English corner: Unsaturated fish oils impaired glucose tolerance

How stored PUFA shifts away the capacity of oxidation of sugars
Main ideas
- Transition from glycolysis mode to lipolysis mode and conversely.
- Lipid peroxidation of polyunsaturated fatty acids produces the protein damage about 23 times faster than the simple sugars do.
-  Stored PUFA makes the blood vessels weaker, damages the mitochondria and suppress thyroid functions.
- These damages reduce the ability to oxidize sugar and to produce energy.
- Role of PUFAs in the glucose homeostasis: Excess Omega-6 impaired glucose tolerance.
- Providing hormone T3 and a well-assimilated amount of sugar tend to shift energy metabolism away from the oxidation of fats, back to the oxidation of sugar, with staples (progressively).
- Poor glycemic control has been associated with hypothyroidism in non-insulin dependent persons
Fats as energy source
Fats are a source of fuel that the body can utilize to produce energy. Fats are not usually utilized directly as energy source. They must be processed by the body, being altered / oxidized then after digestion / assimilation. There are several mechanisms that permit it, in order to recognize fats and specifically to store them for future energy purposes. Excess fat is stored in the form of triglycerides in adipocytes. Triglycerides are three fatty acid molecules bound together with a glycerol molecule.
Each fatty acid molecule is an extended chain of carbon and hydrogen atoms. The process of hydrolysis separates the stored fats into its two separate compounds, fatty acids and glycerol. Glycerol has properties similar to alcohol and sugar; after the release by the [Vous devez être inscrit et connecté pour voir ce lien], the glycerol is passed through the bloodstream for return to the liver for a conversion into a useful energy source, glucose.
Free fatty acids
The [Vous devez être inscrit et connecté pour voir ce lien] released from adipose tissue can be utilized anywhere there is an energy need within the body. The process of releasing these compounds begins with a signal from the pancreas, the organ responsible for the monitoring of glucose concentrations in the blood. The ultimate destination of the released fatty acids is the mitochondria of the subject cells that require energy. The mitochondria is the powerhouse of every cell.
Where do FFAs come from?
FFAs come from food or lipolysis, when the principal postprandial blood reserve of glucose is nearly exhausted and muscles deprived of fuel. So FFAs come from a post-absorptive state. We call this state “lipolysis”, that’s to say the release of fats thanks to the enzyme lipase.
So, FFAs come from adipose tissues (reserve of triglycerides). Lipase enzymes provide then the principal source of lipid fuel in post-absorptive state. The availability of FFA is strongly regulated by hormonal factors that modulate the activity of hormone-sensitive lipase.
What suppresses lipolysis?
One of the basic functions of insulin in the body is to inhibit lipolysis in adipocytes. Recently, we have found that insulin inhibits lipolysis and promotes triglyceride storage by decreasing transcription of adipose triglyceride lipase via the mTORC1-mediated pathway (P. Chakrabarti et al., Diabetes 59:775–781, 2010), although the mechanism of this effect remained unknown.
Fat storage
The body stores fat in two ways for further needs: either in tissues entirely dedicated to this role, the adipose tissue, or inside other types of cells in small vacuoles filled with fatty acids called ««lipid droplets».
Between meals, stored fat is slowly released, while circulating glucose is progressively exhausted, keeping our cells supplied with fuel. While the brain needs glucose, our liver, muscle, and fat cells prefer to burn fat.
What enhances glycolysis and stop lipolysis?
Lipolysis is the metabolic process through which triacylglycerols (or triglycerides) (same molecule), break down via hydrolysis into their constituent molecules: glycerol and free fatty acids (FFAs).
Cortisol in physiological concentrations stimulates whole body lipolysis. In adipose tissue, lipolysis is regulated by two enzymes, hormone-sensitive lipase (HSL; EC 3.1.1.3) and lipoprotein lipase (LPL; EC 3.1.1.34). The activities of these enzymes are reciprocally linked. (…) In vitro, cortisol increases the activity of these two enzymes, enhancing the degradation of fat to serve as fuel, after glycerol has been treated by the liver, in order to make glucose.
When you get anxious your body makes two chemicals, adrenaline and cortisol.
Adrenaline is a stress hormone. A mind full of thoughts, anxiety, and worry can also stimulate your body to release adrenaline and other stress-related hormones like cortisol. These hormones are considered as “fight or flight” hormones (adaptive process to protect men).
So, in emergency state – or when repeated stress occurs – adrenaline tells the brain to produce cortisol in order to get fuel immediately (adaptive process). Whenever glucose isn’t at disposal, glycogen is required, in a normal state. Not in emergency.
Lipolysis takes time, too long. After a night sleep, the reserve of glycogen in muscles is weak. Useful direct fuel is needed. Glycogen can’t do this job on a long period.
Subsequently lipolysis is stopped when you stress much. We need 90 to 120’ to recover a quiet mind. Taking magnesium bisglycinate could help lowering this time period. You can’t lose weight easily if you stressed a lot.
Mobilization of triglycerides
Triglycerides are mobilized in the absence of glucose.
- The action of the bile contributes to the emulsion and the formation of micelles from the triglycerides. Enzymes that hydrolyze lipids are lipases and phospholipases. Their activity takes place in the small intestine. Once entered in the enterocyte, fatty acids are supported by a specific carrier which transports them to the smooth endoplasmic reticulum. They are joined by the 2- monoacylglycerols which have the capacity to cross by passive diffusion. The fatty acids and the 2-mono-acylglycerols are recombined in triacylglycerols by the enzymes of the endoplasmic reticulum.
1. Lipoproteins are forms of transport of hydrophobic fats in blood plasma. Of globular structure, they consist of a hydrophobic heart of triglycerides, surrounded by proteins, cholesterol esters and phospholipids.
2. Chylomicrons synthesized in enterocytes (intestine): form of transport of eating triglycerides towards user tissues and adipose tissue:
- VLDL (very low density lipoproteins) synthesized in the liver.
- LDL (Low Density Lipoproteins) (70 % synthesized in the liver, most of the rest in the intestines)
- HDL (High Density Lipoproteins) synthesized in the blood.
It is in the form of triglycerides that lipids are transported to adipose tissues and it is in the same form that they are transported to user tissues.
Remind
The FFAs we talk about are coming from lipolysis, all the more when the principal postprandial blood reserve of glucose is nearly exhausted. Expressed in other words: triglycerides are hydrolyzed into FFAs when the reserve / fuel is needed.
Free fatty acids and arachidonic acid
The ω-6 polyunsaturated fatty acid (PUFA), arachidonic acid (AA), and its metabolites have attracted a lot of attention in cardiovascular and cancer biology, particularly in relation to inflammatory processes and disease. The importance of AA in biology lies in the fact that it can be metabolized by three distinct enzyme systems, i.e., cyclooxygenases (COX), lipoxygenases (LOXs), and cytochrome P450 (CYP) enzymes (ω-hydroxylases and epoxygenases) to generate an impressive spectrum of biologically active fatty acid mediators.
The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes to a spectrum of bioactive mediators.
AA cascade
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Translation: Arachidonic cascade (AA)
Cellular mediators (messenger hormones) are released, from the fatty acids contained in the cellular membranes, via 5-LOX and COX-1 & 2. This process is called "arachidonic cascade" (AA). It is this path that omega-6 fatty acids follow.
Effects of arachidonic acid on thyroid hormones in men
Several studies have shown that PUFAs inhibit thyroid hormone binding to carrier proteins. (*)
Note: AA is the way the body stores PUFAs in the membranes when PUFAs aren’t used for hormonal purpose (we are surrounded by omega-6).
Omega-3 anti-thyroid effects
• ALA administration leads to a 22% reduction in T3, the most powerful form of thyroid hormone. T4 to T3 conversion rates decrease by 56% in response to ALA ingestion. The ALA even interferes with normal T3 rates if you administer T4 in the cells beforehand. ([Vous devez être inscrit et connecté pour voir ce lien])
• Animals subjected to a diet rich in PUFA compared to an SFA diet (with corn oil or saindoux / white pork fat) have found a significant decrease in the response to thyroid hormone in rats fed with PUFA. ([Vous devez être inscrit et connecté pour voir ce lien])
What is the connection between estrogen and seed oils / PUFA?
PUFA is a xeno-estrogen. So it agonizes the estrogen receptor, and increases the enzyme that creates estrogen. (3) To add to this, it leads to enzymes in the body to change in activity, to lead the body to be less androgenic/ progesteronic and more estrogenic - for example, it increases 11 beta hsd 1 and reduces 5 alpha reductase. This leads there to be less defenders against the effects of estrogen. Furthermore, it makes the cell less saturated and less lipophilic - which leads to unsaturated hormones like estrogen to be uptaken into the cell.
So in basic terms: PUFA mimics estrogen, increases its synthesis and storage in our cells, while reducing natural protectors of estrogen’s effects like progesterone and DHT.
*) Connection between poor sugar metabolism and hypothyroidism
Both underactive and overactive thyroid disorders are more common in people who have diabetes than those who do not have diabetes. But if you suffer from a sluggish liver, you metabolize with difficulty. Your hormone production is erratic. Hypothyroidism has been associated with poor glycemic control in non-insulin dependent persons. Expressed differently those persons are able to burn moderate amount of sugars, at the same time. This is because thyroid hormone affects glucose homeostasis in different ways. (...)

Sources and References
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*) Are PUFAs toxic?
Video of Chris Masterjohn 30’ [Vous devez être inscrit et connecté pour voir ce lien]
Chris Masterjohn earned a PhD in Nutritional Sciences from the University of Connecticut in 2012 and currently researches the physiological interactions between fat-soluble vitamins A, D, and K at the University of Illinois, Urbana-Champaign.
*) Arachidonic acid causes an uncoupling effect and inhibits cellular respiration
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Excerpt                                                   
“It is shown that arachidonic acid causes an uncoupling effect under state 4 respiration of intact mitochondria as well as a marked inhibition of uncoupled respiration.
*)  Unsaturated Vegetable Oils: Toxic      
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Excerpt (main points):
- To defend the seeds from the animals that would eat them, the [PUFA]-oils block the digestive enzymes in the animals' stomachs.
- Their tendency to oxidize is very great. These oxidative processes can damage enzymes and other parts of cells, and especially their ability to produce energy.
The enzymes which break down proteins are inhibited by unsaturated fats, and these enzymes are needed not only for digestion, but also for production of thyroid hormones, clot removal, immunity, and the general adaptability of cells. The risks of abnormal blood clotting, inflammation, immune deficiency, shock, aging, obesity, and cancer are increased. Thyroid and progesterone are decreased. Since the unsaturated oils block protein digestion in the stomach, we can be malnourished even while "eating well."
*) Drug and Fatty Acid Effects on Serum Thyroid Hormone Binding 
DOI: [Vous devez être inscrit et connecté pour voir ce lien] 1988 JCEM
Excerpt
Addition of 2.0 mmol/L oleic acid had a negligible effect, but 3.5 mmol/L oleic acid inhibited T3 and T4 binding significantly. Other long chain NEFA (addition of 1.5 mmol/L) gave increases in free T4 fraction as follows: arachidonic acid, 26%; linolenic acid, 23%; and linoleic acid, 11%. Stearic and palmitic acids were inactive.
NEFA = Non-esterified fatty acid = FFA
*) PUPAs compete from protein binding sides and block thyroid hormone and increase estrogen activity
“While the competition by PUFA for protein binding sites block the effects of thyroid hormone and vitamin A, the actions of PUFA on sex steroid binding protein (SBP, or SSBG, for sex steroid binding globulin) increases the activity of estrogen. That’s because the SSBG neutralizes estrogen by binding to it, keeping it out of cells; free PUFA keep it from binding estrogen (Reed, et al.).”
*) Thyroid and Polyunsaturated Fatty Acids – Impact on T3
10 déc. 2017 — Wiersinga et al showed that PUFA blocks the binding of active thyroid hormone (T3) to its intracellular receptor (Inhibition of nuclear T3 ...
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- PUFA downregulates oxydative respiration
- PUFA blocks thyroid at the receptor level. PUFA downregulates metabolism. Wiersinga et al showed that PUFA blocks the binding of active thyroid hormone (T3) to its intracellular receptor ([Vous devez être inscrit et connecté pour voir ce lien]).
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DOI: [Vous devez être inscrit et connecté pour voir ce lien]  1988. W M Wiersinga e al. Case report, PubmMed.
Abstract
Studies were performed to evaluate a possible modulatory role of lipids on the binding of T3 to rat liver nuclear receptors in vitro. Unsaturated fatty acids were potent inhibitors of the binding of [125I] T3 to isolated rat liver nuclei. Doses (in mumol/L) causing a 50% inhibition of nuclear T3 binding were 10 for palmitoleic acid, 11 for linoleic acid, 22 for oleic acid, 24 for arachidonic acid, and 37 for linolenic acid. Other lipids had less or no inhibitory activity. Unsaturated fatty acids reduced the affinity constant (Ka) of the binding of T3 to nuclear receptors to 57.4% +/- 11.0% that of controls (mean +/- SE 1.04 +/- 0.14 v 1.97 +/- 0.23 10(9) L/M, n = 5; P less than .02) but did not affect the maximal binding capacity (MBC) (1.47 +/- 0.20 v 1.55 +/- 0.10 10(-10) M/L; NS). Evaporated ether extracts of rat liver homogenate pretreated with phospholipase A2 for five to 20 minutes (that liberates unsaturated fatty acids from phospholipids) demonstrated a progressive inhibition of nuclear T3 binding with time when compared with ether extracts of untreated rat liver homogenate (F = 16.1; P less than .01). Evaporated, fatty-acid-rich ether extracts of human sera caused a dose-dependent inhibition in the binding of [125I] T3 to nuclear T3 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
*) Cellular Regulation of Lipolysis
[url=https://link.springer.com/chapter/10.1007/978-1-59259-963-9_48#:~:text=Conversely%2C insulin and other hormones,cytokines%2C insulin%2C and glucose]Springerlink [/url] Allan Green
Abstract
Lipolysis is the pathway by which adipocyte triglycerides are hydrolyzed and mobilized as free fatty acids, during periods when energy expenditure exceeds caloric intake. Hormone-sensitive lipase is the major enzyme involved in regulation of lipolysis. Numerous hormones acutely regulate lipolysis, but the most physiologically important are insulin (inhibitory) and catecholamines (stimulatory). Hormone-sensitive lipase is activated by phosphorylation in response to stimulatory hormones through a cAMP mediated cascade. Conversely, insulin and other hormones that inhibit lipolysis decrease phosphorylation of hormone-sensitive lipase. Lipolysis can also be regulated over the longer term by changes in gene expression in response to growth hormone, cytokines, insulin, and glucose.
Does estrogen increase lipolysis?
Estrogen controls lipolysis by up-regulating alpha2A-adrenergic receptors directly in human adipose tissue through the estrogen receptor alpha. Implications for the female fat distribution.
Does caffeine decrease lipolysis?
Caffeine ingestion stimulates both lipolysis and energy expenditure.
Vitamin D
Through its genomic action, vitamin D participates in the regulation of energy metabolism by controlling the expression of uncoupling proteins. In vitro, vitamin D stimulates lipogenesis and inhibits lipolysis by interacting with mVDR.
High-dose vitamin D increased sensitivity to leptin without significantly affecting the amount of leptin produced per fat mass. This increased leptin sensitivity did not alter appetite but did increase fat free mass adjusted energy expenditure.
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Excerpt:
To examine the hypothesis that high-dose dietary vitamin D provides muscle function benefit beyond normal-dietary vitamin D, we sought to determine the extent to which increasing vitamin D within the normal range (from 20-30 ng/dL to above 30 ng/dL) improved muscle function in adult wild-type mice. Normal dietary vitamin D increased strength over low-dose vitamin D without altering lean mass. As hypothesized, high dietary vitamin D more dramatically improved strength beyond normal vitamin D. However, high-dose vitamin D also increased lean mass without any change in weight. That is, high-dose vitamin D caused the redistribution of calories from fat to muscle.
Replenishment of vitamin D from low to normal decreased serum myostatin and increased the amount of leptin produced per fat mass. High-dose vitamin D increased sensitivity to leptin without significantly affecting the amount of leptin produced per fat mass. This increased leptin sensitivity did not alter appetite but did increase fat free mass adjusted energy expenditure. High-dose vitamin D also increased linear growth and lean mass proportion of weight. Thus, here we report for the first time that high dose dietary vitamin D preferentially allocates excess calories to muscle and growth instead of storing them as fat by decreasing myostatin signaling and increasing leptin production and sensitivity.