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Sunday, May 6, 2012

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

OK, let's get back to some science here :-)  In comments on my recent query for evidence that insulin blocks leptin in the brain, Kindke posted a link to the following article:  Yin and Yang of hypothalamic insulin and leptin signaling in regulating white adipose tissue metabolism.  
ABSTRACT:   Fatty acids released from white adipose tissue ( WAT) provide important energy substrates during fasting. However, uncontrolled fatty acid release from WAT during non-fasting states causes lipotoxicity and promotes inflammation and insulin resistance, which can lead to and worsen type 2 diabetes (DM2). WAT is also a source for insulin sensitizing fatty acids such as palmitoleate produced during de novo lipogenesis. Insulin and leptin are two major hormonal adiposity signals that control energy homeostasis through signaling in the central nervous system. Both hormones have been implicated to regulate both WAT lipolysis and de novo lipogenesis through the mediobasal hypothalamus (MBH) in an opposing fashion independent of their respective peripheral receptors. Here, we review the current literature on brain leptin and insulin action in regulating WAT metabolism and discuss potential mechanisms and neuro-anatomical substrates that could explain the opposing effects of central leptin and insulin. Finally, we discuss the role of impaired hypothalamic control of WAT metabolism in the pathogenesis of insulin resistance, metabolic inflexibility and type 2 diabetes.
Someday, I may or may not get back to the hormonal topics from that paper, but for now it was the bolded line that stuck out to me.  Specifically palmitoleate (or palmitoleic acid), because I've always been under the impression that the fatty acid made in de novo lipogenesis -- DNL, conversion of acetyl CoA to long chain fatty acids -- was the 16C saturated fat palmitic acid or palmitate, while palmitoleic acid is a MUFA.  (The longer stearate/stearic acid is a lesser product in the liver).  This is the process by which carbohydrates are converted to fats, and one of the reasons we're still told carbs make us fat.  One place where DNL occurs is in the liver, and those fatty acids are packaged up in VLDL lipoprotein particles aka "triglycerides".  

I've written about this a lot here, how DNL is not a significant source of body fat, and this paper reminded me of another paper that's always confused me somewhat.  Because from Hellerstein to Jequier to Frayn to just about every reputable source, hepatic DNL (hereafter hDNL) is not a major source of fatty acids in lipoproteins created in the liver or body fat stores.  Even upregulated, it amounts to single digit grams in a day for typical "Western diets".   So if this is the case, how come in Adipose tissue triglyceride turnover, de novo lipogenesis, and cell proliferation in humans measured with 2H2O we learn:
DNL contributes ∼20% of new TG
Now, while I consider that to still be relatively insignificant in the development of obesity -- another way of saying the same thing is that roughly 80% of new triglycerides in adipose tissue come from dietary fat -- I don't think we can dismiss DNL as a source for adipose triglycerides.  But where did the DNL occur?  It would seem to me that if hDNL only contributes a very small amount to VLDL-triglycerides, and adipocytes seem more sensitive to uptake of fatty acids from chylomicrons vs. VLDL particles, there must be a significant amount of DNL going on in adipose tissue, hereafter aDNL.  So to repeat from the original article:
WAT is also a source for insulin sensitizing fatty acids such as palmitoleate produced during de novo lipogenesis
While the SFA palmitic acid tends to be lipotoxic and contribute to IR, the MUFA palmitoleic acid is apparently insulin sensitizing.   Circulating free fatty acids (NEFA) are supposed to come from adipose tissue, and it is the regulation of the triglyceride-fatty acid cycle that occurs both inside and in exchange with circulation to other organs and tissues that is supposed to govern the levels of NEFA.  The dietary fats themselves don't appear to be the problem, but when the adipose tissue gets overfilled, proper function appears to breakdown on the "in" side.    The inefficient trapping of fatty acids released from chylomicrons will lead to a flood of NEFA, and perhaps more importantly, potentially a dramatic difference in the proportions of fatty acids.

I've also been looking again at glyceroneogenesis and although this is relatively new information, it may well be that the adipocyte dysfunction that leads to IR and Type 2 diabetes may well be related to defects in both the glyceroneogenesis and de novo lipogenesis pathways in the fat cells.  Recall, glyceroneogenesis is the major source of glycerol-3-phosphate, the molecule needed to esterify fatty acids to triglycerides for storage.  And this aDNL would also be "adipogenic" -- in other words contributes to the fat content in the fat cells.  In diabetes, these pathways appear to be downregulated, broken, whatever.  Exactly the opposite of what one would think for a person who has gotten obese.

From the originally cited article:  (I de-cluttered the references)
WAT is also capable of synthesizing fatty acids during de novo lipogenesis. Although, quantitatively WAT de novo lipogenesis adds little to the whole body lipid pool, it may serve important metabolic functions that we are just beginning to explore. A recent study has shown that the fatty acid palmitoleate, which seems to be mainly released by WAT, bears systemic insulin sensitizing properties in mice. Data on palmitoleate in humans are mixed. While high circulating palmitoleate is associated with improved cholesterol profiles in men, it is also linked to increased TG levels and insulin resistance. However, these studies did not differentiate the source of palmitoleate, which is important since increased hepatic lipid production is associated with insulin resistance rendering liver derived palmitoleate a possible confounder. Indeed, palmitoleate from exogenous sources (non-liver-derived), such as dairy products, is associated with lower insulin resistance and incidence of DM2 in humans. In rodents, whose lipogenic capacity seems to exceed that of humans, palmitoleate is implicated in improving glucose uptake in vitro and in vivo and to also reduce hepatosteatosis by blocking lipogenesis in the liver. Yet, the exact molecular mechanism of how palmitoleate exerts its insulin sensitizing effects remains to be elucidated. Furthermore, there is emerging evidence that in human obesity WAT de novo lipogenesis is reduced, which may result in lower palmitoleate secretion from WAT contributing to insulin resistance, although this has not been stringently proven. Therefore, failure of WAT de novo lipogenesis may represent an additional feature of WAT dysfunction.
I believe this is a very important avenue of research!   I've got quite a bit more to share with y'all on this.  But the take home messages I got from this part of the Yin Yang article are this:

  • Not all de novo lipogenesis is created equally.  
  • hDNL → palmitic acid → IR         aDNL → palmitoleic acid →? insulin sensitivity
  • aDNL is probably a desired and beneficial metabolic pathway 
This, and the fact that DNL pathways have been identified in skeletal muscle as well, lead me to believe that de novo lipogenesis -- the converting of carbs to fats -- does not deserve the bad reputation it has earned.  And why I feel the bastardized version of biochemistry fed to you by Gary Taubes in GCBC, WWGF and countless lectures, ultimately harms "the cause" ... whatever that is.   I'm not anti saturated fat, but I'll leave you with this for now.  Why would one want to supplement dietarily the saturated fat produced by the body that is detrimental to insulin action?  


MM said...

I looked up palmitoleic acid and found out it's an Omega-7 fatty acid. Does this mean that we're going to have to start taking Omega-7 supplements too? LOL!

Paul Jaminet said...

Palmitoleic acid is made from palmitate. Palmitate can be obtained either from dietary saturated fat that is 16-carbons or fewer, or from DNL. So I guess you would conclude it is the 18-carbon or longer saturated fats that deprive the body of palmitoleate.

My impression is that most DNL occurs in muscle, and fatty acids produced there only gradually migrate to adipose tissue. This is why short-term studies of adipose tissue deposition find little DNL.

It could be that desaturation of palmitate to palmitoleate is an important function of WAT.

Kamal said...

Evelyn-- do you know anything about citrate and DNL?

Someone (Andrew Day) mentioned on facebook that they shy away from excess citrate (e.g. magnesium citrate) due to it's potential unintended metabolic effects. I recalled reading something related to DNL and mitochondrial citrate before, which may have been this:

"It is proposed that in this substrate cycle (depicted in Figure 3), which underscores the interdependency between glucose, lipids and thermogenesis, acetyl-CoA produced from glucose and fatty acid oxidation will overload the Krebs cycle. This will result in excess mitochondrial citrate, which, in the cytoplasm, will exert an allosteric activation of ACCs and, at the same time, under the action of citrate lyase, will provide acetyl-CoA to ACCs for the synthesis of malonyl-CoA. The latter will serve as the main substrate for fatty acid synthase, thereby producing a new pool of fatty acids. Glucose plays a central role in this cycle as a source of acetyl-CoA, Krebs cycle intermediates and NADPH molecules, which are required for the synthesis of FAs. It might also function as a stimulator of de novo lipogenesis, based upon the above-mentioned recent demonstrations in muscle satellite cells" you happen to know how tightly mitochondrial citrate is regulated?

Geoff 99 said...

If you havent come across it before, this paper has an interesting take on DNL:

The authors have tried to carefully analyze the source and quantity of DNL during carbohydrate overfeeding, with some interesting results.

"On the basis of both substrate balance data and respiratory gas measurements, we found that after 4 d of carbohydrate overfeeding our subjects were synthesizing a minimum of 170 g fat/d. Even though hepatic lipogenic activity at this time was increased 35-fold, it only accounted for 2% of whole-body fat synthesis (~3 g fat/d). We found about the same proportion between whole-body and hepatic fat synthesis during early (day 1) and late (day 4) carbohydrate overfeeding."

" ... the hepatic contribution to whole-body carbohydrate-induced lipogenesis is minor. Other tissues, most likely adipose tissue, play the major role quantitatively when surplus carbohydrate energy is converted into fat in the human body."

Evelyn aka CarbSane said...

Hi Paul, I'm finding quite a bit on this being an important function of WAT. I need to read more closely in case I missed it, but Lehninger doesn't talk about differences in DNL though re: your first statement, it may be that in adipose tissue DNL just has the extra desaturation step for some reason. I tend to agree with your impression that most DNL occurs in muscle because the most I've seen hepatic DNL to be is like 3% and adipose DNL ~40% is the most I've seen. So it has to go on somewhere! If you look at the resting energy expenditures reported in the paper Geoff99 linked to, by day 4 of massive carb overfeeding (2.5X normal daily EE) REE had increased almost 60% from baseline! Looks like some futile cycling going on (remember this? I disagree that the FA produced would gradually migrate to adipose tissue. Around a year ago I came across some really interesting work on lipid droplets in muscle cells. Like fat tissue being metabolically active in the whole body, there is evidence for LD's as being metabolically active organelles in the cell, storing excess fatty acids in triglyceride form. We don't see a lot of DNL w/o caloric excess even on a very high carb diet.

Evelyn aka CarbSane said...

Hi Kamal, I blogged on that paper here:

I've not looked into any potential for dietary citrate to alter metabolism. My gut feeling is that most of chemical reactions in our body are highly regulated by enzyme activity, and many are not dependent on substrate availability, so I would think excesses are simply excreted in urine. I found this on a quick look:

Evelyn aka CarbSane said...

Very interesting paper Geoff! The REE's jumped off the page at me -- almost 60% increase by Day 4 -- and in the discussion they cite a number of sources that put adipose DNL rather low. So that got me thinking of the old blog post on the study about carb-DNL-fatty acid oxidation futile cycling in muscle. Makes sense!
Metabolic advantage high carb! ;)

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