Nutrient Fates after Absorption

Random Bump

This held the top spot in terms of readership here at the Asylum for quite some time.  Always worthy of a bump.

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Original post:  7/15/10

Nutrient effects: post-absorptive interactions BY ERIC JEQUIER   (1995)

After a meal, the metabolic fuel selection at the whole-body level depends on the plasma concentrations of nutrients such as glucose, non-esterified fatty acids (NEFA) , amino acids, and on hormonal responses. Over the last 10 years, there has been great interest in studying the metabolic effects following the ingestion or the intravenous (i.v.) infusion of the three macronutrients, carbohydrate (CHO), fat, and protein (or amino acids for i.v. infusion). The aim of the present brief review  {I'm thinking it's not so brief!}  is to summarize the main mechanisms which determine the post-absorptive interactions between the nutrients.

This is an older paper, but still recent enough to provide some good info on the basics.  I'm going to do something a bit different with this one and I otherwise would be quoting huge chunks.  So I'll do bullet point summaries with select summary quotes from the paper in italics.

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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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Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.

{shhhhhhhhh .... don't tell Gary Taubes, this might just upset his 21DaySugarDetox approved green apple cart!}

You know how the story goes by now, right? In more recent lectures, Taubes is fond of using the slide below.

source

These are two quotes that Taubes cites from Lehninger's Principles of Biochemistry and he juxtaposes them to convince you how misguided such textbooks are.  How can, on the one hand fat cells "fatten" according to the action of insulin, but human beings get fat due to positive energy balance?   The simple answer is that insulin is not some renegade hormone and your pancreas is not a master organ in the body placating your rebellious adipocyte's every whim.

Yes, tis true that insulin has a stimulatory role in the storage of fatty acids by acting on LPL on the intake side, and yes, tis true that insulin "traps" those fatty acids in the adipocytes by suppressing HSL mediated lipolysis and release of same.  Sounds like a slam dunk.  If there's too much insulin, ostensibly from chronic spiking due to chronic carbohydrate consumption, the fat cells get stuck in storage mode and the horizontal growth disorder is primed for obesity!

Not so fast.  How can the results of this study be then?  Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.   The abstract, bullet-pointed for ease of reading:

• When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. 
• FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. 
• Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet–fed mice. 
• In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. 
• The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. 
• In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. 
• In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. 
• In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. 
• Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity.

Cliff Notes Version:  Decreased lipolysis from WAT increased skeletal muscle glucose uptake and DNL in the liver without resulting in increased WAT mass.  In the obese, suppressing WAT lipolysis induces DNL in the fat tissue.  This improves glucose metabolism.

All of the evil things you were told insulin did to you -- turning carbs to fat in your liver and fat tissue and suppressing lipolysis from fat tissue -- are actually good for you.  And the (temporary) trapping of fat in the adipose tissue improves insulin signaling and glucose handling in the skeletal muscle.  

Imagine that ...

July 4, 2013 Over the Hump Bump: Where does insulin resistance start? The adipose tissue

The readership in this blog continues to grow and it is not lost on me that a vast majority of current readers are unfamiliar with the bulk of my work here on this blog.  I think I'm closing in on 1000 posts which would make me one of the more prolific bloggers around ... for better or worse!  As such, I more than understand that it would be darned near impossible to catch up, etc.  So a few comments in that vein.  

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That 5000 Calorie Jokesperiment

Note:  I started this article with the intent of it being a single stand-alone before Smash the Fat's Sam Feltham had done his final summary of his overeating stunt.  Since then, however, he has written said summary and I've written two posts discussing this disconnect between the you-can-eat-all-the-calories claims and the current uber-restrictive low carb plans many long time low carbers are actually following themselves.  See:  Fast or Feltham and Fast or Feltham II

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Apologies in Advance:  I wrote this with updates/edits over several days and with "new information" coming in the interim.  It could probably use a good bit of editing and crunching down, but as this is just a blog, I'm going to publish it up w/o wasting time on that.  Please forgive the length, repetitiveness, etc.  Thanks!

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De Novo Lipogenesis Again (and Science and Science Reporting)

In my last post, I just posted a graphic taken from an "FYI" inset by a scientist, Marc Hellerstein, whose work I've blogged on quite a bit here. (Anyone wanting to refresh can click on the image and enlarge.)  One good post to begin with if you are not familiar with that name is Where do Triglycerides Come From? I would say that between Marc Hellerstein's No common energy currency: de novo lipogenesis as the road less traveled and the works of Eric Jequier such as Nutrient effects: post-absorptive interactions, the case that hepatic DNL is quantitatively insignificant in human energy balance/fat accumulation is strong and has not been refuted by some newer scientific findings.    

I do hope to expand on the role of adipose DNL at some future point -- teaser: I have a paper showing that reducing WAT lipolysis upregulates adipose DNL and improves glucose homeostasis in the IGT irrespective of body weight  -- but adipose DNL had not been central to the arguments of folks from Taubes to Lustig to Eades to Naughton to a list far too long to go through here.  The claim has been that excess carbs are converted in the liver to fat and sent to the fat tissue for storage.  

Does this occur?  Yes.  Is it significant?   Only if you consider a couple grams fat synthesis per day significant at the metabolic cost "wasting" one gram carb for every four grams converted to fat ... and only if you consider a few grams of fat significant in the context of consuming 100, 200 or more grams of fat that is already fat.

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Do Carbohydrates Turn into Fat?

From Discovering Nutrition

Insel, Turner & Ross,  copyright 2010

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The Problem with Science in the Incestral Health Community

I've been discussing lately the entangled web of relationships and referencing in this community, and I have decided that henceforth I'm going to call it on this blog what I've called it in my head for a very long time:  The Incestral Health Community.   This is because everyone has ties to everyone else (or enough) and apparently nobody feels even the slightest bit interested in vetting one another, let alone any professional obligation to do so before slapping the affiliate logo on their website or inviting fellow IHC members to speak at their events.  

I've also been highlighting credentials of late, and will continue to do so when I feel that it is pertinent.  I want to make sure that everyone reading here understands that I am not passing judgment on anyone's academic record, highest degree held, etc.  Fer crying out loud, two of the smartest women I've had the privilege of knowing both dropped out of high school in the 9th grade.  And sadly, the number of functional illiterates matriculating at prestigious institutions these days is mind-blowingly astounding. This is not about academic elitism or snobbery.  It IS about discussing just what makes for an authority, an expert, etc.

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Obesity Related Diabetes & How Gary Taubes has it all Bass Ackwards

Starting sometime in April, I started coming across a deluge of new information related to diabetes -- the classic obesity related T2 diabetes (roughly 80% of T2's are obese, those are the ones I'm talking about here).  There's so much, and by research groups I'd "researched" before, I'm simply amazed I somehow never came across it before.  It's frankly sidetracked me quite a bit from where I was going before the first light bulb over head find, because it all just seemed to fall in place like dominoes fall in some of those intricate arrangements that I'm always intrigued by.  

The first discovery was not in a journal article, however.  It was that I finally got my paws on Lehninger Principles of Biochemistry, 4th Ed (2004) and 5th Ed (2008).    This book is cited frequently by low carbers due to the fact that in recent years Taubes snickers at how stupid the scientists who wrote the book are with two short excerpts he claims are in conflict.  You probably know what I'm talking about, where one quote discusses all the ways insulin puts and keeps fat in cells, and then the next one states something to the effect that obesity is the result of calories in exceeding calories out.   Around that time I came across this interesting, almost memoir, written in 2004 by Richard Hanson.  It's even poignant at times and I enjoyed reading it.  As Taubes tells it, he ran Chapter 22 in GCBC by Hanson (and he's thanked in the credits) and had interviewed him for the book.  A major component of Taubes' Adiposity 101 was the part of this chapter dealing with our old and forgotten molecular friend:  glycerol phosphate aka alpha glycerol phosphate aka glycerol-3-phosphate, I'll call it G3P.

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Insulin Injection Effect on Fat Tissue

I'm sure most of you are familiar with the picture of the unfortunate woman below from Gary Taubes repeated use of this picture in lectures.    The top is a screenshot from Google Books of Endocrinology:  An Integrative Approach, 2001, Nussey & Whitehead, page 31.  At the lower right, I've copied the discussion of Box 2.8 from the previous page.

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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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Review & Critique: The Skinny on Obesity ~ Part II Sickeningly Inaccurate

Previously:  Intro & Part I

The second installment of the University of California production, The Skinny on Obesity, featuring Dr. Robert Lustig and colleagues is entitled Sickeningly Sweet.  I've embedded the video at right.  I've entitled this installment of my Review & Critique Sickeningly Inaccurate.  That is, frankly an understatement about the information presented in this episode.  This video epitomizes what's wrong with many of the "anti-establishment" nutritional experts.  You do not counter bad science with more bad science.  This is what Lustig does here.  And it's not controversial -- at least there's some evidence supporting the lipid hypothesis -- but the "science" here is counter to known basic biochemistry and in opposition to the vast majority of the evidence of metabolism such as de novo lipogenesis.

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Fructose, Fat & Obesity

The other day, Stephan Guyenet shared some of his own thoughts on David Despain's can't-say-enough-nice-things-about-it interview with Dr. John Sievenpiper.  In case you missed it, Stephan discusses his post looking at the links or lack thereof  between sugar consumption per se and obesity.  See:  Is Sugar Fattening?  At the end of the current post is the following footnote:

** If fructose is fattening due to its ability to become fat, then dietary fat should be even more fattening because it doesn't have to undergo an inefficient conversion process-- it's already fat.

Excellent point!  I might add that if saturated fat is such a healthy fat for your body, fat produced by de novo lipogenesis -- mostly palmitic acid in the liver -- would be an even better source of that fat as it would give you a "metabolic advantage"!   It takes almost no calories to digest and store dietary fat in body fat.  It is highly energy intensive to convert fructose to fat, so you get some free calories!

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Great Interview on Fructose ~ The "Other" Side

This one is too good just to tweet.  One of those gems I mentioned the other day is David Despain's Evolving Health blog.  He's been posting quite a bit of late on fructose.  His latest:   Fate of fructose: Interview with Dr. John Sievenpiper.

It's definitely worth reading the whole thing, but I'll excerpt a few things that address the problems with many of the fructose studies and problems with them, and some nice correcting of Lustig & Co.:

• The 50th percentile for intake in the United States is 49g per day, which is just a little less than 10 percent per day of energy from fructose. ... the 95 percentile for intake for NHANES for fructose consumes 87g of sugar or little less than 20 percent energy.

It seems to me that sugar consumption in the US is often inflated, and the inflation is done by those who seem to have an "crisis agenda" -- by that I mean looking to whip up a crisis for the purpose of enacting legislation or finding a new tax revenue stream. So related to the quote above, Sievenpiper takes issue with the "superphysiological doses" of fructose used in most studies.

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Intermittent Fasters might be interested in this.

METABOLIC ADAPTATIONS TO A "STUFF AND STARVE" FEEDING PROGRAM. I. STUDIES OF ADIPOSE TISSUE AND LIVER GLYCOGEN IN RATS LIMITED TO A SHORT DAILY FEEDING PERIOD

This is quite an old study, published in 1962, and it's in rats who are known to have greater DNL in adipose tissue.  This was a fairly short study, wherein rats were put on a 2 hr/day ad libitum eating schedule for one week.  Intake was 60% lower on day 1, but back up to 95% of normal ad libitum intake by the second day.  Thus the rats lost weight early on, but were back within 10% of their start weight by week's end.  

Essentially it appears that in short order with a switch to such a regime, adipose tissue storage and DNL in adipose tissue is upregulated considerably (10 fold).  Normally a 24 hr fasted rat will have depleted glycogen stores as some is burned along with fatty acids.  Rats adapted to this regime had full liver glycogen after the 24 hr fast indicating that they likely use fats preferentially for fuel.  

Interesting ... not sure what it means in humans.  But if something similar occurs, it could explain the insulin resistance many IF'ers seem to have, as non-oxidative glucose disposal -- e.g. glycogen synthesis -- is a major route of glucose disposal that is "defective" in IR states when reserves are high.  Especially with LC, if glycogen is spared and glycogenolysis doesn't provide blood glucose, gluconeogenesis would be upregulated. The combo with hepatic IR may well be the reason why IF'ers often have quite high fasting blood glucose.

De Novo Lipogenesis ~ Another Case of an Undeserved Bad Reputation?

OK, let's get back to some science here :-)  In comments on my recent query for evidence that insulin blocks leptin in the brain, Kindke posted a link to the following article:  Yin and Yang of hypothalamic insulin and leptin signaling in regulating white adipose tissue metabolism.  

ABSTRACT:   Fatty acids released from white adipose tissue ( WAT) provide important energy substrates during fasting. However, uncontrolled fatty acid release from WAT during non-fasting states causes lipotoxicity and promotes inflammation and insulin resistance, which can lead to and worsen type 2 diabetes (DM2). WAT is also a source for insulin sensitizing fatty acids such as palmitoleate produced during de novo lipogenesis. Insulin and leptin are two major hormonal adiposity signals that control energy homeostasis through signaling in the central nervous system. Both hormones have been implicated to regulate both WAT lipolysis and de novo lipogenesis through the mediobasal hypothalamus (MBH) in an opposing fashion independent of their respective peripheral receptors. Here, we review the current literature on brain leptin and insulin action in regulating WAT metabolism and discuss potential mechanisms and neuro-anatomical substrates that could explain the opposing effects of central leptin and insulin. Finally, we discuss the role of impaired hypothalamic control of WAT metabolism in the pathogenesis of insulin resistance, metabolic inflexibility and type 2 diabetes.

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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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The Dietary Source of Body Fat

Over on Stephan Guyenet's blog, in the comment section of his post on Humans on a Cafeteria Diet, a little discussion was started by one disgruntled reader (or I suppose ex-reader since this post apparently pushed him over the edge to unsubscribe) regarding where the fatty acids in our body fat came from.   Stephan wrote:  

When a diet of mixed macronutrient composition is eaten to excess, the carbohydrate is preferentially burned off, while the fat is mostly shunted into fat tissue. This makes sense, because why would the body go through the inefficient process of converting carbohydrate to fat for storage when it can just shunt dietary fat directly into fat tissue?

Said reader commented:  "This post has good info, but suggesting the fat is stored as fat is absolutely wrong and is bad science."    A discussion, contributed to by yours truly, ensued.  I think this is illustrative of just how damaging towards ultimate progress in the realm of understanding, preventing and treating obesity Gary Taubes has been.   On page 387 (according to Google books, my ebook page numbers are off) of GCBC, Taubes writes:

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What Does Insulin Regulate Anyway?

Sorry about the acronyms.  A glitch in my new system.  I'll edit in later if I get a chance.

I hate semantics, and at the same time I can be a stickler for the notion that "words count" at times.  When I hear the word regulate, as in A regulates B, I substitute the word control.  So A controls B.  And this ultimately means that A determines what B is.  

Part of TWICHOO is that insulin *fundamentally regulates* fat accumulation.  What Taubes is saying is that insulin regulates fat tissue mass.  Insulin controls fat tissue mass, and ultimately that means that insulin levels determine how fat you are.  

To state his case, Taubes zeros in on the TAG/FA cycle that occurs continually in the fat cell, and the known fact that insulin regulates this cycle (to large extent).  This is not in dispute, although the relative weight of insulin's actions on the outcome may be somewhat argued in these circles.  The full TAG/FA cycle is pictured at right (from Reshef et.al. 2003) -- the version Taubes discusses in GCBC.  We see that triglycerides and free fatty acids are constantly cycling in the fat cells, and between the fat tissue and the liver and muscle tissues.  Some is taken back up again.  

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