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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Some Suggested Reading ...

In light of other recent events, I present some suggested posts from this blog on the questionable accuracy of the blogging of one Peter Dobromylskyj aka Hyperlipid.

1.  Bloggo Science ~ A Hypothetical Post ~ III: Fasting Insulin & Weight Loss

Summary:  The third post in a series (links to I & II within) outlining how Peter deliberately fudged the data from the "infamous" Grey & Kipnis study.  He even told his readership he was doing it and tips his hat to Ancel Keys.  I feel to this day that if anyone can read this series and take Peter seriously after that.  It was done in all seriousness on his part.  

2.  Bloggo Science ~ LIRKO Wars Edition

Summary:  Peter blogged on the LIRKO mouse with a "cute" quiz about making jam from the urine of this mouse.  One problem, LIRKO doesn't get glucosuria.  Other claims made are also easily dispelled including that this mouse's liver (and other cells) can't process glucose so they burn through fatty acids like mad and that's why they don't get fat,  and that this mouse's muscle cells "internalise their insulin receptors".

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LIRKO vs. TWICHOO X.0

from this study, image from this post

It occurred to me as I was thinking again about LIRKO, that this little mouse not only countered TWICHOO 1.0, but it pretty much puts the lid on TWICHOO X.0.  This profoundly hyperglycemic and hyperinsulinemic liver insulin-receptor knockout mouse, is not fat.  Though not statistically significant, the trend is to eat a tad less, be a tad smaller, and pack on fewer fat grams  than controls.  But let's just call it a wash.

For any newer readers, TWICHOO stands for Taubes Wrong Insulin-Carbohydrate Hypothesis Of Obesity.  Version 1.0 was that which was put forth in Good Calories Bad Calories.  In this version, Taubes put forth four ways by which the carbohydrate could promote obesity:

1.  Carbohydrates stimulate insulin which stimulates fat storage and/or traps fats in our fat cells so fat accumulates.

This was pretty much the "lead singer" of his Barbershop Quartet singing the TWICHOO jingle.  Carbs stimulating insulin basically led to chronically elevated insulin levels.  The other three are:

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Remember LIRKO? Grey & Kipnis?

So a recent research paper has been making the rounds.  It has a "red meat" title for the die hard TWICHOOB:  Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production.  This paper was brought up in my comments section as well.   Every time this happens I really do feel like I'm in some sort of nutritional remake Groundhog Day.    I'm a bit backlogged at the moment, but luckily Stephan Guyenet has weighed in with his analysis and included some additional studies in support of his position.  

Whenever I think hyperinsulinemia causes obesity,  I'm reminded of the LIRKO mouse.  LIRKO is normal except its liver lacks insulin receptors.  The result is a mouse with raging hyperglycemia and hyperinsulinemia throughout much of its young life until its liver poops out.  I blogged on this mouse here:  Bloggo Science ~ LIRKO Wars Edition.  (Incidentally that post links to an older post by Stephan on the role of hyperinsulinemia here.)     Here's the rundown on LIRKO:

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Fat Tissue Regulation ~ Part IX: ASP, LPL and the Triglyceride/Fatty Acid Cycle

In this installment, we reunite with our old friend C3KO mouse to learn a little bit more about the role of acylation stimulating protein, ASP, in the regulation of fat tissue (and muscle) from this study:  Differential regulation of fatty acid trapping in mouse adipose tissue and muscle by ASP.  The C3KO mouse was discussed in Part II of this series.  This mouse lacks the gene to produce a protein called C3 (short for Complement 3) which is a precursor for the formation of ASP.  Thus C3KO mice are ASP deficient.  The C3KO is to ASP as a type1 diabetic is to insulin.  These mice are also resistant to obesity.  BTW, hyperASPemia accompanies the hyperinsulinemia and hyperleptinemia of obesity when it's measured.

ASP-deficient mice have delayed postprandial triglyceride (TG) clearance and reduced WAT mass. The objective of this study was to examine the mechanism(s) by which ASP deficiency induces differences in postprandial TG clearance and body composition in male KO mice.

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Insulin Resistance III: Glucose Uptake and GLUT4's

So far with this series, I've discussed the many difficulties involved in discussing and characterizing insulin resistance, IR.  See Part I: A condition in dire need of diagnostic clarity  and Part II: The Complexity of Hormone Resistance Phenomena.    Insulin-mediated glucose transport, or "disposal" from circulation is the major action/phenomenon usually assessed or being discussed when a person (or lab animal) is described as "insulin resistant".  

So in this part, I wanted to discuss glucose transport.  This link is a nice tutorial about the action of insulin that includes an animation of ONE of its functions:  glucose transport.  Glucose cannot traverse membranes unassisted.  In essence it must pass through protein "channels" from one side to the other.  There are always glucose transporters, called GLUT's, present in the cell membrane, but they are not always at the exterior surface of the cell to receive glucose.  Insulin binds to the receptor which signals movement of the transporters to the surface (translocation) allowing glucose to flow down the concentration gradient through the GLUT "channel".   I've labeled the components in the screenshot below, and "taped" a short video of the animation from the tutorial so you don't have to go off-blog if you don't want to:

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More Bloggo Science

Sigh.  I would normally comment on a person's blog if I read something like this:  Insulin, the Un-dead and coffin nails, but since Peter doesn't want to distract his readership with potentially productive discussions amongst them, I refrain from posting there.  In the article he makes two statements I find rather outrageous:

Hyperglycaemia causes insulin resistance. This is not controversial, as far as I am aware.

It's not controversial in those circles who repeat it uncritically.  It's not really controversial that this statement is wrong.    Let's take this together with another statement:

Let's summarise. This is very, very important:
   Excess insulin causes insulin resistance
End summary.

This is just day to day internal medicine. You have to pay the mortgage somehow.

Only this too is at the very least controversial, and almost certainly not true in most cases.
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Insulin Resistance II ~ The Complexity of "Hormone Resistance" Phenomena

It's been a while since Part I of this series ... too many irons in too many fires and all that jazz.  But one research track I went down recently reminded me of this lingering series and I thought I'd finish up this second installment. We hear all the time truisms such as that the acute effects of a hormone differ from the chronic effects, and whenever a hormone is present in excess of normal levels, the term "fill in hormone here resistance" is sure to be close behind.  Now there is no doubt that hormone resistance is a very real phenomenon, but what does it mean, specifically?

The concept of insulin resistance, IR, is highly complicated by the fact that insulin has varying actions in various tissues and organs.  I do intend to discuss tissue-specific IR in more depth as this series unfolds.  But for today, I am going to limit the discussion to insulin and the muscle cell.  After all, when general IR is discussed, it is usually systemic or skeletal muscle insulin resistance.   

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Of Mice & Men: My Rodent Study Disclaimer

The purpose of this post is to have a sort-of "disclaimer" to link to (if I can remember) whenever I discuss a rodent study here at the Asylum ... A small manifesto if you will, on my feelings on the utility and limitations of rodent studies in relation to human beings.   Also, I look at this post as a way to remind older readers and/or inform newer readers as to my background.  I spent roughly five years in the company of countless rats and mice, working for Big Pharma, and when I speak of rats, I'm not talking about my colleagues ;-)  My job was half analytical chemistry, half metabolism.  I worked on mostly discovery level drug candidates (a level before development) characterizing the absorption, metabolism and routes of excretion of these drugs, mostly antidepressants.  As such I've chopped the heads off of more rats than I care to recollect, opened up countless abdomens of mice to get maximum blood samples from the vena cava, removed/homogenized and analyzed countless livers, brains and intestines, observed behavior of these animals in their cages when dosed with the drugs I was giving them, etc.etc.etc.   As such, I do take somewhat personal affront to those who issue blanket dismissals of any animal studies.  As far as I'm concerned you're all a bunch of hypocrits unless you have never taken anything more than an aspirin and/or never intend to and plan to die a "natural death" feeling full pain and discomfort from whatever might befall you on this journey we call life.  I'm not going to turn this into a defense of Big Pharma, I have no affiliation, and since the days when I worked there (late 80's) I've felt our country is vastly over-medicated (and it has only gotten so so much worse since).  But I mention this because I believe my perspective is a bit unique in this regard.

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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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Bloggo Science ~ LIRKO Wars Edition

Well, a little back and forth is going on these days over the LIRKO mouse.  What's a LIRKO mouse?  Well, the acronym says it all, LIRKO = Liver Insulin Receptor Knock Out.  This mouse's liver doesn't see insulin.

So back in May, Peter/Hyperlipid posted about the LIRKO mouse,  LIRKO mice (1).   This post referenced this study:  Loss of Insulin Signaling in Hepatocytes Leads to Severe Insulin Resistance and Progressive Hepatic Dysfunction.  Almost simultaneously he posted  LIRKO mice (2) which dealt with this study:  High Circulating Leptin Receptors with Normal Leptin Sensitivity in Liver-specific Insulin Receptor Knock-out (LIRKO) Mice.    (A peeve:  The full texts of both of the studies referenced in these posts are available free online.  Why not link directly to the full text?)

About a week or so ago, continuing with his own dismantling of TWICHOO, Stephan Guyenet posted Does High Circulating Insulin Drive Body Fat Accumulation? Answers from Genetically Modified Mice.  Single line smackdown:  A lot of hyperinsulinemic mice out there aren't accumulating fat tissue as a result.  One of the gen mod mice Stephan mentions just so happened to be Peter's friend LIRKO.  

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Fat Tissue Regulation ~ Part V: C5L2KO - Meet the New Droid, Kinda Like the Old Droid

It seems that our friend C3KO city mouse has found his country mouse cousin:  C5L2KO.  In keeping with the Star Wars saga, albeit stretching things a bit with this one, I've found the depiction of our new friend!

To catch up, C3KO is a knockout mouse lacking the ability to produce Complement 3 (C3) protein which is a precursor for production of acylation stimulating protein, ASP.  Therefore C3KO is ASP deficient.  The result of this genetic mutation is to produce a mouse that is resistant to obesity, and essentially an ASP equivalent of insulin deficiency -- Type 1 diabetes.  If you've not read about C3KO, here are the links to the two relevant installments in this series:
  Fat Tissue Regulation ~ Part II: Meet C3KO
  Fat Tissue Regulation ~ Part III: C3KO Meets Obi No Leptinobi

It is known that fat tissue expresses insulin receptors.  Indeed this has been exploited to more clearly elucidate the roll of insulin acting on fat tissue in the form of insulin receptor knockout mice, the FIRKO mouse (F = fat specific, IR = insulin receptor) to be exact.  As it is less well characterized, ASP action on fat tissue is not universally well known or acknowledged.  Indeed ASP is pretty much a TWICHOOB's worst nightmare.  It seems silly to me to even be having this part of the discussion because it is absolutely not controversial that ASP plays a critical role in clearing dietary fat into the adipose tissue.  Or, we are to believe the fat tissue itself manufactures such a hormone for no purpose related controlling its own function.  Huh?  In any case, one piece of the puzzle that was missing was how ASP works and the absence of an identified receptor.  This piece of the puzzle was found in 2005 by Katherine Cianflone's group.

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Fat Tissue Regulation ~ Part III: C3KO Meets Obi No Leptinobi

In the previous post in this series, we met the C3KO mouse, a mouse that is ASP deficient.  In this post, I'm going to discuss what happens when you take a leptin-deficient ob/ob mouse and also make it a C3KO.  Humor me my fun with Star Wars characters ;-)

It turns out I had discovered this study and blogged on it over a year ago:  Acylation-stimulating Protein (ASP) Deficiency Induces Obesity Resistance and Increased Energy Expenditure in ob/ob Mice   (Xia, Sniderman & Cianflone).

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Fat Tissue Regulation ~ Part II: Meet C3KO

I've shortened the title of this series from The Full Physiological Regulation of Fat Tissue to allow for some descriptions of each installment without generating 30 word blog post titles.  Yes, I did consider TFPRFT {cheeky grin} but thought the wiser of that one! 

Allow me to introduce you to C3KO 

(note my high tech graphics skills!  LOL)

No, C3KO is not a character in Star Wars Episode MMXI*:  Battle for the Adiposity Galaxy.  Rather, there is a protein known as Complement 3, C3 for short.  The complement system is an important one in the functioning of our immune systems and has long been recognized for mediating inflammation.  In studying the role of this protein in physiology, researchers created a C3 knockout mouse -- one that does not produce C3.  This mouse is sometimes called C3KO**   

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