Saturday, October 12, 2013

The Carbohydrate Monster Under your Bed Part 3

"To fear is one thing.  To let fear grab you by the tail and swing you around is another."  ~Katherine Paterson

In this section we are just going to examine two things that was discussed in the last section: De Novo Lipogenesis and The Adipose Tissue. DNL is the transformation of nonfat pre curers into fat which could potentially become body fat i.e Carbohydrates, proteins, ethanol etc. Although as  the title of this series suggests we will just be examining the carbohydrate pathway. However, we must first look at the tissue that receives the most hatred... the adipose tissue.

-- The Adipose Tissue --

More commonly known by the general public as "fat", the adipose tissue serves as more then just a cushion or some extra "junk in the trunk". The most notable aspect of this tissue that scientists and doctors are familiar with is it's ability to accommodate increased lipids through hypertrophy of existing adipocytes. Although as we will see, the Adipose tissue is more then just a place to store excess carbon in the form of fatty acids. The adipose is an important endocrine organ, with various feedback systems that regulates it's size, growth rate, etc.(50)  Before we get into the growth and formation aspects of the adipose lets first look at the basic physiology and biochemical aspects.


The major form of adipose tissue in mammals is White Adipose Tissue or more commonly written as WAT. (there is also Brown adipose tissue but we will discuss this a little later) What are these WAT's Made off?? Well to start with, WAT is comprised of adipocytes held together by a loose connective tissue. These white Adipocytes are a round shape cell that contain a single large fat droplet which takes up 90% of the cells volume. The remaining 10% of the cells volume consists of the cells nucleus and mitochondria. Other characteristics of the WAT is there sensitivity to the hormone leptin.

In addition to the adipocytes, The WAT contains leukocytes, fibroblasts, macrophages, adipocyte progenitor cells, and endothelial cells. These various parts work to secrete various proteins and hormones which communicate with the rest of the body such as Leptin, TNF-A, Interleukin-6, resistin, etc



The adiposites can be become bigger or smaller depending on one very simple formula, seeing as fat accumulation is determined by the amount of fat synthesized - the amount oxidized:

Pay attention because this will be repeated over and over again. Here is quick analogy:

Walter White has a certain amount of Methamphetamine that he cooks everyday and then he sells that methamphetamine to a distributor. In this analogy The methylamine required to cook is the food we eat (regardless of macro nutrient sources), the cooking of the Methylamine into Blue Crytsal and packaging for sale is the storage of lipids in our adipose tissue, the selling of the final product to random Junkies, Gus, Neo nazi's or whoever is the Fat leaving our adipose tissue.

Scenario 1: If the amount of methylamine coming in and being cooked is more then we can unload then we will have a build up of Blue Crytsal at 99.89% purity and the adipose will grow.

Scenario 2: if the amount of Methylamine coming in falls because Todd is an idiot and loses a barrel and the demand remains constant then the fat stores will empty out until they are almost completely gone.

Scenario 3: The amount of Methylamine being supplied remains constant but the demand goes up stores will be emptied and methylamine will be in high demand.

I think you can see now how all these scenarios play out, in order to keep the operation running smoothly we need a constantly even supply and demand scenario or tons of people end up dead in a prison, getting blown up by a guy in a wheel chair or thrown in a ditch in the middle of no where.

Circling back to the biochemistry if we could from the Formula above:

fat synthesized - the amount oxidized = Fat Balance (+/-)

So before we get into the formula, lets look at how fatty acids get transported in and out of our adipose tissue.

The main function of the adipose is take in excessive TAG for storage during times of surplus and to release FFA during times of negative energy balance. So how do all these actions take place and get subsequently regulated? Go ahead and take a look at the picture below:

http://www.nature.com/nrd/journal/v3/n8/fig_tab/nrd1469_F4.html#figure-title
--> As you can see from the above, FFA are catalyzed from circulating VLDL via LPL i.e lipoprotein lipase through both passive diffusion and active transport.

--> FFA are the converted to FFA via Acetyl COA via acyl-CoA synthase (ACS)

--> The Acetyl- COA is then used as a substrate for two Parallel TAG Synthetic Pathways in the endoplasmic reticulum (ER)

--> One Pathway coming from G3P and the other from lipogenesis leading to MAG. Both leading to the conversion of diacylglycerol (DAG) and the subsequent TAG Via DGAT diacylglycerol acyltransferase.

--> Nascent Lipid Droplets that are generated from ER are then coated with one of the PAT Proteins ( i.e ADRP, S3-12, TIP47) 

--> The Lipid Droplets are then coated in perilipin to become apart of the mature Lipid Body

--> Once the Perilipin is phosphorylated, HSL is able to access the lipid droplets  which results in the hydrolysis of TAF to FFA. The FFA are then released from the adipocytes where they can be oxidized via Beta Oxidation in other parts of our body. HSL is suppressed by the protein hormone insulin just like in the liver where insulin suppresses the release of Glucose. However Insulin is not the only thing that suppresses HSL as we will see in a study in a later section. 

Fat Synthesis can be broken down into two parts, De Novo Lipogenesis and re-esterification where oxidation is Lypolysis aka the release of fat from you fat cell. The First Process is discussed in the second part of this series but here is where we take a more in depth look:

-- Exploring The De Novo Lipogenesis Pathway --


As we can see from the previous section, There are many pathways that glucose can take in the body and there are even some pathways we have yet to discover. This pathway ( glucose to Fatty acids) has become somewhat of importance in the eyes of the public/non scientific population because there seems to be some misconceptions in regards to the relationship between carbohydrate intake and adipose tissue. Many people have been spoon fed the story that carbohydrate ingestion will automatically lead to substantial increases in new fat making. To put it more simply:

Eat Carbohydrates - > Carbs Get Turned into Fat -> You Accumulate Fat - > Obesity... It's like Magic

 Just to recap; we discussed the Bio Chemistry( see picture in part 2) in the sub section titled: Lipid Synthesis/ Lipogenesis which I have copied here

De novo lipogenesis indicates the synthesis of new lipids/Fatty Acids from various non fat precursors, mainly glucose but also from amino acids and ethanol. Basically, any substrate that produces Acetyl Co-A during its Catabolism is susceptible to be converted to fatty acids in the intermediary metabolism. (Remember from the above how after glucose goes through glycolysis the pyruvate is converted to Acetyl Co-A to enter the Kreb's cycle, see picture to the right.) So how exactly does this process take place?

Ever time we eat a carbohydrate meal some amount of Fatty Acid Synthesis will take place in the cytoplasm (outside the mitochondria) as cells will take the carbon from the sugar and make into the carbon of the fatty acid.( see image to the right). In order for fatty acids to be made we require 4 main ingredients

-- AcCoA
-- NADPH
-- CO2
-- ATP.

--> First,  Glucose will enter glycolysis and be converted to pyruvate which will then enter into the mitochondria and into the prep step to make Acetyl Co-a once acetyl CoA enters the Kreb cycle it is first turned into citrate by oxaloecetate and then generates ATPs, NADH Etc

--> once the kreb's cycle has pumped out a substantial amount of ATP and NADH, the top enzyme Isocitrate Dehydrogenase will be inhibited and thus the citrate will be shuttled out of the mitochondria back out into the cytoplasm via the citrate shuttle

--> Once in the cytoplasm, the Citrate is then made into Acetyl CoA where Insulin stimulates the enzyme Acetyl carboxylase which also requires CO2 and ATP to attach carbon onto the Acetyl - CoA to produce Malonyl CoA

--> Then with the help of NADPH and Fatty acid synthase, the Malonyl CoA is synthesized into the end product Fatty Acid Palmitate which is the only Fatty acid which humans make from scratch, we can synthesize other fatty acids but not from scratch like the Fatty acid Palmitate (16:0)

 We shall now look into some of the studies surrounding this set of processes leading to lipid synthesis in humans and mice.

 So while it does remain true that carbohydrates can be turned directly into fat via a metabolic pathway known as De novo lipogenesis via the liver or adipose tissue, that does not necessarily mean that they will take this pathway nor does it mean that when they do get converted to fatty acids it is detrimental to our health in certain respects.

In this next bit of information we examine an overfeeding study where we see that in order for De novo lipogenesis to take place Glycogen stores must be fully saturated. More importantly the subjects were consuming over 3,600 -5,000 calories a day and approx 850-1000 Grams of Carbohydrates to achieve this...no one is consuming that amount on a daily basis from year to year and if they were; it should not come as surprise that the individual in question is overweight and has high Triglycerides**. We would have to literally force feed ourselves an excess amount of carbohydrates and calories to increase de novo lipogenesis and again it is not producing as much fat as we would assume.

**Once again Triglycerides and VLDL were elevated in carbohydrate overfeeding, but what we need to remember is that this not normal consumption by any means.
Table 2 Consumption during Experiment

"Skeletal muscles and liver are the principal sites for storage of glycogen in the body. Liver glycogen concentrations vary with the diet with values in the range of 50-500 mmol absorptive state (mean 270mmol [44g] glcosyl residues/kg liver) (3). liver glycogen varies appreciably during the day in relation to the patterns of eating and fasting (2). Glycogen concentrations in biopsy samples from the quadriceps femoris muscle were found to be in the range of 60-120 mmol glycosyl residues/kg with a mean of 85 mmol (14g) glycosyl residues/kg tissue(4) however, the glycogen concentration in skeletal muscle also depends upon the muscle group being investigated (4). For a 70-kg man with ~40% of his weight as skeletal muscle a liver weighing 1.8 kg, one can estimate that ~3 mol glycosyl residues or almost 500g of glycogen are stored in the body." - (29) Simliar to what was quoted in the below from Hellerstein and co

"The diets were prepared by trained dietitians at the institute of Physiology. The restricted high-fat, low-carbohydrate diet consumed on days 1-3 and 13-14 provided ~6.7 MJ (1600 Kcal) composed of 15% protein 75% fat and 10% carbohydrate. During the overfeeding period (days 4-10 inclusive) the High Carbohydrate- low fat diet provided ~ 15 MJ (3600 kcal composed of 11% proetin, 3% fat, and 86% carbohydrates) on day4. Energy intake progressed each day...by Day 10 the energy intake had thus increased to ~21 MJ (5000 kcal)." (29)
"Although the values reported in this study may seem surprising the metabolic balance data does agree with the observed body weight changes. At the end of the overfeeding period after the glycogen stores had been reduced slightly by the high rate of lipogenesis and carbohydrate oxidation, body weight had increased by 4.6 kg and 700 g glycogen remained. assuming that glycogen is stored with two to four times its weight of water (23,24), ~ 2.1 -3.5 kg of the change in body weight can be accounted for. Cumulative gains of body fat by de novo lipogenesis and from that which was provided in the diet amounted to 1.1 kg fat" (29) ---> (A measly 2 pounds)

"We (6,7) and others (5) demonstrated that humans can ingest relatively large amounts of carbohydrates with-out initiating de novo lipid synthesis at rates exceeding concomitant fat oxidation. These results are consistent with in vitro data demonstrating very low fatty acid synthase activity in human liver and adipose tissue(27) even after the ingestion of a carbohydrate rich diet after 3 days....Our Data suggest that glycogen stores must increase by ~ 50 g before appreciable de novo lipogenesis begins. provided that massive amounts of carbohydrate continue to be ingested, the glycogen stores become saturated so that the only way of disposing of additional excess carbohydrate is by fat synthesis in addition to maximal use of glucose for energy generation..."(29)

Is this next study 6 healthy lean subjects ate a single meal containing whooping 479 Grams of carbohydrate in a single meal. Their RQ was measured and for the majority of subjects it did not exceed 1 but it got very close (about .96 and .98 were the highest for some) however the conclusions from the study repeat what is generally recognized by the medical community...Lipogenesis from carbohydrates is a quantitatively minor pathway

"The data imply that: (1) The capacity for glycogen storage in man in larger than generally believed, and (2) Fat synthesis from CHO will not exceed fat oxidation after one high-carbohydrate meal, even if it is uncommonly large. When a single high-carbohydrate meal is consumed, dietary CHO merely has the effect of reducing the rate of fat oxidation. These findings challenge the common perception that conversion of CHO to fat is an important pathway for the retention of dietary energy and for the accumulation of body fat." -(30)

This next analysis comes from Yves Schutz in Switzerland and I highly suggest that you read the entire article on your own time as it is very well written and constructed. Below are some excerpts from the paper:

In a respiration chamber, fat balance equation is generally calculated over a period of 24 h or more.

For many years it has been darn near impossible to accurately asses fat balance outside the laboratory in free living conditions. However inside the laboratory, nutritional researchers use something called a respiration chamber as referred to in the above to asses the changes by using the following equation:

Fat balance (static) = total metabolizable fat intake - whole body fat oxidation

But First, what exactly is this Reparation Chamber you speak of?


And more importantly why is this measurement tool important in our experiment?

"Despite a large number of studies on human energy expenditure, it is not clearly established how much food man requires since continuos measurements of energy expenditure in man over 24-h periods have been seldom undertaken. It is noteworthy that most studies on energy expenditure have been performed over short periods of 2-4 hours. (3-10) Extrapolation of these data to energy expenditure over 24 hours or several days is open to question since energy expenditure markedly changes with activity, after meals, and during sleep (11). Therefore, there is a need to measure energy expenditure continuously for periods over 24-hour period or several days, in order to asses human energy expenditure more precisely(12)." -(31)

The purpose is to then simultaneously measure the amount of oxygen being consumed , CO2 production and urinary nitrogen excretion from the individual in the chamber to help us understand energy balance over a 24 hour period.

How does it work? What are advantages and drawbacks?

"The respiration chamber (12, 1 7) built in Lausanne, is an air-tight room (5 m long, 2.5 m wide, and 2.5 m high) which forms an open circuit ventilated indirect calorimeter (Fig 1). Outside air is continuously drawn into the chamber and the flow rate of air at the outlet is measured using a pneumotachograph with a differential manometer (Digital Pneumotachograph, model 47303 H, Hewlett Packard). A fraction of the extracted air is continuously analyzed for 02 and CO2 concentrations with a thermomagnetic 02 analyzer (Magnos 2T, full scale 19 to 2 1%, Hartmann and Braun, Frankfurt, Germany) and an infrared CO2 analyzer (Uras 2T, full scale 0 to 1%, Hart- mann and Braun). These analysers are calibrated twice a day using a gas mixture pre- pared immediately with a proportional mixing pump (H Wosthoff, Bochum, Germany). Air flow rate, 02 and CO2 concentration of outflowing air are computed on line to obtam VO2, VCO2 (under STPD conditions), respiratory quotient, and consequently energy expenditure using the equations previously described (12). "-(32)

From the Respiration chambers we can gather data on the effects of dietary changes the changes in energy expenditure/metabolism and total oxidation. Thus the chambers help us in our understanding of fat balance. Unfortunately it is only for a short period of time, but the studies and analysis done are still of importance as seen in below excerpts:

"Negative balance leads to body fat loss. Positive fat balance leads to body fat gain and obesity can only result from a chronic state of positive fat balance. Here, for the purpose of simplicity, fat oxidation is considered separately from CHO balance, but one should realize that fat and CHO oxidation are not mutually independent and there is an intimate interrelationship between them [11]. Indeed, in isocaloric conditions, at a fixed energy expenditure level and keeping protein intake constant, there is a precise inverse relationship between CHO and fat oxidation: the greater the proportion of CHO oxidized, the lower the proportion of fat oxidized.Obesity develops during a dynamic phase during which fat balance remains positive for a prolonged period of time (Fig. 1). However, this process is not necessarily sequentially on consecutive days: positive fat balance on one day may be partially compensated (or not) by negative fat balance on subsequent days. What counts is the cumulative effect!" -(33)-- Long term stuides matter, seeing as major changes in energy balance are achieved over decades --


"In the model of Flatt [9,10], de novo lipogenesis is taken into account: it diverts carbon atoms to fat tissue just as a sort of "sink" process. According to Flatt, this process plays little role in the regulation of carbohydrate balance, since under habitual feeding conditions, glycogen levels may remain relatively low and therefore they do not induce appreciable rate of lipogenesis. The site of de novo lipogenesis is thought to be mostly the liver. In fact, the exact site of fatty acid synthesis has not be clearly determined in humans. The fact that the key enzymes involved in fatty acid biosynthesis are present in both the liver and adipose tissue suggests that the latter contribution may not be negligible [1]. Furthermore, the proportion of de novo lipogenesis accounted for by liver vs. adipose tissue in different nutritional conditions remains to be further investigated." -(33)

"More than 20 years ago, the late Bjorntfrp and Sjostrom [6] have pointed out that, even with high isocaloric CHO meals, de novo lipogenesis was a quantitatively minor process in obese and nonobese individuals maintaining body weights. Yet, several investigators, based on animal data, believe that de novo lipogenesis constitutes a mechanism by which substantial fat accumulation can occur in humans [8].In order to assess the effect of food intake on the magnitude of de novo lipogenesis, two situations must be considered, in addition to whether or not the diet has a high proportion of CHO:

-- (1) Isoenergetic conditions of feeding, i.e., when energy balance is in equilibrium. It has been reported in healthy subjects that on diets containing a very high proportion of CHO (75%) for 25 days, the fractional de novo hepatic lipogenesis increased [13]. However, the conversion of CHO into fat does not provide any net storage of fat to the body: the fat synthesized by de novo lipogenesis in tissues is balanced out by simultaneous fat oxidation in another tissue. -(33)

-- (2) Overfeeding conditions, i.e., in persisting positive energy balance. Based on a review of several published studies [33], one can conclude that, in hyperenergetic conditions, high prolonged carbohy- drate overfeeding leads to a net gain in body fat due to two processes: (1) an enhanced de novo lipogenesis and (2) a decreased whole body fat oxidation (i.e., a sparing of endogenous fat) consecutive

to the rise in CHO oxidation (Fig. 5). In parallel, triacyglycerol plasma concentrations increased [14] and if prolonged, deleterious effects are observed such as fatty liver and hepatic dysfunction [8]. -(33)

"However, since the net energetic efficiency of conversion of CHO to fat is much lower than the net efficiency of storage of exogenous fat in adipose tissue, the excess energy storage will theoretically be lower with CHO as compared to fat overfeeding." -(33)

"In conclusion, in conditions of energy balance, high- CHO low-fat diets do not result in a large stimulation of net de novo lipogenesis. On the contrary, such diets when prescribed ad libitum have shown to induce progressive slow weight losses (in the order of a few kilograms) in individuals of various body weight and BMIs [7,16,22], suggesting modest negative energy balance. As a result, the increase in lipidaemia generally observed with controlled high-CHO diets [14] may be offset by the weight loss resulting from the low spontaneous ad lib consumption of such diets."
 -(33)

This Study is titled: Measurement of De Novo Hepatic Lipogenesis in Humans Using Stable Isotopes by Marc Hellerstein

" Previous estimates based on inferential methods such as whole-body indirect calorimetry (1-4) have indicated that net conversion of dietary carbohydrates into fat is a minor pathway i.e only 1-2% of 500g carbohydrate meal was calculated by respiratory caliorimetry (2,3) to be converted to fat in normal humans. If True this would suggest that neither hypertriglcyerdimeia nor obesity could result from carbohydrate overfeeding alone." -(34)


"After an overnight fast,de novo lipogenesis accounted for only 0.91±0.27%(mean±SE,n= I1)ofVLDL- palmitate and 0.37±0.08%(n= 11)ofVLDL-stearate.Even after 8 h of re-feeding with Ensure to deliver 7-10 mg/kg per min carbohydrate,the denovo pathway accounted for only 1.64±0.42%(n= 7)ofVLDL-palmitate and 0.64±0.23%(= 7)ofVLDL-stearate(Fig.8).Results from Ensure re-feeding i.v.glucose re-feeding and mixed meal re-feeding were similar In individual subjects,VLDL-stearate and VLDL-palmitate de novo synthesis did not necessarily move in parallel(TableI).It is apparent that de novo lipogenesis contributes a very small fraction of circulatingVLDL-palmitate and stearate under these dietary conditions.By inference,most circulating FA must either be derived from re-esterification of preformed FFA or were "old".-(34)

"Our results demonstrate clearly that de novo lipogenesis is in fact a quantitatively minor pathway under non-overfed conditions in normal men (TableI,Fig.8 as seen to the left)).This is the first direct measurement of de novo lipogenesis inhumans of which we are aware. It should be noted that these subjects were receiving significantcarbohydrate loads (7-10 mg/kg per min for 9 h or 3.5g/kgasameal).However,they were not chronically overfed or obese and they had fasted from 8:00p.m.the prior evening. These arefairly lifelike fasting and feeding conditions.Under such conditions,it is likely that most circulating and adipocyt fat is ultimately derived from dietary sources other than glucose (i.e.,faty acids,perhaps ethanol)."
.-(34)

Here I have presented some excerpts from No common energy currency: de novo lipogenesis as the road less traveled by Marc Hellerstein

"Most experimental data in humans, however, contradict this view of the function of de novo lipogenesis. Initial studies in which indirect calorimetry was used showed little or no net de novo lipogenesis after short-term carbohydrate overfeeding (1). Subsequent isotopic studies confirmed the absence of quantitatively significant flux through hepatic de novo lipogenesis under most conditions of carbohydrate energy surplus (2, 3)."(35)

"McDevitt et al report that hepatic de novo lipogenesis was stimulated by 4 d of surplus carbohydrate energy in women, that this stimulation was not significantly different when the surplus carbohydrate was in the form of glucose or sucrose, and that the de novo lipogenesis values reached were similar for lean and obese women. Additionally, McDevitt et al report that, in all settings, the total de novo lipogenesis flux represented a small fraction of both the surplus carbohydrate energy ingested and the total fat stored in the body. The authors calculated that between 3 and 8 g fat/d was produced through de novo lipogenesis compared with 360–390 g carbohydrate ingested/d and 60–75 g body fat stored/d." (35)

"Thus, the addition of excess carbohydrate energy to a mixed diet so that total energy intake exceeded total energy expenditure (TEE) increased body fat stores, but not by conversion of the carbohydrate to fat. Instead, the oxidation of dietary fat was suppressed and fat storage thereby increased."
(35)

Net storage was a byproduct of excess consumption not increased fat making from the de novo lipogenesis pathway.



Here is a Per Gram Example:

http://www.medbio.info/horn/pdf%20files/carbohydrate_metabolism.pdf

In this next study researchers wanted to see if there was a difference in DNL between Lean and Overweight Individuals after a high carbohydrate load because many of the previous studies only looked at lean individuals response to High Carbohydrate loads on DNL.

"DNL was significantly higher before and after meal intake in the overweight men and was positively associated with fasting serum glucose and insulin concentrations. Furthermore, postprandial DNL
was positively correlated with body fat mass, EE, and triacylglycerol."(37)


"... it is well known that fatty acid synthesis is stimulated by high-carbohydrate, low-fat diets in
both animals and humans (8–10), but it is generally thought that de novo lipogenesis (DNL) is a quantitatively unimportant metabolic pathway in weight-stable men (11). Nevertheless, DNL
may be higher in overweight hyperinsulinemic men than in lean men, depending on the type of carbohydrate in the diet (12)."(37)

"Using tracer techniques, several authors assessed the effect of carbohydrate on DNL both in isoenergetic diets (10, 15, 18) and during surplus-carbohydrate diets (15, 33) and reported that carbohydrate consumption produced a dose-dependent increase in fractional DNL. Nevertheless, it remained unimportant to body fat stores because it represented only a few grams per day, when the absolute rate of lipogenesis was measured. However, those studies included only lean men and an area of uncertainty was whether the carbohydrate intake could produce a higher stimulation of DNL in overweight humans. Furthermore, it was seen that insulin-resistant men showed a modestly increased fractional DNL, but the absolute rate of DNL accounted for only a few extra grams of fat per day (19, 34)...." (37)

"In the present study, when a stable isotope technique was used it was evident that DNL occurred at NPRQs < 1, even with only a single carbohydrate meal. Indeed, this metabolic pathway was qualitatively higher in overweight individuals, although with no positive net lipogenesis." - (37)

As we can see from the above, the majority of the medical literature still supports that glucose utilization favors supplying energy to our internal organs and storage as glycogen over the de novo lipogenesis pathway in healthy individuals when consumed in normal amounts. (21, 22232425262728) Thus, carbohydrates do not seem to induce significant fat gains in normal healthy individuals unless there is an over consumption of calories in general and even then the excess calories could be from fat or protein and fat tissue would increase(36).

Lastly, here is some counter intuitive thought for us to chew on. What if de novo lipogenensis serves an important substrate for health and with out it we become unhealthy? I say this because everyone I come across with a fear of carbohydrates seems to think that any carbohydrate amount getting turned into fat is a Negative thing. But, what if it ends up being a positive thing... up to a certain point and serves as an important pathway in whole body homeostasis?  Examine the following.


"The absence of a simple correlation between carbohydrate ingestion and the quantity of DNL in humans supports the concept that DNL may serve physiological functions aside from its role in the macronutrient energy economy. While most cells perform DNL, liver cells and adipocytes are particularly well adapted. DNL in liver has detrimental effects, including elevating serum triglycerides and increasing intrahepatic lipid (steatosis), leading to nonalcoholic fatty liver disease and steatohepatitis (Fig. 2) (5). In addition, elevated hepatic DNL strongly correlates with insulin resistance (6). In contrast, increased lipogenic enzyme expression in adipose tissue is associated with enhanced insulin sensitivity in humans (Fig. 2) independent of obesity (7)."(38)

"...investigation of the molecular mechanisms regulating DNL in liver and adipose tissue also supports the view that adipose DNL, unlike hepatic DNL, may be metabolically beneficial. Liver-specific deletion of SCAP, a protein required for cleavage of SREBP1c to its active form, reduces hepatic DNL (10). This is accompanied by a compensatory four-fold increase in adipose DNL associated with improved fasting glycemia, glucose tolerance and insulin sensitivity. In addition, genetically deleting adipose tissue lipid chaperones aP2 and mal1 increases adipose DNL and renders mice resistant to diet-induced obesity, fatty liver disease, insulin resistance and Type 2 diabetes (1). The improved metabolic phenotype has been attributed to insulin-sensitizing properties of palmitoleate, a potentially beneficial fatty-acid species produced at increased rates as a result of increased adipose DNL (1). These genetic studies causally link increased adipose DNL with beneficial effects on whole-body metabolism."(38)

"Thus, growing evidence suggests that increasing adipose tissue DNL may provide beneficial health effects in contrast with the effects of DNL in liver tissue. Strategies to enhance DNL specifically in adipose tissue and to identify and administer salutary bioactive lipids may provide new therapies for metabolic and cardiovascular disease."- (38)


As we can see from the above there are two sides to this story, too much DNL in the liver can potentially lead to insulin resistance while not enough DNL in the adipose can also potentially lead to some negative metabolic aspects. For one to say that DNL as whole is a negative aspect altogether would not only be out of sync with the medical data but could potentially lead to some uneducated choices in a person's dietary decisions. For instance the popular myth I see floating around is regurgitated as such:

An individual eats Carbohydrates so often the muscle become insulin resistant --> as a result the carbs get stored as fat in the adipose tissue leading to obesity. ( I will discuss this in the next section titled insulin resistance and lipotoxicity as well)

The storage of Fat as you can see from the above requires the process of turning glucose into fatty acids via DNL but increased DNL in the adipose tissue (not the liver) seems to lead to favorable changes in metabolism and an increase insulin sensitivity not the opposite as some would assume. It would seem that insulin resistance in the fat tissue leads to the most metabolic issues in this case and not the muscles for the normal pathologic formation of metabolic syndrome related afflictions.

http://www.quickandstrong.com/wp-content/uploads/2012/04/Insulin-Fairy.jpg



"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."(39)

" 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."  (39)

"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." (39)

More research is needed in this area but once agin it would foolish for us to think that DNL serves no purpose other than to make us fat and diabetic when clearly the research that has been done so far does show some potentially positive metabolic effects and protection from afflictions like hyperglycemia, insulin resistance, obesity etc.

While it is important to recognize that this metabolic pathway for increased fat making from carbohydrate consumption does exist, what we need to remember is that this is a very inefficient process.

In the next section we will review the storage of fatty acids in the adipose tissue and re-esterification.

For Part 4 Click Here

To start from the beginning click Here