Pregnenolone For Obesity And Insulin Resistance

[haidut]

I wrote in another thread about the history of PCN, which is just a slightly modified proprietary pregnenolone. This study shows that a human equivalent dose of 3.5mg/kg prevented the obesity caused by high-fat diet. The duration of experiment was 7 weeks.
Other noteworthy findings were that pregnenolone improved insulin sensitivity, lowered blood glucose, and lipogenesis. All of these negative metabolic effects can also be caused by high cortisol. Given my other thread of PCN powerfully stimulating the thyroid, and considering that it is a cortisol antagonist, I think this anti-obesity, pro-metabolic effect is certainly to be expected.
Again, the other well-known cortisol antagonist DHEA has been also been shown to have these effects in animal models and in some human trials. However, given the DHEA estrogenicity in higher doses, pregnenolone may be a safer method.
Basically, Ray knows his stuff

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377726/
"...In this study, we demonstrate that activation of PXR by PCN prevented development of high-fat diet-induced obesity and relieved obesity-related insulin resistance and hepatic lipid accumulation (Figures 1, ​,3,3, ​,4).4). The beneficial effect of PCN treatment was achieved by inhibition of lipogenesis and gluconeogenesis in the liver (Figures 3E and ​and5)5) as well as inhibition of lipid uptake in liver and WAT (Figures 5c and ​and7c),7c), by enhanced lipolysis in adipose tissue (Figures 7C, 7F), and by increased peripheral fat mobilization and energy expenditure in BAT (Figure 8)."

 

[burtlancast]

Don't you think it's somehow controversial that insulin resistance would be improved by enhanced lipolysis ?

Ray mentioned the Randle cycle as the cause of diabetes, and advised to block lipases enzymes freeing the body fat reserves by using aspirin and niacinamide.

Unless the decreased gluconeogenesis is the main mechanism helping insulin resistance ?

 

[haidut]

Don't you think it's somehow controversial that insulin resistance would be improved by enhanced lipolysis ?

Ray mentioned the Randle cycle as the cause of diabetes, and advised to block lipases enzymes freeing the body fat reserves by using aspirin and niacinamide.

Unless the decreased gluconeogenesis is the main mechanism helping insulin resistance ?

I think increased gluconeogenesis is a sign of high cortisol, and lowering it probably shows pregnenolone's anti-stress effects. Lipogenesis is usually a sign of high insulin, so lowering that suggests lower insulin as well.
As far as the fat oxidation - yes I do think it is controversial, but I don't quite understand Peat's point on it. He says that in a resting state muscles burn primarily fat, so obviously fat burning happens all the time. I think it's the free fatty acids (FFA) he is concerned about - circulating around and preventing oxidation of glucose.
In addition, PCN had differential effects as described here.

"...Results shown in Figures 4 and ​and66 demonstrate that PCN-mediated PXR activation significantly prevented the lipid storage in adipose tissue and the liver. Except for inhibiting lipogenesis, a more important characteristic of PXR in diet-induced obesity was reduction of lipid uptake in liver and adipose, confirmed by inhibiting up-regulation of Cd36 expression by high-fat diet. Cd36 codes for a scavenger receptor with broad ligand specificity. Activation of Cd36 facilitates free fatty acid uptake from circulation and also contributes to obesity, hepatic steatosis and type-2 diabetes [24], [37]. Previous studies show that Cd36 is a shared transcriptional target of LXR, PXR and PPARγ in their regulation of lipid homeostasis [25]. In the PXR-transgenic mice, Cd36 was up-regulated when fed with regular chow, which is different from our result obtained from the high-fat diet-fed mice. In our opinion, as in drug metabolism, PXR may serve as a “sensor” for maintaining energy homeostasis.
Unlike the effect of PCN in the liver and WAT, PCN treatment increased Cd36 transcript level by approximately 2-fold compared to the DMSO-treated group in BAT (Figure 7F). Accumulation of lipids induced by a high-fat diet was blunted, indicating another mechanism existed in BAT. The main function of BAT is to generate heat for thermogenesis. Bartelt et al. [38] reported that increased BAT activity enhanced triglyceride-rich lipoprotein metabolism in mice. Exposure to low temperatures drastically accelerated plasma clearance of triglycerides as a result of increased uptake into BAT, which was mediated by an increase of transmembrane receptor CD36. Although it remains to be demonstrated for increased energy expenditure, mice with PCN treatment had a much slower decrease in body temperature than the control group (Figure 8A), suggesting that the activation of PXR enhanced the thermogenesis activity in BAT. At the same time, data from real-time PCR showed a significant increase in the transcription of genes involved in fatty acid β-oxidization (Figure 7F) and thermogenesis (Figure 8B), indicating increased energy expenditure in BAT, which contributed to cleaning more lipids in BAT."

So, in summary, PCN inhibited uptake of fat by liver and fat tissue, and increased thermogenesis and energy expenditure. That translates into more fat oxidation as well. Other agents do the same - i.e. DNP, aspirin, and caffeine all increase fat oxidation in doses that uncouple the mitochondria.
Whether that's beneficial or not, I am not sure. But given the positive effects of the above uncouplers on features of the metabolic syndrome and even diabetes, I guess getting rid of the extra fat in liver and fat tissue is beneficial overall.

 

[RPDiciple]

Peat has no problem with burning fat, its only bad if the stored fat your are burning are stored PUFA. Like he says children can go long time without eating without it causing any stress reactions because they just burn saturated fat wich dont create stress

To much PUFA released at once can cause damage to organs

 

[haidut]

Peat has no problem with burning fat, its only bad if the stored fat your are burning are stored PUFA. Like he says children can go long time without eating without it causing any stress reactions because they just burn saturated fat wich dont create stress

Actually he has said that he does have issues with burning fat. It generates less CO2 than burning carbs and it also contributes to the diabetic state. Of course, burning PUFA is that much worse, but he has said that fat oxidation is a hallmark of stress. The increased fat oxidation is probably inevitable for people trying to lose weight, but for the rest fat oxidation (other than what the muscles do at rest) is probably best avoided.

 

[jyb]

It generates less CO2 than burning carbs and it also contributes to the diabetic state.

When it comes to saturated fats, both of those claims are being debated in the non-Peat world, though.

 

[haidut]

It generates less CO2 than burning carbs and it also contributes to the diabetic state.

When it comes to saturated fats, both of those claims are being debated in the non-Peat world, though.

Sure, they are being debated, but the Randle effect applies even to saturated fat. I think Peat's point may be that oxidizing saturated fat makes you temporarily insulin resistant but as soon as glucose is available this resistance is reversed. But with PUFA, there is actual damage to the mitochondria which is only partially preventable by substances like vitamin E.

 

[burtlancast]

It generates less CO2 than burning carbs and it also contributes to the diabetic state.

When it comes to saturated fats, both of those claims are being debated in the non-Peat world, though.

Sure, they are being debated, but the Randle effect applies even to saturated fat. I think Peat's point may be that oxidizing saturated fat makes you temporarily insulin resistant but as soon as glucose is available this resistance is reversed. But with PUFA, there is actual damage to the mitochondria which is only partially preventable by substances like vitamin E.

“I’ve known people who were eating 2-3 pounds of meat a day and who were getting sicker and sicker as their free fatty acids and free amino acids increased. That started me reading more about the free state of fatty acids in the blood. Just about everything that goes wrong, involves free fatty acids increase. If they’re totally saturated fatty acids, such as from coconut oil and butter, those are less harmful, but they still tend to shift the mitochondrial cellular metabolism away from using glucose and fructose, and turning on various stress-related things (by lowering the carbon dioxide production, I think, is the main mechanism).”

“When mitochondria are functioning fully, either glucose or saturated fats can safely provide energy. Some glucose or saturated fat can be converted to polyunsaturated fats, that can be used as regulators or signals, for example to activate the formation of stem cells. But those PUFA don’t create disruptive cascades of increasing excitation or inflammation or excessive growth, and, from the evidence of animals that are fed fat free diets, or diets lacking omega -3 and omega -6 fatty acids, they aren’t toxic to mitochondria.”

 

[tomisonbottom]

I wrote in another thread about the history of PCN, which is just a slightly modified proprietary pregnenolone. This study shows that a human equivalent dose of 3.5mg/kg prevented the obesity caused by high-fat diet. The duration of experiment was 7 weeks.
Other noteworthy findings were that pregnenolone improved insulin sensitivity, lowered blood glucose, and lipogenesis. All of these negative metabolic effects can also be caused by high cortisol. Given my other thread of PCN powerfully stimulating the thyroid, and considering that it is a cortisol antagonist, I think this anti-obesity, pro-metabolic effect is certainly to be expected.
Again, the other well-known cortisol antagonist DHEA has been also been shown to have these effects in animal models and in some human trials. However, given the DHEA estrogenicity in higher doses, pregnenolone may be a safer method.
Basically, Ray knows his stuff:)

Activation of Pregnane X Receptor by Pregnenolone 16 α-carbonitrile Prevents High-Fat Diet-Induced Obesity in AKR/J Mice
"...In this study, we demonstrate that activation of PXR by PCN prevented development of high-fat diet-induced obesity and relieved obesity-related insulin resistance and hepatic lipid accumulation (Figures 1, ,3,3, ,4).4). The beneficial effect of PCN treatment was achieved by inhibition of lipogenesis and gluconeogenesis in the liver (Figures 3E and and5)5) as well as inhibition of lipid uptake in liver and WAT (Figures 5c and and7c),7c), by enhanced lipolysis in adipose tissue (Figures 7C, 7F), and by increased peripheral fat mobilization and energy expenditure in BAT (Figure 8)."

So, can the same lack of fat gain effect be achieved by using a regular pregnenolone; a non-proprietary pregnenolone?

 

[haidut]

So, can the same lack of fat gain effect be achieved by using a regular pregnenolone; a non-proprietary pregnenolone?

That's my understanding, even though when I asked the authors of the PCN study they said that while pregnenolone MAY be effective they did not try it since it metabolizes so easily into other steroids and they wanted a compound that stays as pregnenolone-type substance. However, higher doses of pregnenolone have been shown to keep pregnenolone levels high in humans, so there is indirect evidence that pregnenolone does work and stay as pregnenolone in humans, even though a portion of it metabolizes into progesterone and DHEA.