High-Fructose-High-Coconut-Oil Diet Disregulates Leptin, Stearoyl-CoA Desaturase, And Spatial Memory

[Terma]

Yeah it turns out Leptin is major SCD1 regulator independent of insulin and methionine through the complicated ERK1/2 signaling pathway. The article would be correct about that. And in typical rat studies, fructose ruins leptin.

The rest I would pretty much ignore on account of rats and the fact rats stopped being relevant for fructose liver studies at least 5 years ago (if I'm not drastically underestimating), I'm sure you can find the arguments in threads that are now old. This is completely stupid:

Both experimental diets had an energy density of 4.8 kcal/g and contained 50.8% carbohydrates from fructose, 11.7% protein from casein, and 37.5% fat from soybean oil or coconut oil as an abundant source of PUFAs or SFAs, respectively.

I mean,

 

[Hans]

The theory can't even explain why omega-3 would behave very differently from o-6

This is because longer than 18 carbons unsaturated fats mostly undergo beta-oxidation in the peroxisomes, which do not generate NADH or FADH2.

From: Roles of Reactive Oxygen Species on Insulin Resistance in Adipose Tissue
According to the study, there are three main sites of ROS production. NOX4, NOX2, and the mitochondria.
"Certain saturated free fatty acids (SFAs; laurate, myristate, and palmitate) increase inflammatory genes in adipocytes [17]. These events are associated with the generation of reactive oxygen species (ROS) and nuclear factor κB (NF-κB) transactivation. Excess glucose and/or certain SFAs increased ROS generation and NF-κB translocation [17]. Treatment with the antioxidants, N-acetyl cysteine, catalase and superoxide dismutase (SOD) repressed ROS generation and NF-κB translocation stimulated by excess glucose 4tate, and decreased inflammatory gene expression [17]. Thus, glucose- and palmitate-stimulated ROS generation appears to play an important role in adipocyte inflammation."

also

"We previously have shown that excess glucose and palmitate are not metabolized to a major extent via mitochondrial oxidation. Instead excess nutrients activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX). Members of the NOX family are membrane-bound enzyme complexes that transfer electrons from NADPH to oxygen, generating superoxide."

The pentose phosphate pathway (PPP) generates NADPH, and glucose-6 phosphate dehydrogenase (G6Pdh) is the rate-limiting enzyme in the PPP. Indeed, G6Pdh overexpression is associated with increased adipocyte inflammation and ROS generation. And silencing NOX4 decreased ROS generation stimulated by excess glucose as well as palmitate.
The reason ROS from NOX4 is so important, is that it improves adipogenesis by improving insulin sensitivity in adipose tissue. In NOX4 null mice, expression of PPARgamma and CCAAT-enhancer-binding protein α [C/EBPα] is inhibited. This allows adipocytes to become more hypertrophic and thereby leading to adipose tissue inflammation and insulin resistance and then as a consequence metabolic syndrome.

The other major site of ROS production is the electron transport chain. Beta-oxidation of saturated fat produces more NADH and FADH2 compared to unsaturated fat and would reduce more ubiquinone. A high ratio of ubiquinol to ubiquinone drives ROS production.
The study further says:
"Although glucose excess presumably drives the overflow of electrons in mitochondria, other energy sources in adipocytes are preferred in the late stages of obesity since uptake of glucose is limited by the insulin resistance of adipocytes. When glucose consumption is reduced by insulin resistance, adipocytes start to use FFA from triglyceride stores for energy (Fig. 2). This alteration of energy flux into β-oxidation could overwhelm the capacity of mitochondria, leading to leakage of electrons"

It's not only the leakage of electrons through the electron transport chain that is the problem, its that β-oxidation cannot keep up with the fat flood and causes incomplete oxidation. High rates of beta-oxidation outpace metabolic flux through the TCA cycle, leading to accumulation of incompletely oxidized acyl-carnitine intermediates.

These partially oxidized lipids that are floating around in the mitochondria are then prone to oxidation by ROS, and creates even more toxic byproducts such as 4-hydroxynonenal (4HNE). And only PUFAs can be oxidized by ROS, which is called lipid peroxidation.

Saturated fats are protective, because it generates the most ROS and causes insulin resistance in the muscle, so that the cells can't be flooded by more glucose. The higher ROS produced by saturated fat and glucose oxidation will inhibit the enzyme aconitase and increase malonyl-CoA production, which will inhibit the enzyme carnitine palmitoyltransferase 1 (CPT-1). This will prevent the mitochondria from being flooded by more long chain fats, preventing excessive beta-oxidation.

PUFAs, which generate less ROS through the electron transport chain, will not shut down glucose influx as much, will not produce as much malonyl-CoA and will not inhibit CPT-1 as much as saturated fat would. This will temporarily "improve beta-oxidation" and insulin sensitivity, allowing the cell to be flooded with more substrates than it can handle. This might look like a good thing in the short term, but then the ROS will oxidize the free PUFAs in the cell as well as in the cell membranes and also the cardiolipin, leading to mitochondrial dysfunction and cell death.

Saturated fat does cause insulin resistance, but it's protective. There are many studies to show it. And PUFAs, such as omega 3, improve insulin sensitivity, but in the long run it leads to trouble. Overeating in general leads to problems.

I'm also a bit skeptical about the ROS production through reverse electron transfer to be the major contributor, because the electron transport chain isn't one long chain, but is composed of supercomplexes such as a supercomplex of complex I, III & IV and complex II, III & IV. This way complex II doesn't "get in the way" of complex I's forward electron flow. These supercomplexes are held together by cardiolipin, and if the cardiolipin are mostly unsaturated fat, they will be oxidized by ROS leading to a loss of these complexes. A loss of electron chain complexes increase ROS production, because of a high ubiquinol to ubiquinone ratio.

 

[Wagner83]

Saturated fats are protective, because it generates the most ROS and causes insulin resistance in the muscle, so that the cells can't be flooded by more glucose. The higher ROS produced by saturated fat and glucose oxidation will inhibit the enzyme aconitase and increase malonyl-CoA production, which will inhibit the enzyme carnitine palmitoyltransferase 1 (CPT-1). This will prevent the mitochondria from being flooded by more long chain fats, preventing excessive beta-oxidation.

PUFAs, which generate less ROS through the electron transport chain, will not shut down glucose influx as much, will not produce as much malonyl-CoA and will not inhibit CPT-1 as much as saturated fat would. This will temporarily "improve beta-oxidation" and insulin sensitivity, allowing the cell to be flooded with more substrates than it can handle. This might look like a good thing in the short term, but then the ROS will oxidize the free PUFAs in the cell as well as in the cell membranes and also the cardiolipin, leading to mitochondrial dysfunction and cell death.

Saturated fat does cause insulin resistance, but it's protective. There are many studies to show it. And PUFAs, such as omega 3, improve insulin sensitivity, but in the long run it leads to trouble. Overeating in general leads to problems.

What do you eat yourself ? Very low fat or mostly MUFAs as in olive oil? I haven't seen much information against quality olive oil, although the latter is very hard to find.

 

[Hans]

What do you eat yourself ? Very low fat or mostly MUFAs as in olive oil? I haven't seen much information against quality olive oil, although the latter is very hard to find.

I drink fat free milk and eat starches and fruits at the moment. So I'm experimenting with very low fat, but I'm going to increase fat in the future, probably to between 20 and 40gs a day. The fat will mostly be from milk, beef, cocoa and some coconut oil.
I'd always eat saturated fat and stay away from mufas and pufas.
Mufas are between saturated fats and pufas in terms of affecting insulin signalling. If I had to improve my insulin signalling, I would rather go fat free for a while and then slowly reintroduce fats. But I guess if someone doesn't do so well on a fat free diet, or coconut oil, olive oil could work. Experimentation is key.

Another thing about the study is that lauric acid is oxidized very rapidly compared to palmitic and stearic acid and would create more ROS compared to stearic acid thus would theoretically contribute to a greater extent to insulin resistance.

 

[Kartoffel]

Saturated fat does cause insulin resistance, but it's protective. There are many studies to show it. And PUFAs, such as omega 3, improve insulin sensitivity, but in the long run it leads to trouble. Overeating in general leads to problems.

Thanks. This is the argument I made at very beginning and why I wrote "resistance". It is simply an adaptation to the physiological situation and substrate availability. The insulin "resistance" caused by saturated fat prevents the cells from burning more energy than it can handle, and that's protective. This situation creates it's own problems such as a higher likelyhood of forming AGEs in the blood, but I think the benefits clearly outweigh the negative effects. There is also evidence that increased ROS induce the formation of new mitochondria to increase the ability to oxidize energy substrates.

This is because longer than 18 carbons unsaturated fats mostly undergo beta-oxidation in the peroxisomes, which do not generate NADH or FADH2.

Are you sure that peroxisomal beta-oxidation doesn't generate NADH? I'm pretty sure it does. Also, if I remember it correctly most long chain fatty acids are shortened to 8 carbon fatty acids in peroxisomes and then shifted to mitochondria where they undergo normal ß-oxidation producing NADH and FADH2. I always thought that the lower FADH2 ratio from PUFA is mainly a results of the latter's lower reducing potential compared to SFA. Since every double bond represents an inability to reduce FAD to FADH2 you have a lower potential to reduce FAD to FADH2 the more unsaturated the fatty acid is.

 

[Hans]

From the study: "During the first eight weeks the food intake was significantly greater in the experimental groups compared with the controls; however, no differences were observed between the two experimental groups (data not shown for brevity)." This shows that food intake was not controlled between the groups, which makes it suspicious.

Anyway, I found another, very similar study. Soybean Oil Is More Obesogenic and Diabetogenic than Coconut Oil and Fructose in Mouse: Potential Role for the Liver
They had 5 groups. 1 was control, HFD was mostly coconut oil, SO-HFD was coconut oil replaced with soy bean oil, F-HFD was fructose added to the coconut oil diet, and F-SO-HFD was fructose added to the soybean oil group. All groups ate exactly the same calories and macros.
Their diet looked like this:

Some interesting points:
"Mice fed SO-HFD gained more weight and at a faster rate than mice fed HFD (Fig 1A left). Addition of fructose also increased body weight above HFD (Fig 1A right), although not as much as soybean oil"

"SO-HFD mice gained slightly more weight than F-SO-HFD mice, although this difference was significant only between weeks 8 and 16". Looks like fructose protected against the obesogenic effects of PUFAs.

"The amount of mesenteric and subcutaneous white adipose tissue (WAT) was significantly greater in SO-HFD than HFD mice"

"To our surprise, we found that at 20 weeks the F-HFD did not cause diabetes (fasting blood glucose level > 200 mg/dL) whereas the SO-HFD did (Fig 4A). Furthermore, the F-HFD mice were just barely less tolerant to glucose than the Viv mice while the SO-HFD were extremely intolerant. Interestingly, the addition of fructose to SO-HFD (F-SO-HFD) actually slightly ameliorated the glucose intolerance of SO-HFD. Notably, the diet consisting primarily of coconut oil (HFD) did not show any diabetes or glucose intolerance at 20 weeks."

"Even more striking were the results of the insulin tolerance test. At 33 weeks, the SO-HFD mice were the most insulin resistant and much more so than F-SO-HFD mice, which were indistinguishable from F-HFD and HFD (Fig 4B). All told, these results indicate that a moderately high fat diet of coconut oil, either in the presence or absence of fructose, does not induce significant diabetic symptoms (elevated fasting blood glucose and glucose intolerance) while isocaloric diets with soybean oil (either with or without fructose) do. Counter intuitively, our results also suggest that the addition of fructose to the diet may even protect against the IR caused by soybean oil."

The soybean and coconut oil significantly effected different genes, soy for the bad and coconut for the good:

"the pro-inflammatory eicosanoid 12-HETE (an AA metabolite) and the marker of lipid peroxidation 13-HODE+9-HODE (LA metabolite) [91–93] were significantly decreased in HFD versus Viv (normal chow) at both 16 and 35 weeks, suggesting that coconut oil may be protective against inflammation"

"We show here that in mice dietary fructose does in fact induce obesity but less so than soybean oil. However, it did not induce diabetes or IR"

I advise to read the whole study for yourself.

 

[Hans]

There is also evidence that increased ROS induce the formation of new mitochondria to increase the ability to oxidize energy substrates.

True. But diabetes have elevated ROS and they have reduced mitochondrial number. I guess there is a balance to what is good and bad. Still SFAs will be the most beneficial. I also read that a high fat diet increases PPAR and PGC-1 and this mitochondrial number, but it didn't restore insulin signalling, because excessive beta-oxidation is the problem, and not necessarily mitochondrial number. Metabolic efficiency is key.

Are you sure that peroxisomal beta-oxidation doesn't generate NADH? I'm pretty sure it does. Also, if I remember it correctly most long chain fatty acids are shortened to 8 carbon fatty acids in peroxisomes and then shifted to mitochondria where they undergo normal ß-oxidation producing NADH and FADH2. I always thought that the lower FADH2 ratio from PUFA is mainly a results of the latter's lower reducing potential compared to SFA. Since every double bond represents an inability to reduce FAD to FADH2 you have a lower potential to reduce FAD to FADH2 the more unsaturated the fatty acid is.

Yes sure. It only generates hydrogen peroxide, but it's only minor. Yes it's shortened to C8 and then shuttled into the mitochondria for further beta-oxidation. When there is a double bond, other enzymes is necessary to convert it to acetyl-CoA and they do not generate FADH2, but still NADH. Things like linoleic and a-linolenic acid will generate the least FADH2, whereas longer unsaturated fats will not because of partial oxidation through the peroxisomes, providing a fat with less double bonds.

 

[Peater Piper]

-snip-

Saturated fat does cause insulin resistance, but it's protective. There are many studies to show it. And PUFAs, such as omega 3, improve insulin sensitivity, but in the long run it leads to trouble. Overeating in general leads to problems.

Great information, thanks. And that basically goes along with what tyw was saying. His concern though, was that saturated fat + fructose is different from saturated fat + glucose. You don't believe this would lead to even greater ROS and H2O2 in the mitochondria?

From the study: "During the first eight weeks the food intake was significantly greater in the experimental groups compared with the controls; however, no differences were observed between the two experimental groups (data not shown for brevity)." This shows that food intake was not controlled between the groups, which makes it suspicious.

I prefer ad libitum diets when trying to extend results to humans since we're not in labs 24-7 with food intake being controlled. Fructose has been shown, in humans, to typically increase appetite and calories, so caloric restriction in lab animals isn't really a fair comparison. But I'm to the point now where I don't trust most studies that try to extend the results from lab animals to humans.

Wouldn't it make sense that the saturated fat group had more visceral fat because medium chain triglycerides and fructose both require metabolism via the liver and so an abundance of both bottle necked it leading to hepatic build up and subsequent metabolic syndromes?

Yes, I agree. Obviously the liver was having some success exporting all that energy, we can see that from the lab results, but it was still insufficient to prevent visceral accumulation.

 

[Peater Piper]

Thanks. This is the argument I made at very beginning and why I wrote "resistance". It is simply an adaptation to the physiological situation and substrate availability. The insulin "resistance" caused by saturated fat prevents the cells from burning more energy than it can handle, and that's protective. This situation creates it's own problems such as a higher likelyhood of forming AGEs in the blood, but I think the benefits clearly outweigh the negative effects. There is also evidence that increased ROS induce the formation of new mitochondria to increase the ability to oxidize energy substrates.

From what I understand, maybe Salmonamb can correct me, is that this "protection" is very short term. Having multiple substrates from a meal in the blood at the same time will cause a transient insulin resistance. This should lift once the substrates are processed (either stored or burned). Once you're in a position where glucose and FAs are elevated 24-7, I think you're entering a pathological condition. It's one thing to be insulin resistant on a low carb diet because you won't have excess glucose in the blood stream, but being in a position where both are elevated seems like a recipe for diabetes and atherosclerosis down the road, and in fact, even minor glucose disturbances can predict some of these outcomes a decade or more down the road unless there's an intervention.

 

[Kartoffel]

From what I understand, maybe Salmonamb can correct me, is that this "protection" is very short term. Having multiple substrates from a meal in the blood at the same time will cause a transient insulin resistance. This should lift once the substrates are processed (either stored or burned). Once you're in a position where glucose and FAs are elevated 24-7, I think you're entering a pathological condition. It's one thing to be insulin resistant on a low carb diet because you won't have excess glucose in the blood stream, but being in a position where both are elevated seems like a recipe for diabetes and atherosclerosis down the road, and in fact, even minor glucose disturbances can predict some of these outcomes a decade or more down the road unless there's an intervention.

Of course, this situation indicates a physiological problem, and an excess of energy that should be corrected. Nevertheless, the discussion was whether the "normal" blood glucose amd insulin in the soybean group were preferable. I don't see why you would be at a greater risk of developing atherosclerosis and diabetes with coconut oil than with soybean oil, even if combined with high carb intake.
Again, I think the fact that a high-carb diet combined with PUFA makes you much fatter than a combination with coconut oil tells you something about which situation might be more pathological. PUFA kill beta cells, and glucose helps them regenerate.
I think the insulin resistance caused by SFA should disappear quickly once the energy surplus is gone. In the real world the addition of saturated fat would probably help you to stabilize your blood sugar and thereny prevent overeating. Here we are talking about an experiment where the "participants" can't choose their foods, and 50% fructose is an impossible diet.

 

[Peater Piper]

I don't see why you would be at a greater risk of developing atherosclerosis and diabetes with coconut oil than with soybean oil, even if combined with high carb intake.

Because elevated A1C leads to higher risk for all of these things. We're not just talking about glucose. The system is also overloaded with free fatty acids. Beta cells aren't safe just because the fat is saturated. The liver is overloaded. I'm not sure it's possible to really be healthy with NAFLD. I'd rather have that fat in subcutaneous storage than in the liver.

I think the insulin resistance caused by SFA should disappear quickly once the energy surplus is gone. In the real world the addition of saturated fat would probably help you to stabilize your blood sugar and thereny prevent overeating. Here we are talking about an experiment where the "participants" can't choose their foods, and 50% fructose is an impossible diet.

Well, I could just as easily say the soybean group, if placed back on the standard chow, would lose the weight and be fine, too. But they didn't test that, so it's not an assumption worth making, imo.

Anyway, judging by how many here have gained weight, in some cases, substantial amounts of weight, from combining saturated fat and sugar, I would guess that the combination doesn't prevent overeating. The people I've seen succeed with it tend to eat only a couple of large meals a day, plenty of time for the liver to export all the excess energy and return blood values to normal. Otherwise, it seems the majority of people who have success with very high fructose consumption are keeping overall fat very low.

 

[Hans]

saturated fat + fructose is different from saturated fat + glucose. You don't believe this would lead to even greater ROS and H2O2 in the mitochondria?

Yes because the cell can control glucose influx and not so much fructose influx, thus leading to more H2O2 production.

I prefer ad libitum diets when trying to extend results to humans since we're not in labs 24-7 with food intake being controlled. Fructose has been shown, in humans, to typically increase appetite and calories, so caloric restriction in lab animals isn't really a fair comparison. But I'm to the point now where I don't trust most studies that try to extend the results from lab animals to humans.

I don't like ad libitum diets because that's how someone gets fat. Overeat and you get fat. Controlled diets, not calorie restriction, should give a pretty good idea what the differences would be between substances. Though overeating studies do have it's place, but that is usually how researchers put fructose in a bad light. Plus a 60% fructose diet is impossible. Fructose never occurs alone and most people eat 75g of fructose daily.

"Fructose consumption has increased from ~37 g/day in 1977 [29] to ~49 g/day in 2004, with the highest intake among teenage males (75 g/day) [30]." Soybean Oil Is More Obesogenic and Diabetogenic than Coconut Oil and Fructose in Mouse: Potential Role for the Liver

I agree, animals and humans are very different and results should be carefully interpreted.

Having multiple substrates from a meal in the blood at the same time will cause a transient insulin resistance. This should lift once the substrates are processed (either stored or burned).

Yes

Once you're in a position where glucose and FAs are elevated 24-7, I think you're entering a pathological condition.

You won't have glucose and fats elevated together if you're not already in a pathological condition. PUFAs cause inflammation (NF-kappaB, etc.), which shut insulin signalling down. From my above post, SFAs and glucose increase ROS, which allow for adipogenesis in caloric excess, allowing "healthy" fat gain. PUFAs doesn't cause as much ROS, but do increase adipocyte insulin sensitivity, which allow adipocyte hypertrophy and inflammation. This allows for unhealthy fat gain. In such a case, when the fat cells can't take in any more fats, the fats leak out and flood the system. When this happens, the only place for the fats to go is inside muscles, around and inside organs, against the artery walls, etc.
Insulin will inhibit CPT-1, increase malonyl-CoA, inhibit lipolysis and inhibit gluconeogensis. PUFA increases lipolysis compared to SFA. PUFAs don't increase malonyl-CoA as much as SFA. PUFAs allow for lower insulin signalling and thus don't shut gluconeogenesis down as much. This leads to both hyperglycemia and hyperlipidemia at the same time.
Initially, PUFAs increase insulin sensitivity (according to the ROS model), but then it causes inflammation and shuts down insulin function altogether, damages the beta-cells and leads to type I diabetes.
SFA will protect the cells and ensures normal functioning, and when eating an excess of calories, it will ensure safe fat gains. PUFAs are the opposite.

Caloric excess in general leads to problems I think. PUFAs are just the most obesogenic and problematic. I'd also say that it would be best to avoid anything that interferes with your primary fuel, such as fats interfere with glucose oxidation. But everyone has different tolerance levels, so everyone have to experiment to see what their perfect macro ratio would be.

 

[dreamcatcher]

Percentages of fructose and fat were the same in the soybean group. I assume because soybean oil is so high in PUFA, it didn't impair glucose oxidation as significantly as the CO group. Still, 20-weeks isn't a short study for rats, and it's hard to say the CO group looked any better in any health category by the end except for in overall body weight (and we could actually look at that as a failure to thrive). Still, it was definitely an extreme dietary approach, and in rats which aren't always comparable to humans, so I doubt we can really draw any real conclusions. I don't believe fructose and saturated fat are a great combo though, which is kind of anti-Peat, but there's plenty of evidence they don't play well together, at least in the same meal, and can lead to long term problems when used in combination.

Hmm my 6 year old daughter who naturally follows a Peaty diet, is not really keen on fruits but eats moderate amounts of saturated fats. I think Chris Masterjohn talks about the same, too much sugar intake COMBINED with a high fat diet has damaging effects on the body..?

 

[Jon]

Hmm my 6 year old daughter who naturally follows a Peaty diet, is not really keen on fruits but eats moderate amounts of saturated fats. I think Chris Masterjohn talks about the same, too much sugar intake COMBINED with a high fat diet has damaging effects on the body..?

How cool! My wife is the same way and she's extremely healthy lol. Always nice to have prime specimen as a study lol.

 

[dreamcatcher]

How cool! My wife is the same way and she's extremely healthy lol. Always nice to have prime specimen as a study lol.

Exactly! Children naturally follow their instincts..if they're allowed.

 

[chrismturner89]

Exactly! Children naturally follow their instincts..if they're allowed.

What sort of diet do you refer to, especially if not eating much fruit?

 

[dreamcatcher]

What sort of diet do you refer to, especially if not eating much fruit?

Starch over fruit (potatoes and rice).

 

[Jon]

Starch over fruit (potatoes and rice).

+1.