Where do triglycerides come from? Part I (Updated)

This post contains sufficient updates from the original (dated 5/11/11) that I consider it more of a fully updated version vs. a bump.   This began with my intent to link to this post in an upcoming discussion of triglycerides, when I noticed that Dr. Ronald Krauss was amongst the authors.   This study originally caught my eye because of   Marc Hellerstein's name, he of DNL not a major pathway in humans fame, that I've blogged on previously.

Now I have excerpted copiously from the discussion because the authors make several points relevant to the discussion of what comprises a healthy lipid profile.  As part of updating, I am breaking those excerpts up a bit more and adding some/more emphasis and additional commentary.

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The Vascular Functions of Insulin

Random Replay

Was having a discussion on FB about insulin this morning and while going through some blog posts this one popped up.  I find reading some old stuff interesting at times ... this is over 3 years old.  

If someone goes on a low carb diet and this manages their hyperglycemia, this is a classic example of treating symptoms while not addressing the cause of the problem which is pancreatic beta cell dysfunction, and in the case of the T2, coupled with hepatic insulin resistance.  

What low carb doesn't do is restore normal insulin secretion and signaling, and insulin plays many roles in the body beyond glucose transport.  For one, it also assists amino acid transport (and protein synthesis) which is why the IR often have elevated circulating levels of the most insulinogenic (e.g. insulin requiring) amino acids, the BCAAs.  

This post is a flashback of some of the other things insulin does.  Further it discusses the role of NEFA in all of this ... the forgotten biomarker I think most low carbers with whacky lipids should have measured as they are likely elevated.  

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Aug. 1 Over the Hump Bump: Baby Your Pancreas? Part II: Go all Jillian Michaels on your Liver?

On Facebook today, Mark Hyman MD (functional medicine doc) posted:

There are no essential carbohydrates. There are essentials fats and essentials proteins, but if you never had any carbohydrates again, you would survive.

The Teaspoon Party

This was brought to my attention but also reminded me that Richard Feinman is at it again with a recent blog post on this no essential dietary carb canard, couched in a history lesson of sorts:  Revolutions. Political and Scientific.  He discusses Claude Bernard finding sugar in a dog that hadn't been fed any carbohydrate.  The question is why ... again ... why ... now?   This idea has earned him an honored place in the group at right.

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The Myth of Starving Cells II and NEFA Levels Again.

UPDATE (and a tiny bump for feed subscribers):  I noticed a bit of traffic to a prior related post, so I'm just linking to that one here as well:  Insulin Doing Its Thang! And Still No Starving Cells.  It discusses another study by Keith Frayn that shows increased NEFA uptake into the muscle cells of men with hyperinsulinemia.  It may be worth a read for newer readers along with The Myth of Starving Cells.

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Original Content:

A little sidetrack here, but I came across an article the other day. I just had to blog on it before I forgot!  

A little background as well -- A couple of years ago I wrote:  The Myth of Starving Cells.  As the story goes, as related by science journalist Gary Taubes, to Low Carb Diet Doctor Mike Eades, to Fat Head Naughton, insulin traps our fat in our fat cells, causing "internal starvation" as the rest of our cells go without, triggering hunger and overeating.   We overeat because we are getting fat, or some nonsense like that.   In the post, I discussed studies demonstrating the opposite is true.  In obesity, there is failure to properly suppress NEFA release from fat cells, NEFA are elevated in the fasted state, and irrespective of absolute concentration, NEFA delivery to cells is higher.  The last point leading to accumulation of fat within ectopic cells, such as muscle cells (called intramyocellular triglyceride or lipid, IMTG, IMCT or IMCL).  The cells have plenty of fat fuel to burn ... indeed this is a problem!

So I was looking for a  link to that Ebbeling et.al. study the other day -- this one: Effects of Dietary Composition on Energy Expenditure During Weight-Loss Maintenance.  In the study, a group of obese people were put on a relatively high protein (25%), relatively low fat (30%) and moderate carb (45%) diet and lost between 10 and 15% of their initial body weight.  After which they were weight stabilized and then fed one of three maintenance diets for 4 weeks in randomized cross-over fashion.  These diets were P/F/C:  low fat = 20/20/60 , low GI = 20/40/40, and low carb = 30/60/10.  

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Why We Get (Sick) Fat (and Sick Livers) - Lessons from a Cafeteria Rat

Since we're talking about fructose and the liver of late, I thought I'd bump this post.  In this study groups of rats were fed one of four diets.  The "low fat" diet is better described as a high sucrose diet as 35% of the diet was sucrose.  This replaced 35% of the fat in the 45% "high fat" diet.  While the LF and HF rats gained a little more weight than the standard (also LF at 12%) chow rats, it is clear that the high fat has rather more negative metabolic effects.  I don't think the 35% sucrose diet was beneficial, rather the contrary, but that level of sucrose consumption, every single day for 10-15 weeks (which is a very long time for a human) is also hardly indicative of even SAD consumption.

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Original Posting:  3/8/11

It seems fairly generally accepted that whatever the cause or progression, the so-called Metabolic Syndrome, Syndrome X and Type 2 Diabetes are associated with a dysregulation of adipose tissue metabolism, and fat tissue that is infiltrated with macrophages and secretes excessive amounts of inflammatory molecules called adipokines (e.g. TNF-α, IL-6).   A term has been coined, adisopathy, to describe this "sick fat".  

I've recently discussed the "Cafeteria Rat" study  as pertains weight gain in general.  But the other thing about this study is that it looked at the fat tissue with the different dietary interventions.  To recap, four groups of rats were fed ad libitum different diets:

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Stick a Toothpick in It? Taubes' 4-pronged Carb/Insulin "Fork" Loses its Tines

I'm bumping this today, because in the weeks to come I hope to update, flesh out, and reference it fully.  Looking back at something written almost 2 and a half years ago it seems rough, but nonetheless it  still summarizes what I call TWICHOO and the arguments against it pretty well.  

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This post updated slightly 6/22/2012.   Original publication date 1/23/11

In the comments at Jimmy's blog on my interview podcast, several comments either directly or by inference say I failed to make my case against Taubes.  Well, I think I did pretty much get to what I consider the four prongs of Taubes carb/insulin hypothesis, but I've decided to try and summarize this in a blog post.  Another common comment is that I'm somehow nit-picking at minutia, basically if folks lose weight on low carb, it doesn't matter the details of why.  To those, if they are reading this, I would say that any objective view of my arguments would lead to the conclusion that these are NOT minor details, they are the sum total of Taubes' evidence in support of his hypothesis.  Not only has he NEVER debunked the calorie-based theories on obesity, but almost all evidence in support of his "alternate" theory HAS been.  

I will not be referencing this post, it's all been done before here, and I don't have the time to trace down every link etc.  

So, what do the four prongs of the fork stuck in the potato above represent?  

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An American Justice System for Food ~ Part I Intro and Carbs in General

The cornerstone of the American justice system:  Innocent until proven guilty.  According to Wikipedia: sometimes referred to by the Latin expression Ei incumbit probatio qui dicit, non qui negat (the burden of proof lies with who declares, not who denies).  I like the first part of that Latin expression and suggest that what is truly needed in nutritional circles is to put the burden of proof on those making claims.  My point here is not a political one, it is not to argue the merits of my country's justice system or its implementation, or anything of the sort.  It is to put forth a suggestion -- that ALL who demonize foods be tasked with proving their charges.   I suggest this because it is darned near impossible to do the opposite especially in the face of baseless charges.  

It is a bit of a stretch, but keep in mind that many of the compounds, such as water, can be toxic at some level of ingestion.  Furthermore, some of the chemical and/or physical properties of many innocuous compounds found in foods can seem quite daunting when taken out of context.   This is an obvious spoof, but hopefully it makes a point.

Now, the vegans and vegetarians and raw and fruitarian crowds are all just as guilty of this, but since I've never been even remotely a part of any of those communities, I'll leave it to someone else to call out their hyperbole, scaremongering and outright disinformation.   I'm also not talking about new non-foods such as artificial sweeteners, chemically modified foods (e.g. hydrogenated fats), non-food chemicals such as preservatives and I'll even throw in GM in with substances that should be considered unsafe until proven otherwise.  

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Surrogate Biomarkers for NEFA?

For reasons related largely to the difficulty (thus presumably expense) in measuring them, one fasting lipid that is not routinely assessed in lipid panels are the free fatty acids (FFA) aka the non-esterified fatty acids (NEFA -- Wholly irrelevant but I prefer the latter acronym as I like to sound them out in my head and knee-fah "sounds" better than eff eff ay to me).  And yet, like glucose, it is NEFA that is elevated in diabetes.  Unlike glucose, however, NEFA is elevated in non-diabetic obese as well as elevated NEFA preceding frank hyperglycemia in the progression of Type 2.  

One of insulin's primary roles vis a vis adipose tissue is to regulate the "basal" triglyceride/fatty acid cycle, acting on both adipocytes and the liver, to keep NEFA in a relatively small range of levels (amounting to roughly half to three-quarters of a gram in circulation under normal fasted circumstances).  

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Chronic Exposure to Free Fatty Acid Reduces Pancreatic β-Cell Insulin Content by Increasing Basal Insulin Secretion That Is Not Compensated For by a Corresponding Increase in Proinsulin Biosynthesis Translation

Coming next in the discussion of diabetes I am going to discuss insulin secretion in greater detail.  I was reminded of this post in the writing process.  So ... Bump!

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Original Publish Date:  4/4/11

Chronic Exposure to Free Fatty Acid Reduces Pancreatic β-Cell Insulin Content by Increasing Basal Insulin Secretion That Is Not Compensated For by a Corresponding Increase in Proinsulin Biosynthesis Translation

JD McGarry contributing author.

{Please note:  Excerpts from the text will be edited somewhat to avoid "cluttering" references, statistical values, and some rounding of numbers.  Text will sometimes be presented in bullet form or with paragraph breaks to ease reading.  It is not my intent to plagiarize nor to alter the content.  If anyone feels I've altered the content in any meaningful way, do please let me know!}  Direct quotes will be indented.

FFA are an important physiological fuel for islets, and act as a supplemental nutrient secretagogue to potentiate insulin release acutely in the presence of glucose.

Translation:   β-cells run on fatty acids but this fuel also serves to stimulate insulin secretion.

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Exogenous Insulin Stimulates Endogenous Insulin Production

Continuing with our discussion on diabetes ...

In my last post on the topic, I introduced this paper:  β-Cell dysfunction vs insulin resistance in type 2 diabetes: the eternal “chicken and egg” question.  This got me to thinking again about early insulin treatment for Type 2.  In an ideal world a more thorough post on EIT for T2 would precede this one, but I've got a paper on this open in the browser and don't want to forget it.  There are, however, several studies out there employing insulin early in the diagnosis of diabetes that have had remarkable results and this is worth revisiting briefly here.  Three of these studies are summarized in the table below from this paper

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Lessons from LIRKO

The LIRKO mouse has no insulin receptors in its liver.  It's one pretty sickly mouse.  In most studies it becomes hyperglycemic and hyperinsulinemic very early in life, but by six months or so of age is either normoglycemic or hypoglycemic.  Despite the concurrent hyperglycemia and hyperinsulinemia, the LIRKO remains normal weight, it is even a bit underweight if anything.  This is despite the fact that  circulating free fatty acids (FFA, or my preferred acronym, NEFA)  are suppressed by 40%.  {Here are the two papers I've discussed in previous blog posts: Loss of Insulin Signaling in Hepatocytes Leads to Severe Insulin Resistance and Progressive Hepatic Dysfunction , High Circulating Leptin Receptors with Normal Leptin Sensitivity in Liver-specific Insulin Receptor Knock-out (LIRKO) Mice both links are to free full texts}

LIRKO presents two problems for the TWICHOOB:

1.  Chronic hyperinsulinemia does not cause rampant fat accumulation 

2.  Insulin "locking away" fats does not lead to hyperphagia (overeating)

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Hacking Jimmy Moore's Latest Lipid Report

So Jimmy Moore has released his latest lipid panels, after losing 50-or-so pounds in 5 or so months of his nutritional ketosis experiment.  Before I comment on these, a huge revelation was made in the post:

Interestingly, before I started on the Atkins diet in January 2004, my highest total cholesterol was only about 230. Of course, my doctor put me on both Lipitor and Crestor to lower that number and it did get down to 130 at some point (don’t know what the breakdown was of HDL and LDL nor do I know what my triglycerides or LDL-P were at the time either).

Ummm ... Jimmy, do you even bother to look back at your own blog? Seems not, which is a darned pity for someone so darned and determined to figure all of this out, but who doesn't even look at his own data.  

Before I started livin’ la vida low-carb, my HDL was a dismal 21 and my triglycerides hovered over 250. My LDL was about 250 which brought my total cholesterol to around 275. It wasn’t a pretty picture.

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Insulin Doing Its Thang! And Still No Starving Cells

In comments yesterday, Wayne/ProudDaddy wondered whether triglycerides might be the bad guy instead of NEFA based on this study from Keith Frayn's research group: Adipose tissue fatty acid metabolism in insulin-resistant men.

Aims/hypothesis  Increased NEFA production and concentrations may underlie insulin resistance. We examined systemic and adipose tissue NEFA metabolism in insulin-resistant overweight men (BMI 25–35 kg/m²).

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Exercise & Fat Mobilization ... and starving cells & hunger

There's no denying it, TWICHOO is down to a broken toothpick where the science is concerned.  (See here for the toothpick reference if you're a newer reader.)   The remaining claim supporting TWICHOO rests on the action of insulin on the fat cell.  Insulin does indeed act to stimulate esterification and suppress lipolysis, favoring deposition and accumulation of triglycerides in fat cells.  They even teach this stuff in some medical schools I'm told!  So these days it's all about how carbs make you hungry and overeat (although overeating is so inane) because they stimulate insulin which traps all your fat calories in your fat starving the rest of your cells of energy.  Now, that part's not true, but let's for the sake of argument assume it is.  What, then, would cause you to lose weight and not be hungry?  Why anything that favors net mobilization of fat stores -- that is stimulates lipolysis and fatty acid release from fat cells.  This will raise the circulating free fatty acid, NEFA, levels and make them available in abundance to your cells.  Hunger be gone!  It's all about the balance of the TAG/FFA cycle.

Well, if that is the case, then exercise would be THE most effective means of preventing or reversing fat accumulation.  Hands down.  No argument.  Oh ... and it wouldn't make you hungry, quite the opposite, because your body is awash in fatty acids.  Work with me here TWICHOOB's.  If you have your hypothesis, you must fit it or apply it to all situations.  Exercise is the ultimate TWICHOOB miracle weight loss dream.   Because if anything that works to put fat into fat cells is fattening, then anything that works to get fat out of fat cells is de-fattening.

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There's no dietary need for saturated fat ...

... or monounsaturated fats, MUFA, for that matter.  Therefore low fat diets, where most of the fat is essential PUFA, are optimal.  The body can make all the SF and MUFA we need from carbohydrates.  Furthermore, relying on this metabolic pathway as a source of body fat is metabolically advantageous for weight management as making fat from carbohydrate is an energy intensive process.  

Sounds a little silly, right?  I think so.  But so, too, is the ridiculous mantra from low carbers citing the fact (true) that there's no dietary necessity for carbohydrate.  You know the drill, we can make all the glucose we need by gluconeogenesis (just saying that makes me feel smarter) therefore LC diets are optimal.  There is a metabolic advantage built into LC diets because gluconeogenesis requires energy to convert protein to glucose.

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The Triglyceride/Fatty Acid CycleS and the role of Glyceroneogenesis

Thanks to a certain journalist, much of the discussion of fat tissue metabolism on the internet presents a very myopic view of things taken out of context.  One example of this, is that in Chapter 22 of GCBC, Taubes lists all of the hormones acting on adipocytes.  The caption on the graphic reads:

In 1965, hormonal regulation of adipose tissue looked like this: at least eight hormones that worked to release fat from the adipose tissue and one, insulin, that worked to put it there.

Let's leave aside for a moment that in the four subsequent decades preceding the writing and publication of his book, probably the most potent regulatory hormone of fat mass, leptin, was discovered.  Let's also leave aside all of the other adipokines (the term for the collection of hormones and peptides produced by adipocytes most of which appear to be secreted).   There's a lesson to be learned solely from Taubes' narrow, outdated view.  Under the title "Hormones that promote fat mobilization", Taubes lists:   Epinephrine, Norepinephrine, Adrenocorticotropic hormone (ACTH), Glucagon, Thyroid-stimulating hormone, Melanocyte-stimulating hormone, Vasopressin, and Growth hormone.  In the opposing column under the title "Hormones that promote fat accumulation", he lists only one:  Insulin.  He precedes this with what he seems think is information either unbeknownst to or forgotten by researchers in the field -- that fatty acids are continually cycling in and out of fat tissue, and that caloric excess is not required for deposition, nor is caloric deficit required for mobilization.

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Energy deficit w/o LC alters resting carb oxidation and FA availability

Originally lucky post #13 made on March 23, 2010

In light of all of the "fat burning" , respiratory quotient and mitochondrial mayhem discussions of damaged metabolisms, I thought this might be a fitting post to bump to the top today.  The take home message of this study, IMO, is that the body burns what it needs to burn, and hormone levels adjust accordingly, not so much the other way around.  

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Energy deficit without reducing dietary carbohydrate alters resting carbohydrate oxidation and fatty acid availability

Reduced carbohydrate (CHO) availability after exercise has a potent influence on the regulation of substrate metabolism, but little is known about the impact of fat availability and/or energy deficit on fuel metabolism when dietary CHO availability is not reduced. The purpose of this study was to determine the influence of a postexercise energy deficit, independent of CHO availability, on plasma substrate concentrations and substrate oxidation.

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My Sump-Pump Analogy for the ß-Cell

I'm going to try to make this as short and to the point as possible.  It's just me thinking out loud a bit, drawing on the massive amount of peer review research I've read on the topic -- a mere fraction of which I've formally blogged on -- but without any references so that I can just get this out there.  No ... this is not some manifesto grand theory on diabetes and all that to be analyzed and picked apart as if I'm presenting this as fact.  It's just a plausible analogy for what I think happens when metabolic mahem turns to "diabetes".  I'm also going to simplify things and deal with only glucose and fatty acids here.

Our ß-cells metabolize glucose and fatty acids the same way our other cells like muscle cells do for energy.  Essentially this metabolism is part of the mechanism by which the ß-cell senses the circulating levels of these energy substrates.  This metabolism also produces ROS -- reactive oxidative species.  While ROS are often seen as detrimental, due to the fact that they are in inappropriate amounts, the ROS molecules also play key signaling roles.  The metabolism of glucose and fatty acids produce a different redox state and ROS so this is roughly how the cells can tell what's being metabolized, etc.  

Insulin is secreted by ß-cells in response to both glucose and fatty acids.  In response to a sharp rise in glucose (e.g. eating a carby meal), an insulin "spike" is mounted -- an acute secretion of insulin -- the GSIS = glucose stimulated insulin secretion.  However we always have some basal level of circulating insulin (and it isn't as simple as some constant slow secretion) that is regulated to a significant degree by the levels of circulating free fatty acids, NEFA. The production of insulin can be simplified to modification of a precursor protein (proinsulin) to form insulin granules packaged in vesicles which eventually are released into circulation by the process of exocytosis.  There is some evidence that high demand for basal insulin depletes the proinsulin stores so that the cell can no longer produce the larger amounts of insulin required for an appropriate GSIS.

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Fat Tissue Expansion: Part II ~ Overview of How it Can Happen

In Part I, I laid out some terminology that we'll use in the discussion of how we get fat.  In this installment, I'm mostly going to list the various means by which fat tissue can expand, emphasis on the word can.  Because as future installments will lay out, while some of these mechanisms are plausible, some of these mechanisms contribute very little if at all to the fattening process. 

So what mechanisms might be involved in the expansion of fat tissue?  It is not controversial that fat tissue expands by two means:

• Adipocytogenesis:  The growth of new fat cells, increased fat cell number
• Adipocyte growth:  Increased size of adipocytes

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Fat Tissue Expansion: Part I ~ Terminology

One of the things that irks me about discussions of various obesity related topics is the inappropriate use of terminology.  I would like to give the benefit of the doubt and presume that for most who do this, it is inadvertent.   Often this is due to not having a complete understanding of human metabolism and physiology (cough ... ahem ... Mr. Gary Taubes) , but at some point, when speaking from a presumed position of authority, this excuse doesn't cut it.  To be fair, the peer review literature and higher level texts are rife with inconsistencies of their own.  Most authors are likely simply using the term they are most familiar with not realizing that those terms mean different things in different contexts.  Still, a careful reading of said literature is all that is needed to understand how they are using the terms and the process to which they are referring.  

This has been briefly addressed here previously.   As with insulin resistance, I think the "fat formation" realm is in dire need of some more clear definitions and applications of the terminology.   The terms adipogenesis and lipogenesis are often used interchangeably (even considered synonymous).  But I would like to propose that -- although it's probably not going to happen -- a revised and expanded terminology should be agreed upon and used consistently.   Expanded?  Yes, because the conversions between types of lipids -- the cyclic conversion of --  fatty acids + glycerol ↔ triglyceride -- is not a "genesis" of anything, it is merely a conversion of one form of lipid to another.  On that note ...

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