Saturday, 19 July 2014

*How* does insulin cause weight gain?

The question of exactly how insulin causes weight gain is not intuitively obvious enough and so it needed testing, and thats exactly what this paper did....

Adipose Weight Gain during Chronic Insulin Treatment of Mice Results from Changes in Lipid Storage without Affecting De Novo Synthesis of Palmitate

They infused mice throughout the day with mini-pumps containing extra insulin. This lasted for 7 days until the mice were sacrificed and their fat stores examined. All mice were put on a low fat chow diet.

First to note, is that there was a non-significant increase in food intake in the insulin treated mice, although there was a slight trend to the upside.

LI= low insulin group,  HI= high insulin group

Surprisingly they did not detect any increase in the de novo synthesis rate of palmitate in the insulin treated groups. So the lipogenesis pathway was essentially unaffected by the insulin treatment. This could have been because the palmitate de novo pathway was already running at maximum capacity, amoung other possible reasons they present in the discussion.

Second, the insulin treatment mice had a persistent decrease in their blood sugar levels, this may have been what caused them to eat *non-significantly* slightly more.

Did the insulin treated mice increase their fat stores? yes....

Only the increase in the high insulin group's fat stores was deemed statistically significant. The punchline however is that the newly formed fat in the high insulin group came almost exclusively from newly synthesized triglyceride ( subQ depot ).  There was a slight decrease in lipolysis as well which also contributed to the net fat gain.

 Our findings indicate that insulin treatment likely reduced whole body fat oxidation rather than increasing de novo fatty acid synthesis, and altered TG deposition and lipolytic rates in different depots, but the whole-body macronutrient energetics responsible for insulin-induced increased gain in weight and adipose fat remain to be fully explained.

So... there you have it. Atleast in this model. Insulin causes fat gain by diverting fatty acids that would otherwise have been oxidized for energy to instead be assembled as triglyceride and deposited into your adipose tissue.

The applicability of this to real life weight gain in humans is (probably ) not a straight forward translation,, but I think you can rest assured that, in situations of large amounts of insulin floating around, your likely to find excess triglyceride accumulating in your subcutaneous fat.

Is our food more insulinogenic now than it was 50 years ago? And is everyone carrying more triglyceride than we were 50 years ago?.....................

Monday, 26 May 2014

Dieting update

Ive been having quite a bit of weight loss success recently, love handles have gone down a bit and waist looks tighter, also people have been giving me complements that I look "healthy".

I still have fat to lose and it is all subcutaneous fat, which is murder to get rid of. But here's what im doing at moment

Melanotan II - Ive had to stop this completely because im very dark now and get weird looks from everyone in the street.

Clenbuterol - 20-40mcg per day, im using this because I need an edge to get rid of the stubborn subcutaneous fat and especially the love handles that have higher alpha receptors. I dont really like using Clen because the sides are pretty intolerable, MAJOR headache, shaky, anxiety,, jittery etc. But hey, it works.

CJC1295 with DAC - this is a growth hormone promoter, im just experimenting with it at the moment, been on it 4-5 weeks which is probably still a bit early to talk about results.

Nicotine Gum - 4-8mg per day, mainly to help shed the fat. I havent found nicotine gum to be addictive at all. If I go without it for a few days I feel absolutely no urge to use it. Works well as an appetite suppressant.

Diet - this is the thing that has made the biggest change. Ive made up my mind to stick with a cyclic keto diet. 6 days per week will be ultra low carb, only cheese,cream, meat, seafood, vegetables, avocado,  nuts, eggs. whey, butter. Some strawberries or raspberries if im feeling a slight sugar craving.

1 day per week I do ultra high-carb BUT low fat. My carb sources have been mainly banana, honey, beans, potatoes.   Infact I do about 12 banana's during my carb re-feeds, dipped in honey.   I try to keep the carb sources clean and stay away from the dirty carb's like bread, pizza, doughnuts etc. As I said, I think its key to keep fat low during the carb refeed, So its just whey, lean meats, and carbs.

If we look at the graph below, we see that the co-ingestion of carbs with fat causes a huge spike in the intestinal hormone GIP which is known adipocyte insulin sensitizer.

So ideally, you dont want to spike your GIP through the roof and insulin sensitize all your fat cells so much. Although there is no comparison to protein + carb in this study graph so im making a bit of a guess that its not as high as with fat, but fat is known to be the strongest promoter of GIP secretion.

During my low carb days I usually make breakfast 50g whey, 50g coconut oil, 4 tablespoon vinegar.  All these have been shown to reduce waist circumference and if there's one thing everyone should take on board its that getting a tiny waist is paramount to your physical attractiveness.

Another thing I want to comment on is that LC, or rather low insulin, seems to upreglate beta-receptors. I noticed after a few days of almost zero carb im extremely sensitive to clen, also side effects of clen seem to vanish as soon as you eat something that spikes insulin. Indeed there is a study floating around out there showing that beta-receptors become phosphorylated only 30mins after insulin exposure.

Wednesday, 7 May 2014

The problem with introverts

Having recently come from a holiday with my family where most of them are highly extroverted ( my cousin and his gf are super extroverts ) it kind of occurred to me what the main difference between the two is.

I have noticed when I am in a large group or in particular, with a strong extrovert, my brain shuts down. Ive seen alot of other introverts report this aswell. If you google search this topic you will also find similar testimonials, of introverts being unable to speak/think in the presence of ( strong ) extroverts. On these googled websites they will tell you some pseudoscience rubbish that introverts are "sensitive" to dopamine. And that too much dopamine "shuts" your brain down.

Here's what I think is happening......

If we remember from sapolsky's texts, dopamine is involved in the "pursuit of reward". Even better, I think its fairer to say that dopamine is a "do it" and "action/reaction" driving neurotransmitter.

When an organism receives a stimulus from the environment, the magnitude of the dopamine spike in response to that stimulus determines the magnitude of the reaction that the organism makes to that stimulus.

So, the problem with introverts is that the random small talk bullshit that extroverts like to spew forth doesn't cause a dopamine spike in an introverts brain, and thus the response from the introvert is either very short/breif/dull/boring.

Its not that your introverted brain is "shutdown". Its that the pointless banter of the extrovert doesn't stimulant it.

Its not that introverts are "boring", but rather Introverts like to talk about stuff that interests them, stuff that is meaningful, has logical purpose, is relevant to our survival, or conducive to success and improved quality of life.  That is what they dopamine spike to.

If you as an extrovert ask me a question to which I return a vacant blank stare and dull short response, its because im too polite to say "stfu , im not interested in that irrelevant shit"

There is no willpower, or conscious thought, involved in dopamine spikes, they are completely involuntary responses, and so your instinctual urge of how to respond is also pre-programmed and involuntary.  "boring" or "dull" has nothing to do with it.

Another problem with introverts is there brains are less likely to retain information that is not helpful for their survival or future success. This is an additional reason why small talk with introverts is hard because they dont care to remember WORTHLESS fucking details.

Saturday, 26 April 2014

Fat Digestion explained

Here is a lovely text detailing how fat digestion is handled.

Its worth reading the entire text but in summary ....

1 )  Eaten fat ( triglycerides ) is acted on by lipases in the GI-tract which split it into free fatty acids.

2 ) free fatty acids are absorbed by the enterocytes  ( cells of the GI tract )

3) enterocytes partition the fatty acids into different fate's, one of which is package onto a chylomicron

4 ) the chylomicron's are released into the systemic circulation where they float around and eventually interact with lipo-protein lipase in the endothelium of the various organs, one of which is adipose tissue. LPL then begins to break down the triglyceride from the chylomicron's into free fatty acids.

5 ) the presence of chylomicron's in the adipose tissue blood vessels also stimulates the release of ASP, acylation-stimulating protein  from adipocytes, which helps shuttle free-fatty acids liberated from chylomicrons by LPL into the adipocyte.

6 ) free-fatty acids that not are shuttled into the adipocyte escape and enter the systemic circulation, where they become part of the serum FFA pool. This contribution can be anything from 5-35% of the total serum FFA concentration.

7 ) once inside the adipocyte, free-fatty acids are once again packaged up into triglycerides, and are assembled into small lipid droplets in the endoplasmic reticulum.

8 ) the smaller lipid droplets are then acted on by lipid droplet proteins like FSP27 which fuse smaller lipid droplets into larger ones, eventually combining them with the large central lipid droplet present in the adpiocyte, at which point the fat can now be considered "body fat".

You should of noticed by now that there was no mention of insulin anywhere. So yes, dietary fat can be stored as body fat "without" involving insulin. But its worth noting that the stimulation of ASP by chylomicron's is enhanced in the presence of insulin ( link )

I expect that in the absence of high insulin levels, more of the fatty acids liberated from chylomicron's "spills" over, escaping adipocyte trapping and entering the systemic serum FFA pool. I remember from one of peter's post he mentions that high serum FFA = high energy expenditure, provided ofcourse again we keep insulin low since insulin inhibits fat oxidation.

So at this point one must be wondering, does this mean eating lots of fat and calories even without insulin stimulating carbs, we can get obese? I have doubts about this. The fact that chylomicron's stimulate ASP ofcourse is the ultimate evidence that we dont need ( elevated ) insulin to store dietary fat as body fat. The problem is this..... obesity is so much more than just "excess" triglyceride stored in adipocytes. I think all we can say is that eating alot of fat and calories will likely result in a *bit* of weight gain, as sam feltham proved.

Indeed I do not know of any studies of over-feeding keto in normal lean humans, only to follow them up several years later and find they maintained the elevated fat mass and are resistant to weight loss, both key features of the "obesity " phenotype.

Also of mention is that, although chylomicron's directly stimulate fat storage via ASP induction, researchers do not use chylomicron's in culture when attempting to cause preadipocytes to differentiate into mature adipocytes. They do however, use insulin and glucose.

Monday, 21 April 2014

GLUT4 over-expression in muscle = ????

Quick post.

What happens if you over-express GLUT4 in fast twitch muscle?

( for the record, the over-expressing mice appeared to have about 150% increased basal and insulin-stimulated GLUT4 expression )

Answer: You get a mouse that eats 45% more food than controls but weighs slightly less than them aswell!   Not only that, the over-expressing mice seemed to be quite fond of exercise, with a reported fourfold increase in voluntary wheel running..  So........... theres something about disposing of alot of glucose into muscle that makes you want to move.

This really makes me wonder about the association of obesity and laziness. Reduced GLUT4 on muscle partitions calories towards FAT.   We could hypothesize here that the reduced GLUT4 on muscle not only makes you lazy, but fat aswell. Its a double whammy.

I recently posted how, some weeks ago when I re-started melanotan-II injections, I seemed to recover a surge and urge to move, and even found the motivation to start going to the gym again. And well, we saw in the last post that melanotan-II / MC4R signalling in the brain dramatically increases GLUT4 on muscle. It all seems to fit together. ........atleast in theory.

Another correlation here is obese people have reduced secretion of GLP-1 in response to carb ingestion, and GLP-1 potently facilitates glucose disposal in muscle.

Saturday, 19 April 2014

How sensitive are you?

WIDE AWAKE Mediates the Circadian Timing of Sleep Onset.

Got this link from Bill, it suggests that sleep onset is mediated by an increased sensitivity to GABA in certain area's of the brain. The reason I found this so interesting was because of the idea that a particular cell/tissue can rapidly change its sensitivity to a hormonal signal and that this in-turn controls the behavior of the cell/whole organism.

 This phenomenon seems to exist in other area's of physiology aswell. For example, in tanning. with UV exposure, the MC1R is upregulated in the skin, this in-turn increases the production of eumelanin which is a darker pigment and gives your skin a darker appearance or "tan" .

Another situation that this seems to exist is in exercise and muscle hypertrophy, it seems resistance training increases androgen receptor's ONLY in the exercised muscle, and its thought this increased sensitivity to androgens is what mediates muscle hypertrophy.

In the last post we saw a similar thing with brain melanocortin signalling and insulin sensitivity , I.E. an injection of MT-ii into the brain potently increased skeletal muscle GLUT4.

Anyway, its worth remembering that considering cell sensitivity is just as important if not more important than considering the generalized changes in concentrations of hormones in the blood/cerebral-spinal fluid.

Saturday, 12 April 2014

weight control with a MC4R agonist

I have to make another post about Melanotan-II ( mt2 )

About 3-4 weeks ago I started another course of mt2. I take 1mg per day ( I am skin type I, "only burns and never tans" probably due to a genetic defect in my MC1 receptor ) , 5 times per week. After 3 weeks everyone asks you "where" youve been on holiday, lawl.

I had forgotten how amazing this peptide is. I noticed instant changes when I started taking it, appetite went WAY down, bodyfat started to decrease, carb tolerance is up, urge to move went way up, I even found the energy and motivation to going to the gym again.

Infact its started to become glaringly obvious to me that weight control with a MC4R agonist is almost effortless. ALMOST! I can only imagine how wonderful leptin must be for reduced obese people, if im having this much of a good time on mt2.

.Feeling revitalized on mt2 I decided to go back and check the literature on this drug, and heres some interesting studies,,,,

Melanocortin receptors in leptin effects. - this study highlights the important point that Mc4R is essentially downstream of leptin, so much so that leptin doesnt work in ob/ob mice if you block MC4R.

Novel α-MSH analog causes weight loss in obese rats and minipigs and improves insulin sensitivity

Central effects induced by MTII following peripheral dosing - provides evidence that subc administration of mt2 can still cross the blood-brain barrier. This is important because a large portion of mt2's effects on bodyweight occur via central mechanisms.

The leptin-like effects of 3-d peripheral administration of a melanocortin agonist are more marked in genetically obese Zucker (fa/fa) than in lean rats. - Further evidence that MC4R is responsible for leptins effects on bodyweight.

Central melanocortin stimulation increases phosphorylated perilipin A and hormone-sensitive lipase in adipose tissues. - mt2 in the brain stimulates rapid mobilization of fat stores.

MTII administered peripherally reduces fat without invoking apoptosis in rats. - unlike leptin, Mc4R doesnt kill adipose tissue.

Intermittent MTII application evokes repeated anorexia and robust fat and weight loss. - the appetite reducing effects of mt2 wear off after about 1-2 weeks, I can confirm this, BUT bodyweight stays reduced.

Melanocortin receptors mediate leptin effects on feeding and body weight but not adipose apoptosis.

Unabated anorexic and enhanced thermogenic responses to melanotan II in diet-induced obese rats despite reduced melanocortin 3 and 4 receptor expression.

Feeding response to melanocortin agonist predicts preference for and obesity from a high-fat diet. - this is a very interesting study, it suggests that preference for dietary fat depends on Melanocortin signalling, such that if Melanocortin signalling is high, you DONT want to eat fat, AND your body is simultaneously burning fat.

Melanocortin activity in the amygdala controls appetite for dietary fat. - high melanocortin signalling = dont want to eat any fat.

Central administration of melanocortin agonist increased insulin sensitivity in diet-induced obese rats. - mt2 in the brain improves insulin sensitivity. I have yet to summon the evidence to prove this, but I have a hunch this is because central melanocortin increases fax oxidation within the adipocyte.

The central melanocortin system directly controls peripheral lipid metabolism. - important study, shows that a lack of melanocortin signalling in the brain causes 1) increased TAG synthesis in the liver 2) decreases glucose use by muscle 3) increases insulin sensitivity of adipose tissue 4) promotes TAG synthesis in WAT

So in short, when melanocortin signalling in the brain drops, you become hungry and want to eat dietary fat, AND simultaneously your body is actively shuttling all fat towards storage.

**Region-specific differences in brain melanocortin receptors in rats of the lean phenotype. - injection of MT-ii into the brain causes increased physical activity.