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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Fat Tissue Expansion: Part III ~ Fat Cell Number

Before reading you may wish to read:  Part I ~ Terminology , Part II ~ Overview of How it Can Happen

As mentioned in Part II, fat tissue expands by an increase (proliferation) of fat cells and/or a growth of the individual fat cells.  This installment concerns the number of fat cells and is likely the least "actionable" in this series in terms of diet, unless you're planning to have a child and/or have young children.   This does, however, lend some assistance to those formerly obese who are considering liposuction or more drastic surgery that may involve fat cell removal.  Bottom line, the number of fat cells we have is virtually completely out of our control as adults (according to current understanding). 

So this post will be rather short, and I plan to expand on the data we have regarding fat tissue development in infancy, puberty and other periods of childhood in subsequent installments.  It would appear that the number of fat cells we are born with is determined somewhat later in gestation.  At right is the progression of the formation of mature adipocytes.    From this article: 

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Fat Tissue Regulation ~ Part VI: Journey & Fate of Dietary Fat

Regulation of fatty acid transport and storage: influence of acylation-stimulating protein

Katherine Cianflone and Sabina Paglialunga, 2006

Commonly, the dietary sources of fat exceed the actual needs and the tissues are faced with dealing with the excess. Under these circumstances, the removal process of dietary triglycerides and fatty acids becomes overloaded, resulting in excessive postprandial lipemia and accumulation of chylomicrons, remnant particles and non-esterified fatty acids. These particles are associated with disruptions in lipoprotein metabolism and changes in inflammatory factors, thus their association with cardiovascular disease, metabolic syndrome and diabetes is not surprising. Dietary factors, not just fat, influence postprandial fluxes. This leads to the question: do we need a standardized fat tolerance test?

I've been reading a lot of studies lately dealing with postprandial clearance of fats from the blood and it certainly seems to me that these are coalescing to a hypothesis that the fat tissue fails first.  Oh but CarbSane, you've been saying this for over a year now  This is news?  Well, yes, in a way.  Gratuitous third person self referencing aside, it does still appear that a breakdown in fat tissue regulation is the precipitating factor in the metabolic dysfunction cascade in the majority of cases.  However this initial breakdown appears to occur on the uptake side of the adipocyte.  Impaired fatty acid uptake by adipose tissue leads to elevated postprandial circulating NEFA that are:

1. Excessive in the postprandial phase when they should be low, and/or 
2. Different in composition, reflecting dietary intake, from the types of fatty acids released from stored body fat.

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24 Hour Leptin Profiles ... Sleep Off Your Spiked Leptinade?

In Science Krispies ... Spiked Pink Leptinade Anyone?,  I took on Dr. Ron Rosedale's claim  that "glucose spikes leptin".  The study I highlighted looked at 9-hour insulin and leptin profiles holding protein constant and essentially comparing a near-zero carb meal to a near-zero fat meal and fasting.  I've copied that graphic to this post:

A&B = women, C&D = men

OK, so we do see that the HC meal results in slightly elevated leptin, more pronounced in women, delayed about 4-5 hours after the meal vs. HF or fasting.  Over on the Perfect Health Diet blog (thanks for the shout out Paul!) , Paul Jaminet wrote:  

CarbSane partially confirms Dr. Ron Rosedale: eating carbs does raise leptin levels compared to eating fat, but it is a mild rise over an extended period of time, not a “spike.”

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Adipose Tissue & Adipokines

Normally these days I'd put this in the library, since I'm not really going to blog on this, but I thought this paper a good one to share.

Adipose tissue and adipokines: for better or worse

In recent years, it has been recognized that adipose tissue (WAT) secretes a number of bioactive peptides and proteins, collectively termed “adipokines”.  These WAT-derived factors play a central role in whole body homeostasis by influencing a variety of biological and physiological processes, including food intake, regulation of energy balance, insulin action, lipid and glucose metabolism, angiogenesis and vascular remodeling, regulation of blood pressure and coagulation. The present review is focused on a restricted number of adipokines, which have been implicated in vascular (angiotensinogen, PAI-1) and energy and glucose homeostasis (ASP, TNFα, IL-6, resistin, leptin, adiponectin).  

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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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The Full Physiological Regulation of Fat Tissue ~ Part I of ?

Look it's late 2011 we have a disorder of excess fat accumulation, and low carb shills are saying that the physiological regulation of fat tissue by hormones secreted by the fat itself is irrelevant.  
~CarbSane channeling her favorite science fiction journalist/author

In this series of who-knows-how-many posts, I'm going discuss the full physiological regulation of fat tissue.   This was prompted by the response of the original LC Internet Kindergarten Cop to CICO vs. Regulation of Fat Tissue ~ Questions for Gary Taubes.  In that post I posed the following question:

  How can any hypothesis on the regulation of 

fat accumulation not include ASP and leptin? 

Indeed Taubes himself acknowledges the plethora of hormones in WWGF.  Note:  It's very easy to imagine how they can be so disturbed so that too much fat gets in and not enough gets out. {click to enlarge} 

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Of Microscopes and Myopic Hypotheses

Surely somewhere somehow in your life you've used a microscope.  If this was in grade school, perhaps the teacher set it up for you, but most do not escape high school or college, even as non-science types, without using one at some point.  Here is your basic microscope you might encounter in a biology or forensic chemistry lab or such.   

The light shines up from the bottom, through your sample, up through the objective lens that magnifies the image and through the eye tube to your eye.  The eyepiece usually adds additional magnification (10X).  A choice of three objective lenses that can be "dialed in" is quite common.  Note the different lengths of these.   The shortest lens is the lowest magnification lens and is often called the low power objective.  As lens length increases so does the magnifying power of the lens.  The technique for using the microscope is pretty universal and begins with something that sounds rather silly:  Finding your sample when you look through your microscope!  If there's dust on the lens or the stage, etc., depending on what you're looking for, you might find yourself looking at something other than your sample.  Dumb as that sounds, it's far more common than you might think, especially if what you're looking at is a hair or a fiber to begin with!  The focus knobs work to adjust the vertical height between the sample and the objective lens -- this is called the working distance -- within the range of heights you see your sample, outside that range you basically see nothing.    The working distance is the longest for the low power objective and can be very small indeed for the higher power objective (which, incidentally, tends to be the most expensive and delicate of the objectives)

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Free Fatty Acids and Cytokines Induce Pancreatic ß-Cell Apoptosis by Different Mechanisms

Free Fatty Acids and Cytokines Induce Pancreatic ß-Cell Apoptosis by Different Mechanisms

(I've scrubbed the distracting reference numbers from some excerpts of the introduction and I'm also going to try to cite only the information pertinent to T2)

Hypercaloric diets containing large amounts of fat, also called the Western diet, contribute to a major extent to the increasing prevalence of obesity and type 2 diabetes mellitus (T2DM). T2DM is characterized by peripheral insulin resistance, pancreatic ß-cell dysfunction, and decreased ß-cell mass associated with increased rates of ß-cell apoptosis. Elevated levels of circulating free fatty acids (FFAs) contribute to the pathogenesis of T2DM. High concentrations of FFAs lead to both impairment of insulin action and ß-cell dysfunction.  Moreover, FFAs have been shown to cause ß -cell death, mainly by apoptosis. 

Of note, increased adiposity is associated not only with increased FFA release but also with adipocyte secretion of a variety of cytokines and cytokine-like adipokines, such as TNF -α, IL-6, leptin, resistin, and adiponectin. TNF-α has direct cytotoxic effects on pancreatic ß -cells, especially in combination with other cytokines.

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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.  

Adipocyte Size & Adipokine Secretion

Relationship between Adipocyte Size and Adipokine Expression and Secretion

Context: Adipocytes are known to release a variety of factors that may contribute to the proinflammatory state characteristic for obesity. This secretory function is considered to providethe basis for obesity-related complications such as type 2 diabetes and atherosclerosis.

Objective: To get a better insight into possible underlying mechanisms, we investigated the effect of adipocyte size on adipokine production and secretion.

Design, Patients, and Main Outcome Measures: Protein secretion and mRNA expression in cultured adipocytes separated according to cell size from 30 individuals undergoing elective plastic surgery were investigated.

Results: The mean adipocyte volume of the four fractions ranged from 205 ± 146 to 1.077 ± 471 pl. There were stronglinear correlations for the secretion of adipokines over time. Secretion of leptin, IL-6, IL-8, TNF-, monocyte chemoattractant protein-1, interferon--inducible protein 10, macrophage inflammatory protein-1ß, granulocyte colony stimulating factor, IL-1ra, and adiponectin was positively correlated with cell size. After correction for cell surface, there was still a significant difference between fraction IV (very large) and fraction I (small cells), for leptin, IL-6, IL-8, monocyte chemoattractant protein-1, and granulocyte colony-stimulating factor. In contrast, antiinflammatory factors such as IL-1ra and adiponectin lost their association after correction for cell surface area comparing fraction I and IV. In addition, there was a decrease of IL-10 secretion with increasing cell size.

Conclusions: The results clearly suggest that adipocyte size is an important determinant of adipokine secretion. There seems to be a differential expression of pro- and antiinflammatory factors with increasing adipocyte size resulting in a shift toward dominance of proinflammatory adipokines largely as a result of a dysregulation of hypertrophic, very large cells.

Fat cells were removed from participants and isolated.  They were then separated into four fractions for each individual.  Fraction I (very small) to Fraction IV (very large).  Plots of the various parameters measured are shown below (see the article for more clarity) comparing the smallest (I) and largest (IV) fractions.

Some excerpts from the discussion:

The results of our study clearly indicate that adipocyte size is an important determinant for the secretion of several adipokines. In particular, the secretion of proinflammatory adipokines is significantly elevated in very large adipocytes compared with small or medium-sized adipocytes, even after correcting for cell volume and surface....

...In contrast to the published studies, which demonstrated associations between average adipocyte size and serum levels or secretion, our study is unique because it investigated the secretory capacity of adipocyte fractions from the same individual separated by cell size. The results obtained by the technique clearly suggest that only the very large adipocytes are dysregulated. Adipocyte hypertrophy appears to cause a differentially impaired secretion between pro- and antiinflammatory adipokines shifting the immunological balance toward the expression of proinflammatory proteins. Thisabnormal function of adipocytes may play an important role in the development of a chronic low-grade proinflammatory state in obesity, which is considered to build the common soil for the development of insulin resistance, type 2 diabetes, and atherosclerosis (5, 68)....

...In conclusion, the results of this study clearly indicate that adipocytes per se are an important production site for manyadipokines, although the relative contribution to the overall secretion from adipose tissue remains to be elucidated.

In the whole chicken-egg debate over obesity and inflammation, it seems that perhaps a certain degree of accumulated fat (large fat cells) sets off the inflammatory environment.   

The discussion in this paper contains quite a lot of background information on both the anti-inflammatory and pro-inflammatory components manufactured in and secreted by adipocytes.  I plan to revisit some of that.

Something else that caught my eye:  Recently, adipocyte size in the sc abdominal depot was identified to be a significant predictor for the future development of diabetes mellitus type 2 (5).  Note:  sc = subcutaneous, not visceral.  Must check this out.