Cortisol Inhibits Metabolism In Fat Tissue

[haidut]

I posted some studies recently on inhibiting the enzyme 11b-HSD1, which is responsible for the synthesis of cortisol. Currently, despite the denials of medicine that elevated cortisol has a causative role in diabetes and obesity, behind the scenes both Pfizer and Merck have experimental drugs for obesity/diabetes whose primary mechanism of action is inhibition of 11b-HSD1. One of these experimental drugs (AZD6925) is mentioned in the study below. This latest study shows that adipose tissue has elevated expression of 11b-HSD1, which contributes to reduced mitochondrial activity and lower levels of adiponectin. Inhibiting 11b-HSD1 and thus lowering cortisol restored mitochondrial respiration and adiponectin synthesis. Supplements that inhibit 11b-HSD1 include vitamin A, DHEA, emodin (cascara, aloe), zinc and bark extracts of Magnolia (Relora).
So there you have it, high stress and thus high cortisol directly prevent you from losing fat by inhibiting oxidative metabolism in fatty tissue. Not to mention cortisol also increases storage of dietary fat and upregulates de novo synthesis of fat from carbs.

http://www.ncbi.nlm.nih.gov/pubmed/25869616

"...In conclusion, increased 11β-HSD1 expression in hypertrophic adipocytes is associated with reduced mitochondrial respiration and adiponectin synthesis. Administration of an 11β-HSD1 inhibitor increases mitochondrial respiration and adiponectin synthesis. These findings support and extend our previous finding that mitochondrial function is necessary for adiponectin synthesis and that mitochondrial dysfunction in adipocytes might explain the reduced plasma."

 

[Nighteyes]

Very interesting... I wonder what the mechanism behind great weight loss and low body fat while on very low carb and high fat might be. I experienced this myself while eating almost zero carb, and certainly felt stressed and unable to sleep properly for months, indicating high cortisol. I have no blood tests to show, but is it even possible to be eating very low carb + sleeping like crap and have low cortisol?

 

[haidut]

post 104431 Very interesting... I wonder what the mechanism behind great weight loss and low body fat while on very low carb and high fat might be. I experienced this myself while eating almost zero carb, and certainly felt stressed and unable to sleep properly for months, indicating high cortisol. I have no blood tests to show, but is it even possible to be eating very low carb + sleeping like crap and have low cortisol?

If you eat low carb, your cortisol will be high unless you have adrenal failure (Addison disease). The brain needs its glucose and will increase cortisol production through ACTH. Sleep issues are very common in high cortisol.

 

[NathanK]

Very cool. Thanks for posting Haidut. Great follow up question too Nighteyes.

I was surprised to see that vitamin A suppressed stress hormones. I guess we lose a lot of zinc, DHEA, and A during stress is part of it.

This explains a lot as too why I gain weight if I use too much caffeine or stimulants. I guess for me, and high stress hormone people in general, the best way to lose weight would be to try to master lowering all mental, physical, and environmental stress as possible (including improving oxidative metabolism) and then introduce low stress long duration activity (maybe low dose caffeine as well) in order to increase metabolism while keeping under the high cortisol spiral activation threshold.

Looking at relora Amazon reviews, it appears Dr. Oz recommended it already so people are using it for their diabetes, weight loss, and resetting sleep schedules. This one had the fewest excipients:
http://www.amazon.com/gp/product/B0...ue&ref_=ox_sc_act_title_1&smid=A1NKO10IC080GY

 

[XPlus]

This explains a lot as too why I gain weight if I use too much caffeine or stimulants.

Interesting thoughts.
I'm starting to arrive at this conclusion, too.
The higher I run my metabolism, the more likely I'm to crash it.
It seems impossible to maintain high metabolism without much rest and consistent feeding, especially on a very low fat diet.

 

[haidut]

post 104742 Very cool. Thanks for posting Haidut. Great follow up question too Nighteyes.

I was surprised to see that vitamin A suppressed stress hormones. I guess we lose a lot of zinc, DHEA, and A during stress is part of it.

This explains a lot as too why I gain weight if I use too much caffeine or stimulants. I guess for me, and high stress hormone people in general, the best way to lose weight would be to try to master lowering all mental, physical, and environmental stress as possible (including improving oxidative metabolism) and then introduce low stress long duration activity (maybe low dose caffeine as well) in order to increase metabolism while keeping under the high cortisol spiral activation threshold.

Looking at relora Amazon reviews, it appears Dr. Oz recommended it already so people are using it for their diabetes, weight loss, and resetting sleep schedules. This one had the fewest excipients:
http://www.amazon.com/gp/product/B007G3 ... O10IC080GY

The active ingredient in Cascara - emodin - also lowers cortisol by inhibiting 11b-HSD1. I typically use both Relora and Cascara to lower stress as needed. The effects are pretty close to those of cyproheptadine, but don't last as long.

 

[LucH]

post 104511 If you eat low carb, your cortisol will be high unless you have adrenal failure

Most people believe that only carbs raise insulin. It's a common mistake. Proteins do so.

Source: Gabriel cousens.
rice = riz
pain = bread
boeuf = beef
yaourt = yoghurt
oeufs = eggs
poisson = fish

Beef is nearly as high as brown rice.
regular Yoghurt (nature) has the top spike.

Here are some examples for all sorts of foods(not easy to interprete):


If you don't like to load files from internet, here is the link source
http://ajcn.nutrition.org/content/66/5/1264.full.pdf
! beans (kidney beans). Beans has high IR (insulin response). Eggs and lentils have medium response.

 

[LucH]

If you want to combine low carbs with paleo, 80 - 150 g carbs are usually needed. If you are exhausted, 200 g carbs. But it's no longer a fat burning mode, at this level. No problem. You'l burn fuel at night or between meals

if you have eaten at least between 15 and 35 g protein (with good NNU), in a meal (22 - 30 g ideal level for avoiding metabolites), you won't overcharge metabolism and it will contribute to anabolism (new muscles).
Source Dr Layman "Getting breakfast right"
http://www.ketogenic-diet-resource.com/ ... ement.html


Let's suppose now you're stabilised (thyro) and already used to lipolyse (fat burning).
50 g carbs maxi for breakfast, 50 g for midday and 50 gr for evening dinner is a good starting point. You'll have to adapt yourself, according to your metabolism / feeling.
Source: Dr Jacques Medart.
LucH

 

[NathanK]

post 104759

post 104742

The active ingredient in Cascara - emodin - also lowers cortisol by inhibiting 11b-HSD1. I typically use both Relora and Cascara to lower stress as needed. The effects are pretty close to those of cyproheptadine, but don't last as long.

Haha, I read the wiki on emodin right after reading this post and it looked like you could have written it. Do you take cascara even when youre having regular bowel movements? Ive never taken it because ive never had that problem. In contrast, when I was low carb I didnt have a full stool for over two years.

Btw, I read a study yesterday while looking to see if B6 had any inhibition properties that circumin powerfully modulates 11b-HSD1. It looks like they are starting to look beyond just diabetes, but to hypogonadism. Unfortunately, circumin is not well absorbed by humans; Ray would say it was estrogenic anyway:
http://journals.plos.org/plosone/articl ... ne.0049976

Oral administration of curcumin (100 to 200 mg/kg/day) or B6 (1–4mg/kg/day) for three days completely prevented the decreases of serum testosterone levels induced by restraint stress in male rats, and oral administration of B6 (4 mg/kg/day) for 2 months also prevented the formation of fatty liver and increase of serum glucose and lipid induced by high-fat diet. Furthermore, db/db and normal C57BL/6J mice were orally administered B06 (0.8 mg/kg/d, daily). The results in serum glucose, cholesterol, triglycerides, oral glucose tolerance tests and insulin tolerance tests support that B06 lower blood glucose levels and improve insulin sensitivity in mouse models of type 2 diabetes.

 

[haidut]

post 104873

post 104759

post 104742

The active ingredient in Cascara - emodin - also lowers cortisol by inhibiting 11b-HSD1. I typically use both Relora and Cascara to lower stress as needed. The effects are pretty close to those of cyproheptadine, but don't last as long.

Haha, I read the wiki on emodin right after reading this post and it looked like you could have written it. Do you take cascara even when youre having regular bowel movements? Ive never taken it because ive never had that problem. In contrast, when I was low carb I didnt have a full stool for over two years.

Btw, I read a study yesterday while looking to see if B6 had any inhibition properties that circumin powerfully modulates 11b-HSD1. It looks like they are starting to look beyond just diabetes, but to hypogonadism. Unfortunately, circumin is not well absorbed by humans; Ray would say it was estrogenic anyway:
http://journals.plos.org/plosone/articl ... ne.0049976

Oral administration of curcumin (100 to 200 mg/kg/day) or B6 (1–4mg/kg/day) for three days completely prevented the decreases of serum testosterone levels induced by restraint stress in male rats, and oral administration of B6 (4 mg/kg/day) for 2 months also prevented the formation of fatty liver and increase of serum glucose and lipid induced by high-fat diet. Furthermore, db/db and normal C57BL/6J mice were orally administered B06 (0.8 mg/kg/d, daily). The results in serum glucose, cholesterol, triglycerides, oral glucose tolerance tests and insulin tolerance tests support that B06 lower blood glucose levels and improve insulin sensitivity in mouse models of type 2 diabetes.

Is this reference to B06 a type of curcumin or is it referring to vitamin B6? Because it just so happens that vitamin B6 is a glucocorticoid antagonist and estrogen antagonist.

 

[NathanK]

post 104938

post 104873

post 104759

post 104742

The active ingredient in Cascara - emodin - also lowers cortisol by inhibiting 11b-HSD1. I typically use both Relora and Cascara to lower stress as needed. The effects are pretty close to those of cyproheptadine, but don't last as long.

Haha, I read the wiki on emodin right after reading this post and it looked like you could have written it. Do you take cascara even when youre having regular bowel movements? Ive never taken it because ive never had that problem. In contrast, when I was low carb I didnt have a full stool for over two years.

Btw, I read a study yesterday while looking to see if B6 had any inhibition properties that circumin powerfully modulates 11b-HSD1. It looks like they are starting to look beyond just diabetes, but to hypogonadism. Unfortunately, circumin is not well absorbed by humans; Ray would say it was estrogenic anyway:
http://journals.plos.org/plosone/articl ... ne.0049976

Oral administration of curcumin (100 to 200 mg/kg/day) or B6 (1–4mg/kg/day) for three days completely prevented the decreases of serum testosterone levels induced by restraint stress in male rats, and oral administration of B6 (4 mg/kg/day) for 2 months also prevented the formation of fatty liver and increase of serum glucose and lipid induced by high-fat diet. Furthermore, db/db and normal C57BL/6J mice were orally administered B06 (0.8 mg/kg/d, daily). The results in serum glucose, cholesterol, triglycerides, oral glucose tolerance tests and insulin tolerance tests support that B06 lower blood glucose levels and improve insulin sensitivity in mouse models of type 2 diabetes.

Is this reference to B06 a type of curcumin or is it referring to vitamin B6? Because it just so happens that vitamin B6 is a glucocorticoid antagonist and estrogen antagonist.

I remember reading in the study that B06 is a more absorbable derivative of circumin. The one mention here of "B6" for all I know was a typo. I'd have to look at it again. The search I used was for the same reason that you said. To see is B6 had any of the enzyme inhibition.

It wouldnt surprise me at all that inhibiting stress hormones would increase androgen synthesis

 

[NathanK]

Whoa, my mistake. I hastily posted the wrong study. I was referring to this one. I couldn't find the full text. Either way, both back each other up: http://www.fasebj.org/cgi/content/meeti ... acts/749.6

 

[NathanK]

Russian paper: Development of 11β
HSD1 inhibitors for the treatment of metabolic syndrome
http://www.bioorganica.org.ua/UBAdenovo ... Lipson.pdf

The role of 11β
HSD1 in obesity and insulin resistance.
Glucocorticoids (cortisol in humans or corticosterone in rodents) are hormones that play an important role in the body’s response to stress as well as regulate energy metabolism and modulate inflammatory and immune responses. They promote gluconeogenesis in the liver and oppose the action of insulin by directly inhibi
ting β
cell insulin secretion in the pancreas and peripheral glucose uptake in the muscle. Gluco
corticoids also increase lipolysis in adipose tissue, leading to fatty acid mobilization when the insu
lin action is low...

An excessive 11β
HSD1
dependent local cor
tisol production increases hepatic glucose output and decreases glucose uptake in adipose tissue and skeletal muscles. Besides, it stimulates lipol
ysis, thereby leading to higher levels of free fat
ty acids, which contribute to the adverse meta
bolic effects of glucocorticoids. An elevated local cortisol level antagonizes the effects of insulin and leptin, thus contributing to the development of insulin resistance and T2DM [10, 11, 18]. In humans, the expression of 11β
HSD1 in adipose tissue is positively correlated with the degree of obesity and is acquired independently of genetic factors...

... examples of natural 11β
HSD inhibi
tors are abietic acid 3, a compound contained in wood products and used in cosmetics because of its anti
irritant and anti
inflammatory effects [44], as well as flavonoid naringenine 4 found in grapefruit juice [45], and anthraquinone emodin 5, an active ingredient of Rheum palmatum. A recent investigation has proved the latter sub
stance to be a potent and selective 11β
HSD1 inhibitor with the IC50 of 186 and 86 nM for human and mouse enzymes respectively.

Interestingly enough, coffee has also been examined as a potential 11β
HSD1 inhibitor due to an antidiabetic effect that coffee consumption is supposed to have. Inhibition of 11β
HSD1 tur
ned out to be seven
to tenfold higher than that of 11β
HSD2. Although coffee clearly demon
strates an inhibitory effect, it has not yet been established what kind of compounds contained in coffee are responsible for this action. It is also unknown whether the compounds in question are readily absorbed following oral ingestion


And it goes on to mention other possibilities and pitfalls including substances that inhibit 11BHSD1 as well as androgenic enzymes to a fault. It appears by looking at recent Chinese and American papers as well that the race is indeed on to find something along these lines to treat diseases.
http://diabetes.diabetesjournals.org/co ... /1/14.full
http://link.springer.com/article/10.100 ... -5#/page-1
http://www.google.com/patents/US20070224298 (a patent on citrus peel extract for weight loss)

And even some questions to it's efficacy:
http://asweetlife.org/karmel/blogs/type ... bulb/9521/
...Harno and White were able to gain some insight from studies of mice which were engineered to lack the enzyme 11β-HSD1 entirely. THe complete deletion of 11β-HSD1 in mice had, overall, inconclusively minimal effects on adrenal action. Mice of a certain genetic background saw a 70% increase in the weight of the adrenal gland, implying increased adrenal activity, but mice of another genetic background saw only a 20% increase, which, given the 46% change in adrenal weight throughout the course of a normal mouse day, is not too jarring.

Looking at the amount of cortisol secreted in the 11β-HSD1 knockout mice, researchers found again inconclusiveness; mice from the first genetic type had a higher base level of cortisol, but peak levels remained mostly unchanged. These knockout mice also took longer to return to base levels of cortisol after stress. However, the 11β-HSD1 knockout mice from the other genetic typing remained largely unchanged, retaining normal levels and rates of cortisol secretion.

Points are added in to the “Pro” column of 11β-HSD1 inhibitors by studies of the inhibitor compounds themselves. In a Merck study of the new drug’s effects on mice and rats, circulating levels of the precursor and co-marker of cortisol were not increased, implying the hypothalamus was not inducing overaction of the adrenal gland. Similarly, the human trials done thus far by drug companies indicate that the hormonal precursors to adrenal cortisol production are not upregulated, and the HPA axis remains unperturbed.

In the end, then, Harno and White conclude that there is a pretty good chance that 11β-HSD1 inhibitors will not increase the release of cortisol from thim adrenal gland. In other words, 11β-HSD1 inhibitors are probably good additions to the diabetic toolbox.

FYI, http://www.ncbi.nlm.nih.gov/pubmed/11270719 (magnolia bark extract, an active ingredient in Relora inhibited 11B-HSD1 without increasing adrenal activity)

 

[Epistrophy]

@haidut Then what is the difference between lipolysis and oxidative fat metabolism? Is lipolysis only happening when needed nutrition (carbohydrates) is not being provided by exogenous means?

 

[haidut]

@haidut Then what is the difference between lipolysis and oxidative fat metabolism? Is lipolysis only happening when needed nutrition (carbohydrates) is not being provided by exogenous means?

"lysis" = breakdown. Lipolysis is just the shedding of fat from stores (fatty tissue) into the bloodstream. Then it gets transported to cells and gets oxidized there (beta oxidation).

 

[Epistrophy]

@haidut Thanks, make more sense not to have PUFA as fat stores.