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?