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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Bump: The Diabetes "Crash" Cure & Pancreatic Fat

Today's 8/15/13 bump was inspired by a comment by Tsimblist (thanks!) alerting me to this paper:  Type 2 Diabetes Etiology and reversibility

Reversal of type 2 diabetes to normal metabolic control by either bariatric surgery or hypocaloric diet allows for the time sequence of underlying pathophysiologic mechanisms to be observed. In reverse order, the same mechanisms are likely to determine the events leading to the onset of hyperglycemia and permit insight into the etiology of type 2 diabetes. Within 7 days of instituting a substantial negative calorie balance by either dietary intervention or bariatric surgery, fasting plasma glucose levels can normalize. This rapid change relates to a substantial fall in liver fat content and return of normal hepatic insulin sensitivity. Over 8 weeks, first phase and maximal rates of insulin secretion steadily return to normal, and this change is in step with steadily decreasing pancreatic fat content.

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The New Paleo Diet Study: Just the Fats Ma'am

A Palaeolithic-type diet causes strong tissue-specific effects on ectopic fat deposition in obese postmenopausal women

I don't know that this study is worth three posts -- grin -- but I decided to break it up anyway.  I blogged on the diet itself here, and the weight loss here.  This post will address the impact on ectopic fat.  So first, I want to mention the "misleading title" peeves.  Ectopic fat is defined in the abstract:

Ectopic fat accumulation in liver and skeletal muscle may be an essential link between abdominal obesity, insulin resistance and increased risk of cardiovascular disease after menopause.

Here's the relevant synopsis of the results:

Liver triglyceride levels decreased by 49% whereas IMCL [intramyocellular lipid] levels in skeletal muscle were not significantly altered.

Which apparently garnered the conclusion:

A modified Palaeolithic-type diet has strong and tissue-specific effects on ectopic lipid deposition in postmenopausal women.

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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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Conjugated Linoleic Acid (CLA) ~ Good or Bad?

While I was looking at something unrelated (except that it was a fatty acid), the following popped up in my search:  Weight loss supplement - conjugated linoleic acid - shows nasty side effects.  Conjugated linoleic acid (CLA) first came to my attention, other than hearing about it as a supplement from time to time, during a discussion on trans fats and trans fat content of certain foods.  CLA is a trans fat, it's just not an unnatural nasty chemical we associate with the term these days.  It's found in meat of grassfed animals in particular, milk/dairy from same animals and eggs.   If you do a search on CLA and trans fat you'll turn up all manner of reports how it's the "good" or "healthy" trans fat.  In addition to some anti-cancer claims, it's also touted as the "belly busting" trans fat.  Sign me up!  

But, not so fast according to the article, which references two studies: (2007, nothing new here, just thought I'd pass this along as I hear buzz over CLA from time to time)

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Ketogenic Diets & Fatty Liver

Non-Alcoholic Fatty Liver Disease:  NAFLD.  Along with diabetes, a disease on the rise in the US and around the globe where the obesity epidemic is rearing it's ugly head.  Near as I can tell, Peter/Hyperlipid subscribes to a "damaged liver" hypothesis of obesity and diabetes.  That the liver gets damaged, throws your insulin and glucose outta whack, and then you get fat.  There can be no doubt that damage to the liver is an integral part of the metabolic syndrome(s) and the insulin resistance that underlies it.  So the question is, do we take it seriously in all contexts?  Or do we try to explain away inconvenient results when it is one's favored advocated diet that might possibly be a culprit?

Sadly, Peter seems bound and determined to spin ever more far-fetched mechanisms with which to explain away inconvenient results.  Having nothing to do with fatty liver, Peter found himself unable to backtrack on his definitive statement that it was fasting insulin levels that determined fat loss.  So bad was the evidence to counter this that he had to resort to manipulating study data to make his point.    It seems where high fat rodent studies are concerned, Peter was hell bent on blaming transfatty acids.  Now I'm no fan of the transfat, and they are indeed evil doers in any body, but they can't be blamed for everything. Indeed one just needs to look around to find high fat rodent diets that are not high in transfats.  Enter the other bad guy by which we can dismiss inconvenient results ... veggie oil PUFA.   True, many high fat rodent diets are very high PUFA ... but there are many that are based on lard.  You know, the stuff us moist eyed female types should wallow in to enter the glories of Slimville via the Ketogenic Highway?!

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Visceral Fat & Hepatic Fat -- Not one and the same

It seems that any time the discussion of fatty livers developing on ketogenic diets comes around, a spate of confusing discussions tend to ensue.  One of the confusing issues is that ketogenic reducing diets are effective at reducing hepatic fat levels.  However, these studies usually start with a fatty liver and with weight loss comes hepatic fat loss.  If there's a study out there where obese people are simply transitioned from a SAD to an equi-caloric ketogenic diet (85+% fat) demonstrating any change in liver fat accumulation, I'm not aware of it.  However I believe the evidence of rodents on such diets is at least enough to be concerned that the change, if any, would be for the worse, not the better.  

A lot of lean people also think, I can't have a fatty liver because I don't have a pot-belly so I don't have visceral fat.  One of the reasons I thought the Eades' 6 Week Cure for the Middle Aged Middle  book was such a disaster is that the first two weeks were supposedly devoted to detoxifying your liver.  There were several references discussing just that, and a reduction in hepatic fat.  I had high hopes for the book at the time, because I was expecting some science on how to specifically reduce visceral fat.  I was disappointed that there was little if any discussion devoted to this topic.  Let's look at the human abdomen.  For starters, the liver is rather assymetrical.  Additionally, although obesity leads to a higher prevalence of fatty liver, lean T1 diabetics have a rather high incidence of the disease.  Roughly a quarter of those with fatty liver disease (FLD) have normal sized livers, so accumulation of hepatic fat does not necessarily increase the size of the liver.  A normal adult liver has a span of 7-10 cm and an enlarged liver is over 2-3 cm larger.  Still, this does not seem to be sufficient to cause a large belly.  Also note the location of the liver.  Most "bellies" are considerably lower.

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Bloggo Science ~ FIRKO-ized!

I have long since ceased reading Peter/Hyperlipid's blog for meaningful information.  There are too many examples of him openly manipulating data and misrepresenting science for me to take him seriously anymore.  Still, our blogs share a certain readership and his readers do participate in other internet realms where I linger or participate.   As such, his blog remains on my feed reader.  Peter has been on a FIRKO mouse kick lately and it has caused me to dust off a few posts from the draft bin where this mouse fits into the discussion.  But his latest latest offering on FIRKO (Fat Insulin-Receptor Knock Out) just tripped my epigenetic BSA* gene switch.  *BSA = Bull Sh!t Alert

In FIRKO-ise, Peter actually compares a genetically modified mouse to putting a mouse on a ketogenic diet.  Really!  To review, the FIRKO mouse lacks insulin receptors.  As a result, this mouse is resistant to obesity on the usual obesogenic diet for rodents (high fat).  This mouse's fat cells do not "see" insulin and this is the low carbers favorite gen mod rodent because it so *clearly* shows that it's all about insulin signaling in fat tissue, and Taubes is right.   I'll have at the various IRKO's in an upcoming post, but the case is hardly airtight for TWICHOO.  

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Chill out, live longer? How do VLC & caloric restriction factor in?

I've been working on a related post when I came across an interesting study that I thought was worth a blog  post on by its own and was more timely for other studies I've been looking at more recently. A sidebar of looking into the claims of L.Ron Rosedale is that he's really all about longevity and believes his diet will deliver on that promise.  What I'm about to say may shock  some of you, but, there's some evidence out there that he might just be right!   The Catch 22, however, is that where he's correct it flies in direct conflict to the claims and theories espoused by the other ardent evangelists of carbohydrate restriction.  

Any research into aging and longevity these days inevitably lands one into a sea of studies on teeny tiny worms known as C. elegans.   I have some stuff in the pike on these worms, but basically, two ways of  "naturally" extending the lifespans of wild type C. elegans are (1) growing them under lower temperature conditions, and (2) forcing the worms through a dauer state (essentially dormant) developmental phase as larva through "starvation".  Both of these manipulations have the effect of producing adult worms with reduced metabolic rate.  (Worms are not intended to be the topic of this post, but here is one review on metabolic rate and longevity for those interested).  The other popular species for longevity experiments is mice.  Caloric restriction in mice has resulted in extended lifespan coupled with a reduced metabolic rate.  At first glance, run hotter/faster, burn out, run cooler/slower ... fade away?

In any case, with worms, the body temperature is easily controlled by manipulating the environmental temperature.  But what of warm blooded animals?  You put a warm blooded animal in a cold environment and their metabolism increases.  In the case of small animals like mice, they are blessed with relatively (to total fat and body mass) large amounts of brown fat (BAT) which is the thermogenic fat in such animals.  As an aside, the original uncoupling protein (UCP1) is that which generates heat in BAT.  Warm blooded animals have a vested interest in keeping their body temperatures within a relatively narrow operating range.  So ... you put a worm in a cold climate and it's metabolism goes down, you put a mouse in one, and it goes up.  A transgenic mouse to the rescue!

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Is MightyMeta Mouse Relevant to Real Humans?

In my last post, I discussed a study demonstrating that mice on a ketogenic diet ate the same number of calories as both mice on standard chow and the obesogenic high fat+sucrose diet, but lost body weight comparable to that seen in mice constricted to eating 66% of the standard chow calories.  I dubbed this a metabolic Mighty Mouse of sorts, MightyMeta Mouse.  I don't think we'll have enough installments of this to warrant an acronym -{grin} - I'll just use short nicks when I tire of typing it out.  

In any case, this study seems to validate some of the magical metabolic claims made by those who are able to eat thousands of calories on VLC diets while having been unable to lose or in some cases even maintain weight eating stand CRD level calories.  Well, I did the math in the prior post, and although Mighty does seem to manifest a metabolic advantage of sorts, this would not translate to much for the humans in question.  A couple of hundred calories a day tops.  

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Adiposopathy

Presented without comment on the content per se:

Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus

This is probably the most exhaustively referenced review article I've ever come across on the etiology of MetS and T2 Diabetes and the role of adipose tissue.  Too extensive to quote w/o copying the whole darned thing, although I may revisit it at some point to do a bullet point summary type post.  

Very Low Carb and Insulin Resistance

In response to my recent post -- Can low carb cause central adiposity? -- James Krieger posted a link to a recent study indicating I may well be on to something.  So I thought I would post this study separately (I don't have access to the full text on this one).

Longitudinal adaptations to very low-carbohydrate weight-reduction diet in obese rats: body composition and glucose tolerance.

Longitudinal effects of a very low-carbohydrate (VLC) and a calorie-matched high-carbohydrate (HC) weight reduction diet were compared in dietary obese Sprague-Dawley rats exhibiting impaired glucose tolerance and insulin resistance. Obese rats were divided into weight-matched groups: 

(i) VLC rats consumed an energy-restricted 5% carbohydrate, 60% fat diet for 8 weeks,

(ii) HC rats consumed an isocaloric 60% carbohydrate, 15% fat diet, and

(iii) HF rats consumed a high-fat diet ad libitum.

HC and VLC rats showed similar reductions in body fat and hepatic lipid at the midpoint of the weight-reduction program, indicating effects due to energy deficit. At the end point, however, HC rats showed greater reductions in total and percent body fat, hepatic lipid and intramuscular lipid than did VLC rats, suggesting that diet composition induced changes in the relative efficiencies of the HC and VLC diets over time.

Yes ... this is a rat study with all the issues inherent in trying to extrapolate to humans, but let's not forget Dr. Eades' favorite c57bl6-mouse that he says provides evidence for the so-called metabolic advantage of low carb diets.  In that study, the growth rate of ketogenic diet fed mice was stunted to that of the calorie restricted diet vs. three other diets.  I'll try to remember to update with a citation, but in one longterm study on epileptic children treated with a ketogenic diet, their growth percentiles (height AIR) declined following treatment.  But I'll leave a dissembling of this study and the conclusions Eades draws from it for another day.  

It is important to note that these were not genetically obese rats, but rather were made obese through diet and then put on weight loss diets.  In this study, the VLC and HC rats lost the same for a period of time but the metabolisms of the VLC rats apparently became more efficient indicating an adaptation.  Anecdotally, most low carbers seem to plateau out well above their goal weight.  The various long term studies of LC diets seem to follow a similar trajectory of rapid initial losses followed by regain that would be consistent with the findings of this study.  My own metabolism is in the tank as I do seem to become very efficient during long strings of low carbing.   It would be an interesting study to recruit a number of long term weight loss success stories and compare the metabolisms of VLC'ers to LF'ers.  

Back to the study:

HC rats showed marked improvement in glucose tolerance at the midpoint and end point, whereas VLC rats showed no improvement. 

This ties in with what I've been saying now in many posts regarding "curing" diabetes with low carb diets.  Whatever the glycemic issues of the VLC rats before diet and weight loss, the underlying metabolic impairment persists.  

 Impaired glucose tolerance in VLC rats at the end point was due to insulin resistance and an attenuated insulin secretory response.

So, again, a VLC diet may not only mask symptoms of IR and impaired insulin production, but could potentially sustain the underlying issues and/or further complicate matters by reducing the insulin response.  

Glucose tolerance in energy-restricted rats correlated negatively with hepatic and intramuscular lipid levels, but not visceral or total fat mass. These findings demonstrate that adaptations to diet composition eventually enabled HC rats to lose more body fat than VLC rats even though energy intakes were equal, and suggest that the elevated levels of hepatic and intramuscular lipid associated with VLC diets might predispose to insulin resistance and impaired glucose tolerance despite weight loss.

This paragraph reads a little vaguely to me b/c they lump the VLC & HC groups into one when they talk about the energy-restricted rats.   It sounds like they are saying that VLC rats had higher hepatic (liver) fat and intramuscular lipid (IMCL) compared to the HC rats and this correlated with impaired glucose tolerance/IR.  But visceral and total fat mass was not associated with IGT so it wasn't just the lesser VAT/SCAT fat loss of the VLC group that was responsible for the observed IGT and IR in these rats.

So, yes, this is a rat study.  But it is adding to concerns over long term low carbing.