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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Life, Risk & Biomarkers

Let's start out with a little nostalgia, eh?  Before video games, there was a time when humans played boardgames, like Life and Risk.

Newman & Kramer play Risk on the subway!

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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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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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Join a discussion on: Saturated fatty acids and insulin resistance

Hi gang!  I'm going to try something a little different here with my blog.  Mirrorball had the idea to start a Scientific Discussion Group of sorts over at the Meeting Rooms, but we're not getting much in the way of takers.    So I thought I'd try a few things.

The first is this post per se, because I know far more people read feeds, etc., to see if we can't snag a few more interested takers for such a thing.

The second is that the really cool thing about my discussion board system is that I can embed a topic right here in this blog post for everyone to talk amongst themselves without going anywhere, yet this thread will be over in the Scientific Discussion sub-forum at the Meeting Rooms.  This should also give those who have trouble logging into blogger the ability to join in as well.  The default is a flat style display, but this should also allow for greater ease in following discussions that have, at times, become very difficult to follow in the comments here.  With the discussion you can view things in list and threaded form to navigate a reply thread and reply inline.  You can even reply by email if you select the "Email replies" option.  How cool is that!

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Some links about Gut Microflora

This is mostly a bookmarking post to put some links out there.

Same poop, different gut - this one deals mostly with fecal transplants to treat bacterial infections

The gut flora as a forgotten organ - mostly dealing with diseases though touts the promise of obesity relationship

The environment within: how gut microbiota may influence metabolism and body composition - An excellent review of the current understanding of the role of gut flora in inflammation, disease, obesity, etc.  The lead author is the researcher who did the fecal transplant study on obese men that demonstrated improvements in insulin sensitivity (see next link).  I recommend reading this one.  IMO, at this point, finding a bacterial solution to obesity seems to be a long-shot and lots of wishful thinking.  

Fecal Transplant Flushes Insulin Resistance  I really look forward to their upcoming publication of this work.  It will be interesting to see the magnitude of the improvements, if it persisted past 6 weeks (e.g. was there a change in the IR as triglycerides returned to "normal"?), and the long term analysis of the microflora pre & post-transplant.  

I wonder how much of this has less to do with the bacteria and more to do with flushing the gut.  We recycle proteins and lipids in our intestines, and perhaps removing cholesterol and other phospholipids tricks the body into thinking it's in a totally different state of nutrition?  If this is so, one would expect things to return basically to "normal" down the line.  

Insulin Is an Anti-inflammatory and Anti-atherosclerotic Hormone

Insulin Is an Anti-inflammatory and Anti-atherosclerotic Hormone  (full text free until end of the month)

Fasting hyperinsulinemia is associated with an increased risk of atherosclerotic complications of heart attack and stroke. This has resulted in the concept that insulin may promote atherosclerosis in spite of the absence of any evidence that insulin is atherogenic either in the human or in experimental models. Recent evidence shows that insulin exerts vasodilatory, anti-platelet and anti-inflammatory effects at the cellular level in vitro and in the human in vivo. Since atherosclerosis is a chronic inflammatory process of the arterial wall, insulin may be potentially anti-atherosclerotic in the long term. More recent data on experimental atherosclerosis in the mouse shows that (1) insulin administration reduces the number and the size of atherosclerotic lesions in apo E null mice and (2) in IRS-2 null mice, the interruption in insulin signal transduction results in enhanced atherogenicity. Finally, the use of a low dose of insulin infusion in patients with acute myocardial infarction has been shown to markedly improve clinical outcomes, both in diabetic and nondiabetic patients. Our own most recent data show that a low dose infusion of insulin in patients with acute myocardial infarction induces a reduction in nflammation (C-reactive protein and serum amyloid A) and oxidative stress, and promotes fibrinolysis. We conclude that insulin is anti-inflammatory and potentially antiatherogenic and may be of use in the treatment of cardiovascular inflammatory conditions.

It seems that the demonization of insulin has followed much the same path as the correlation = causality logic of LDL and atherosclerosis.  Elevated LDL correlates with CVD, but there is not a whole lot of actual evidence demonstrating that the LDL itself directly causing atherosclerosis.   LDL remains a fairly reliable marker for determining risk (though it must be considered along with other factors), and whatever the flaws (and there are many) in cholesterol theories, this shouldn't be ignored out of hand.  If A causes B, and A causes C, then someone with B likely has C.

So with the insulin, we have hyperinsulinemia correlating with CVD, but as stated in the abstract above, there's little evidence that it causes it directly.  The "A" in this scenario seems to be elevated free fatty acids (NEFA/FFA) leading to "B" = hyperinsulinemia and "C" = atherosclerosis.  But in this case the correlation/causation connection may be even more convoluted.  Because there's an intermediate factor in all this -- the ever-increasingly apparent root of all evil: insulin resistance.  The way I see it is this:  Fat stores exceeding an individual's storage capacity lead to IR of the fat cells and/or excessive release of NEFA.  Elevated NEFA induces IR in peripheral tissues.  It is cellular resistance to insulin's inhibitory roles  in these cells that ultimately lead to metabolic dysfunction and/or cell damage/death.  In this regard, the relationship is not so much one of insulin not being the cause of atherosclerosis, etc., but the resistance masks the fact that it would appear that insulin is actually protective against it!  

Inflammation, shmimflamation!  :

Atherosclerosis is an inflammatory process.7 All the major classical risk factors for atherosclerosis, hypercholesterolemia, diabetes, hypertension, smoking, and menopause are associated with (and probably cause) inflammation. If high insulin levels are atherogenic, one would expect it also to exert part of its negative effect on the vessel wall through inflammatory processes. Recent evidence which we shall now review shows that just the opposite is the case, i.e., that insulin is anti-inflammatory.

The article goes on to summarize such research.  I'll let the more science minded read that for themselves (heck, I'm just too lazy at the moment to do a decent summary), but this section concludes with:

In view of the anti-inflammatory and vasodilatory effect of insulin, insulin resistance may be expected to be pro-inflammatory and a proconstrictor state. This indeed is the case.  Obesity,31 type 2 diabetes,32 and other insulin resistant states, such as polycystic ovary syndrome (PCOS),33 are pro-inflammatory and are associated with abnormal vascular reactivity and platelet hyperaggregability.  (clumping & clotting)

........... Insulin sensitizers have been shown to exert anti-inflammatory43–46 and anti-atherosclerotic effects.47,48  Thiazolidinediones (TZD) exert anti-inflammatory effects at the molecular and cellular levels. 

The article goes on to conclude as follows:

These facts, should encourage us to increase our understanding of these novel effects of insulin so that

(1) we have an improved conceptualization of inflammation in states of insulin resistance and the relationship of these states to atherogenesis;

(2) we explore the potential therapeutic role of insulin in inflammatory conditions, such as acute myocardial infarction; and

(3) we investigate novel potential therapeutic application of insulin sensitizers such as thiazolidinediones as anti-inflammatory agents.

I broke these out in more bullet form to address them.

(1)  I take this to mean the lipid hypothesizers need to rethink as much as the carbohydrate hypothesizers do. Both need to re-think the role of dietary composition (and total intake) in terms of its impact on insulin SENSITIVITY, not insulin per se.

(2)  Insulin is, as Martha Stewart would say, a GOOD thing.  There's much promise in using it.  Insulin therapies have evolved from slow acting secretagogues (substances that enhance insulin secretion), to pumps delivering a more consistent, physiological basal level in T1's etc.

(3)  OK, I'm probably in agreement with many who disdain the whole "this gives us more reason to look into more drugs" angle, but we have to be pragmatic about it.  A Type 1 does not make insulin.  In that regard, whatever technology allows them to mimic insulin levels in a normal person, I would be grateful for it.  Type 2 is a far more varied diagnosis as the degree of irreversible damage (as opposed to suppressed function) cannot be assessed with mere fasting glucose levels or tolerance tests.   If you're hyperinsulinemic, you still have functional beta cells.  Temporarily giving them a rest with LC while you lose weight and reverse the IR that is causing the elevated insulin is a great strategy.  But if you cannot adhere to this, or if LC doesn't result in the desired weight loss, then it may well be worthwhile to at least temporarily look into pharmaceutical intervention that allows for insulin to "do its thing".  I wonder, even, if insulin might be helpful to the hyperinsulinemic T2 -- enough exogenous insulin may keep the pancreas from having to work overtime to produce the elevated levels that your body is telling it to anyway.  There's nothing about the hormone that is deleterious!!!!!!!!

Comparative Fatty Acid Toxicity on Macrophages

Comparative toxicity of fatty acids on a macrophage cell line (J774)

In the present study, the cytotoxicity of palmitic, stearic, oleic, linoleic, arachidonic, docosahexaenoic and eicosapentaenoic acids on a macrophage cell line (J774) was investigated. The induction of toxicity was investigated by changes in cell size, granularity, membrane integrity, DNA fragmentation and phosphatidylserine externalization by using flow cytometry. Fluorescence microscopy was used to determine the type of cell death (Acridine Orange/ethidium bromide assay). The possible mechanisms involved were examined by measuring mitochondrial depolarization, lipid accumulation and PPARγ (peroxisome-proliferator-activated receptor γ ) activation. The results demonstrate that fatty acids induce apoptosis and necrosis of J774 cells. At high concentrations, fatty acids cause macrophage death mainly by necrosis. The cytotoxicity of the fatty acids was not strictly related to the number of double bonds in the molecules: palmitic acid>docosahexaenoic acid>stearic acid=eicosapentaenoic acid=arachidonic acid>oleic acid>linoleic acid. The induction of cell death did not involve PPARγ activation. The mechanisms of fatty acids to induce cell death involved changes in mitochondrial transmembrane potential and intracellular neutral lipid accumulation. Fatty acids poorly incorporated into triacylglycerol had the highest toxicity.

 I could C&P the entire introduction to this paper but don't want to do that, so please go read it.  Summary:

• The FFA/NEFA are generally implicated in having toxic effects in non-adipose tissues, aka lipotoxicity
• Saturated fatty acids tend to be more lipotoxic
• Ectopic (non-adipose) triglyceride storage is somewhat protective but this remains under consideration as metabolites/intermediates of triglycerides (ceramides) are implicated in toxicity.
• Cell death contributes to the inflammatory properties of FA's
• PPAR-ɣ increases reduce inflammatory cytokines like IL's and TNF-α

Macrophage infiltration into adipose tissue in obesity is implicated in the inflammatory state associated with obesity.   It should be noted that this study was in vitro (e.g. culture dish) on a non-human (murine to be exact) derived cell line.   But the elevated NEFA associated with insulin resistance and T2 Diabetes would produce a "toxic" state within adipose tissue leading to macrophage death (and adipocyte death?). 

Cell death types:  

• Apoptosis, aka programmed cell death:  When functioning properly, this is the "natural" death of cells for cellular turnover in tissues, etc.  In cancer, apoptosis is short circuited leading to so-called immortal cells.  Some toxic conditions lead to disruption of the normal signals and pre-mature apoptosis.  
• Necrosis:  Premature cell death due to some - always detrimental - external source.  Necrosis initiates a greater immune response as dead cells must be engulfed and removed, and such cells rupture and "spill" more "stuff" into the surroundings than cells undergoing PCD.

Some exerpts:

In the present study, we evaluated whether the induction of cell death could be a mechanism by which FAs modulate macrophage function. Indeed, treatment with different concentrations of FAs was toxic to the macrophage cell line J774, as assessed by loss of membrane integrity and DNA fragmentation.  In most cases, the lowest concentration that caused loss of membrane integrity was the same that induced DNA fragmentation (Table 3), and the percentages were similar. These findings are indicative that necrosis and apoptosis occurred concomitantly.

... high FA concentrations cause macrophage death mainly by necrosis. This effect was also observed by others after treatment of different cell types, such as melanoma, leukaemia cell lines, lung carcinoma and fibroblasts, with high concentrations of FA [49–51].  The results of both loss of membrane integrity and/or DNA fragmentation shown in the present study suggest the following rank of toxicity on J774 cells: PA>DHA>SA=AA=EPA>OA>LA 

... The relationship between lipid accumulation and apoptosis has been demonstrated through a series of experiments with different cell lines [63–65]. Accumulation of excess FAs into the TAGpool has been postulated to divert these molecules from pathways that lead to toxic effects and, thus, lipid bodies may serve as buffers against lipotoxicity [19]. Treatment with all FAs led to an increase of lipid bodies inside J774 cells (Figure 2B).  Cells treated with non-toxic concentrations of the FAs exhibited higher granularity, indicating accumulation of lipid droplets that was observed by fluorescence microscopy. 

A look at Figure 1 indicates a threshold behavior for the toxic effects.

I have not addressed everything in this article and this post is sort-of half book marking, half just putting this out there as I had not seen a discussion of this nature before.

The Anti-Inflammatory Properties of Insulin

Some more articles presented without comment for book-marking purposes:

The anti-inflammatory and potential anti-atherogenic effect of insulin: a new paradigm

Intensive Insulin Therapy Exerts Antiinflammatory Effects in Critically Ill Patients and Counteracts the Adverse Effect of Low Mannose-Binding Lectin Levels

Anti-Inflammatory and Profibrinolytic Effect of Insulin in Acute ST-Segment–Elevation Myocardial Infarction

Insulin: Endogenous Cardio-Protector?

Is insulin an endogenous cardioprotector?

Presented without comment, except to say that hyperinsulinemia is not the problem, it's what causes the hyperinsulinemia.  That being insulin resistance!

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.

Aspirin for Insulin Resistance?

I have just recently come across what seems to be a treasure trove of research indicating salicylates (e.g. acetylsalicylic acid aka aspirin) .  Much of the research is in rodents, but the glycemic lowering properties of this common drug are well known (apparently) and documented in humans, but seemingly ignored?  

Here's one:  Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkß  (Full text is available with FREE registration for anyone interested.  You fill out name and they ask for phone/fax info but I left that blank and had no issues.)

We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IB kinase  (IKK) attenuated insulin signaling in cultured cells, whereas IKK inhibition reversed insulin resistance. Thus, IKK, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikk^+/) protected against the development of insulin resistance during high-fat feeding and in obese Lep^ob/ob mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKpathway as a target for insulin sensitization.

Some excerpts and commentary:

High doses of salicylates [4 to 10 g per day (g/day)], including sodium salicylate and aspirin, have been used to treat inflammatory conditions such as rheumatic fever and rheumatoid arthritis. These high doses are thought to inhibit nuclear factor kappa B (NF-kB) (1) and its upstream activator the IkB kinase b (IKKb) (2),... High doses of salicylates also lower blood glucose concentrations (3–7), although their potential for treating diabetes has been all but forgotten by modern biomedical science. ...

We have found that reduced signaling through the IKKb pathway, either by salicylate inhibition or decreased IKKb expression, is accompanied by improved insulin sensitivity in vivo.

Cautionary note:  These studies were in genetically obese Zucker rats and ob/ob mice.

The aspirin treatment (120 mg/kg/day) resulted in lower blood glucose levels and reduced insulin levels.  Injecting untreated animals with insulin had almost no effect, but the aspirin treated animals did.  This demonstrates that insulin sensitivity was improved (vs. more insulin being produced).  

Increased triglyceride concentrations in the blood of Zucker rats fell from 494 ± 68 mg/dl to 90 ± 58 mg/dl during 3 weeks of aspirin treatment (Fig. 1F). The concentrations of free fatty acid (FFA) dropped as well, from 3.1 ± 0.3 mM to 1.1 ± 0.2 mM. The decrease in the amount of circulating FFA occurred within 1 week of aspirin treatment, preceding reductions in the amounts of triglyceride and glucose in the blood. This is consistent with the hypothesis that increased FFA concentrations contribute to the pathogenesis of hyperglycemia and hypertriglyceridemia.

The reversal is consistent with previous posts, for example in The Progression of IR, the cited article stated that elevated NEFA precedes hyperglycemia (and NEFA are elevated when adipose tissue becomes insulin resistant/dysfunctional).

Our findings demonstrate that increased IKK activity promotes insulin resistance, in obese rodents (12) when the kinase is overexpressed, or when IKK is activated by known stimulators. Conversely, reductions either in IKK activity or in the expression of its IKKb subunit significantly improved insulin sensitivity. Even a 50% reduction in gene dosage improved in vivo glucose and lipid metabolism, which may explain why weak inhibitors of IKKb, such as aspirin and sodium salicylate, have significant effects on glucose and lipid homeostasis. Although not recognized previously, there is an overlap between stimuli that activate IKK and conditions that promote insulin resistance, including proinflammatory cytokines such as TNFa, hyperglycemia, phorbol esters and protein kinase C (PKC) enzymes, Ser-Thr phosphatase inhibitors, and bacterial lipopolysaccharide. These are either in vivo mediators of insulin resistance or experimental mimics in cultured cells. Our findings are consistent with potential links between chronic subacute inflammation and insulin resistance (26, 27), whether this is mediated by TNF-a produced in fat (28–31) or through TNF-a–independent mechanisms. As a potentially important example of the latter, in rodent muscle, FFA infusion activates PKC-u (32), a known activator of IKK (33), and FFA-induced insulin resistance is suppressed by aspirin treatment and in Ikkb1/2 mice (34). IKK activation through any mechanism initiates NF-kB–mediated transcription, which in certain cells would enhance the production of TNF-a.  This positive feedback loop could perpetuate a vicious cycle of low-level inflammatory signaling, leading to insulin resistance. Our findings predict that IKK inhibition breaks this cycle. Too few tools are currently available to treat patients with insulin resistance and type 2 diabetes; IKKb may provide a valuable target for the discovery of new drugs to treat these conditions.

So:  Stuffed adipocytes become insulin resistant and "spill" excessive free fatty acids in the blood.  The elevated NEFA/FFA stimulate IKK that may in turn increase production of TNF-α (tumor necrosis factor α), a known inflammatory.  

Aspirin to "cure" your fat-ache??

Aspirin for Insulin Resistance?

I have just recently come across what seems to be a treasure trove of research indicating salicylates (e.g. acetylsalicylic acid aka aspirin) improve insulin sensitivity and lower blood glucose levels.  Much of the research is in rodents, but the glycemic lowering properties of this common drug are well known (apparently) and documented in humans, but seemingly ignored?  

Here's one:  Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkß  (Full text is available with FREE registration for anyone interested.  You fill out name and they ask for phone/fax info but I left that blank and had no issues.)

We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IB kinase  (IKK) attenuated insulin signaling in cultured cells, whereas IKK inhibition reversed insulin resistance. Thus, IKK, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikk^+/) protected against the development of insulin resistance during high-fat feeding and in obese Lep^ob/ob mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKpathway as a target for insulin sensitization.

 
Some excerpts and commentary:

High doses of salicylates [4 to 10 g per day (g/day)], including sodium salicylate and aspirin, have been used to treat inflammatory conditions such as rheumatic fever and rheumatoid arthritis. These high doses are thought to inhibit nuclear factor kappa B (NF-kB) (1) and its upstream activator the IkB kinase b (IKKb) (2),... High doses of salicylates also lower blood glucose concentrations (3–7), although their potential for treating diabetes has been all but forgotten by modern biomedical science. ...

We have found that reduced signaling through the IKKb pathway, either by salicylate inhibition or decreased IKKb expression, is accompanied by improved insulin sensitivity in vivo.

Cautionary note:  These studies were in genetically obese Zucker rats and ob/ob mice.

The aspirin treatment (120 mg/kg/day) resulted in lower blood glucose levels and reduced insulin levels.  Injecting untreated animals with insulin had almost no effect, but the aspirin treated animals did.  This demonstrates that insulin sensitivity was improved (vs. more insulin being produced).  

Increased triglyceride concentrations in the blood of Zucker rats fell from 494 ± 68 mg/dl to 90 ± 58 mg/dl during 3 weeks of aspirin treatment (Fig. 1F). The concentrations of free fatty acid (FFA) dropped as well, from 3.1 ± 0.3 mM to 1.1 ± 0.2 mM. The decrease in the amount of circulating FFA occurred within 1 week of aspirin treatment, preceding reductions in the amounts of triglyceride and glucose in the blood. This is consistent with the hypothesis that increased FFA concentrations contribute to the pathogenesis of hyperglycemia and hypertriglyceridemia.

The reversal is consistent with previous posts, for example in The Progression of IR, the cited article stated that elevated NEFA precedes hyperglycemia (and NEFA are elevated when adipose tissue becomes insulin resistant/dysfunctional).

Our findings demonstrate that increased IKK activity promotes insulin resistance, in obese rodents (12) when the kinase is overexpressed, or when IKK is activated by known stimulators. Conversely, reductions either in IKK activity or in the expression of its IKKb subunit significantly improved insulin sensitivity. Even a 50% reduction in gene dosage improved in vivo glucose and lipid metabolism, which may explain why weak inhibitors of IKKb, such as aspirin and sodium salicylate, have significant effects on glucose and lipid homeostasis. Although not recognized previously, there is an overlap between stimuli that activate IKK and conditions that promote insulin resistance, including proinflammatory cytokines such as TNFa, hyperglycemia, phorbol esters and protein kinase C (PKC) enzymes, Ser-Thr phosphatase inhibitors, and bacterial lipopolysaccharide. These are either in vivo mediators of insulin resistance or experimental mimics in cultured cells. Our findings are consistent with potential links between chronic subacute inflammation and insulin resistance (26, 27), whether this is mediated by TNF-a produced in fat (28–31) or through TNF-a–independent mechanisms. As a potentially important example of the latter, in rodent muscle, FFA infusion activates PKC-u (32), a known activator of IKK (33), and FFA-induced insulin resistance is suppressed by aspirin treatment and in Ikkb1/2 mice (34). IKK activation through any mechanism initiates NF-kB–mediated transcription, which in certain cells would enhance the production of TNF-a.  This positive feedback loop could perpetuate a vicious cycle of low-level inflammatory signaling, leading to insulin resistance. Our findings predict that IKK inhibition breaks this cycle. Too few tools are currently available to treat patients with insulin resistance and type 2 diabetes; IKKb may provide a valuable target for the discovery of new drugs to treat these conditions.

So:  Stuffed adipocytes become insulin resistant and "spill" excessive free fatty acids in the blood.  The elevated NEFA/FFA stimulate IKK that may in turn increase production of TNF-α (tumor necrosis factor α), a known inflammatory.  

Aspirin to "cure" your fat-ache??

Insulin Resistance and Inflammation

Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance

This is yet another paper demonstrating that the evidence strongly points to the fat cells being the origin of the sequences of events leading to peripheral insulin resistance.  This paper looked at inflammation.

Abstract:

Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues. Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance. However, the underlying molecular pathways are largely unknown. In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO). The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level. Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated. Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells. These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance. We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue.

This group used several models of obesity in mice -- both genetic and diet induced.  Yes, it's a mouse study with all the inherent problems in applying results to humans.  The results:

Expression levels of genes in inflammatory pathways are significantly upregulated in WAT of obese mice. To study obesity and obesity-induced insulin resistance, we performed global transcriptional profiling studies with various tissues (WAT {note:  WAT = white adipose tissue}, brown adipose tissue, muscle, liver, stomach, hypothalamus, small intestine, and pancreas) taken from genetically obese mice, including ob/ob,db/db, tubby, agouti, and DIO {note: DIO = diet induced obesity} mice. Notably, we found that many of the most significantly upregulated genes in WAT were not known to be involved in adipocyte biology; instead, they could be broadly categorized as macrophage- or inflammation-related genes. Of the genes upregulated more than twofold in at least four of these five models, 59% (50/85) could be counted as inflammation genes, as determined by their known functions. The remaining genes were involved in diverse molecular pathways, including fat storage, cholesterol metabolism, DNA modification, transcription, cell division, signal transduction, and unknown functions  

In plain English, almost 3 out of 5 genes that were expressed in greater amounts in WAT are not associated with fat metabolism, but rather can be considered inflammation genes.

... with multiple models of genetic and diet-induced obesity, our data suggest that the inflammatory response is a general phenomenon of the obese state, independent of the availability of the leptin protein. We also noticed that this phenomenon was WAT-specific and was not observed in any other tissues we profiled. 

Inflammation is associated with the state of WAT adiposity irrespective of the various metabolic paths altered in the genetically obese mice or if adiposity was induced through diet.   The discussion does go on to mention that the same genes are not upregulated the same amount comparing various models, but there is consistency in the genes that are upregulated to some extent.

To determine whether the upregulation of these genes occurs prior to the development of systematic insulin resistance, which is characterized by hyperinsulinemia, we tracked the expression levels of these genes in WAT of mice with high-fat diet–induced obesity at multiple time points for 26 weeks. The body weight increased steadily over this period, as did the fasting blood glucose level, although the latter remained within the normal range (<120 mg/dl) until sometime after 16 weeks (Figure 2a). Meanwhile, we observed an increase in expression of some of these inflammation genes as early as 3 weeks on high-fat diet (Figure2b). Around 16 weeks on high-fat diet, a much more dramatic upregulation of these transcripts occurred, which correlated closely with a marked increase in fasting blood insulin levels (Figure 2). It appears that the adipose inflammatory response increases with an increase of adiposity, prior to the increase of fasting insulin level, but intensifies at the onset of hyperinsulinemia.

Lower level inflammation (dysfunction?) in WAT preceded an acute inflammation which seems to trigger insulin resistance (measured by fasting insulin).  This may have a snowball effect as hyperinsulinemia associated with IR may trigger more inflammation may trigger greater IR and so on and so on.  Other tissues (skeletal muscle, liver, spleen, lung) were studied and the inflammation genes were not significantly upregulated compared to lean controls except for the DIO after lengthy exposure (26 weeks) although the effect was still smaller than that seen in WAT.  It seems to me that this liver inflammation doesn't occur until the fat inflammation and IR has long since been established.  

Other conclusions of the study:

• Inflammation is associated with macrophages in WAT that increase in the obese state.
• Macrophage infiltration is a likely explanation for increased macrophages in the WAT of the obese.
• Macrophage accumulation in WAT is highly correlated and perhaps causative of IR.
• Macrophage activities increase after a certain degree of adiposity is achieved but before the onset of insulin resistance.
• Obesity induced insulin resistance begins in WAT but spreads systemically as adiposity increases further.

The last quotation I'll C&P follows:

Macrophage accumulation is likely a direct response to the abnormal fat metabolism caused by the increasing adiposity. The molecular signals that trigger the macrophage activity in obese WAT are not yet known, but several good candidates exist. Adipocytes are known to secrete hormones, cytokines, and FFAs, most of which have been shown to play some role in inflammation and systemic insulin resistance.

The discussion goes on to discuss these various factors, etc.  It's not too bad a read for those interested.

Fiber and CRP

Came across this so just putting it out there.  It's a meta study of 7 clinical trials in which fiber was studied or reported.  In 6 of 7 CRP was reduced.  One study involving just psyllium showed no effect.

The effects of dietary fibre on C-reactive protein, an inflammation marker predicting cardiovascular disease

Conclusions: In the presence of weight loss and modified saturated, monounsaturated and polyunsaturated fat intakes, significantly lower CRP concentrations (25–54%) are seen with increased fibre consumption 3.3 g/MJ). Mechanisms are inconclusive but may involve the effect of DF on weight loss, and/or changes in the secretion, turnover or metabolism of insulin, glucose, adiponectin, interleukin-6, free fatty acids and triglycerides. Clinical studies of high- and low-fibre diets are needed to explore the potential favourable effects as observed epidemiologically, and to understand individual susceptibility to its anti-inflammatory effect and long-term cardiovascular reduction.

Unfortunately for those interested, full text is not free.

Low Carbohydrate, High Fat Diet Increases C-Reactive Protein during Weight Loss

Low Carbohydrate, High Fat Diet Increases C-Reactive Protein during Weight Loss
Janet W. Rankin, PhD and Abigail D. Turpyn 
Journal of the American College of Nutrition, Vol. 26, No. 2, 163-169 (2007)

Studied Variable: Dietary Carbohydrate

Variables Measured: Body weight, IL-6, CRP, urinary 8-epi-prostaglandin, FBG, FFA (fasting)
Variables controlled for: Caloric intake

Protocol Summary: Subjects were ed into two groups followed calorie restricted (~1360 kcal/d) diets varied in composition: LC = 58F/12C/30P ; HC = 24F/59C/18P. Weight, inflammatory markers (IL-6 and CRP) and oxidative stress (8-epi) were measured weekly.

Human Study
Gender:  Women
Age:  adult, premenopausal
Number of Participants: 29
Weight Status: Overweight BMI 32.1 ± 5.4 kg/m2
Health Status: weight stable for at least 6 months, nonsmokers, sedentary, otherwise healthy and unmedicated
Study Duration: 4 weeks

Summary of results:

* LC lost a bit more weight (3.8 ± 1.2 kg LC vs. 2.6 ± 1.7 HC, p=0.04)
* CRP increased an average of 25% in the LC group whereas it decreased 43% in the HC group (p=0.02)
* FBG decreased similarly for both groups
* IL-6 increased similarly for both groups
* 8-epi varied differently between groups but with no consistent pattern.
* Serum NEFA increased for both groups, the increase was greater for LC


Here is a screenshot of the results:  (click on image to enlarge)

Researchers' Conclusion: "Diet composition of the weight loss diet influenced a key marker of inflammation in that LC increased while HC reduced serum CRP but evidence did not support that this was related to oxidative stress."

My Comments: 

Although apparently not statistically significant, the LC group (~190 lbs) was a bit heavier than the HC group (~175 lbs) to begin with in this study.  This could be related to the LC group starting at a higher (although also not indicated as significant) average CRP level.

But look at the CRP graph showing the individual results vs. baseline -- the horizontal axis is the baseline CRP.  I find this disturbing.  The first thing that jumps out is that almost all of the LC group had increases while all of the HC group had decreases.  Also disconcerting is that this effect seems more pronounced for those who had a low level of CRP to begin with -- IOW, LC seems to induce an inflammatory state according to the CRP indicator.   This is not seen for HC where in most cases CRP declines.  If one looks at the right side of the graph, you have the subjects in the highest baseline "inflammatory state".  What happens?  Significant decreases in CRP for the HC group, negligible change either way for LC.

Whether or not to be stressed over CRP levels is a matter of continued confusion and controversy, but higher CRP levels are never, as far as I've seen, considered a good thing.

I came across this article while researching plasma free fatty acids (NEFA, FFA) and am concerned with the effect the LC diet had on fasting FFA's.  The highest fasting level for the LC group was almost 1.5X (50% higher) than the highest fasting level for the HC group.  The high level vs. baseline for LC was ~1.8X vs. ~1.5X for the HC group. 

I don't know enough about 8-epi at this time to comment on that aspect of this study.