2 receptors, it affects heart function more, that's why you get more wired and heart rate and blood pressure go up to a greater degree. Basically, ephedrine has greater side effects due to its relative non-specificity for beta-receptors.

Clenbuterol, by being more beta-2 specific has less effects on the heart (which has fewer beta-2 receptors) and more effects at the fat cell. So clenbuterol mobilizes fat more effectively with far fewer side effects (you don't get as wired and heart rate and blood pressure doesn't go up as much).

A drawback of this is that clenbuterol rapidly reduces the number of beta-2 receptors. It hits them so well and for so long (clen stays in the system for a good 36 hours) that they decrease in number. And clen usually stops working after about 2 weeks. It's been suggested that anti-histamines (think Benadryl) and specifically Ketotifen might prevent the normal reduction in beta-2 receptors by clenbuterol to keep it working beyond those couple of weeks..

As I noted above, different blockers also can be relatively more or less specific and there are two major types of beta-blockers in use. The first are general beta-beta-blockers which antagonize both beta-1 and beta-2 receptors (examples include Pindolol and Propranolol). The second are beta-1 receptor specific drugs. (examples include Atenolol and Metoprolol). Again, there aren't any beta-2 specific blocker drugs.

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