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.










Correlations in obesity

When dealing with obesity, its clear that people, including researchers and doctors, see what they want to see. IF they want to imagine obese people are simply lazy stupid gluttonous pigs, they will seek evidence to support that.

Stephan Guyenet has an interesting post up about the correlation between calorie intake and BMI. In his post we see a strong trend that as calorie intake increases, so does BMI.

But, is this cause or effect?

SURELY eating more food CAUSES increased BMI?

I got this study from a recent Mangan tweet

Here we see that total energy expenditure is higher in obese people, ( lean=2035, obese=2483, reducedObese=2033)

Further, as we look down the other graphs, we see that 24hr carbohydrate oxidation is higher in obese and reduced obese ( lean=218grams,    obese=308grams,      reduced obese=264grams ). Importantly, there are no differences in fat oxidation between lean and obese, BUT reducedObese have 28% reduced fat oxidation compared to lean aswell as 21% higher carbohydrate oxidation.

uh oh! Remember the link between higher RQ predicting weight gain? And we know that reduced obese people are highly susceptible to regain. And here we see evidence of reduced obese people seemingly relying more on carbohydrate oxidation.

However, things get really interesting when we consider these little snippets I dug up....



In particular, the bottom tweet. White Adipose Tissue oxidizes predominately glucose.

So now lets link everything together and see what correlations we have...


  • Calorie intake increases with BMI
  • Energy expenditure increases with BMI
  • Carbohydrate oxidation increases with BMI
  • Adipose tissue increases with BMI
  • Adipose tissue oxidizes mainly carbohydrate.
  • ?????????????


Yes, heres what im saying....

Rather than the same old bollocks of  "fat people are fat because they eat too much", instead we could speculate that fat people eat more calories BECAUSE they have more adipose tissue. And they are simply eating more to fulfill their bodies increased energy expenditure requirements.  The increased energy expenditure requirements appear to be ( atleast partly ) coming from them having increased carbohydrate oxidation needs, that is (probably) occurring BECAUSE of their increased adipose tissue mass.

So essentially we've come full circle, and we're back to the idea that, adipose tissue growth IS the cause of obesity and that probably Taubes was right, fat people eat more because they are getting fat.   because they are growing new adipose tissue.

There is another line of evidence to support this, the fat killing drug adipotide is reported to decrease energy intake,








Thursday, 3 April 2014

Fat has the power to make you slim

Or rather, your adipose tissue does. No need for all that hogwash nonsense about BAT ( brown adipose tissue ) because it seems white adipose tissue is more than capable of  keeping you lean, provided it just gets the correct signal.

A less well known fact about leptin is that leptin receptors are present on the adipocytes themselves and leptin functions within paracrine loop ( link ). No need for leptin resistance in the brain, because leptin resistance at the level of the adipocyte is enough to cause metabolic derangement ( link )

You have to look at this study to really appreciate the power of leptin. Apparently, if you infect the liver with a virus that codes for the leptin gene such that the liver now secretes its own leptin, this leptin acts directly on adipocytes and causes them to completely oxidize all their contents within as little as 7 days.

The implication here is that there is no need to calorie restrict or exercise like a maniac to lose weight, you just need your leptin to be working (properly), and then the adipocyte itself is more than capable of regulating its own size. The novelty of this information is that the adipocytes themselves can massively increase their energy expenditure to keep you slim, the fats do not need to be released into circulation and used up by other tissues, which is what happens if you lower insulin.



Further, the hyperleptinemia induced by the liver-derived leptin did not increase hunger of the rats, even with a severe loss of bodyfat and massive energy expenditure increase, indicating once again that biology and body weight regulation is all about communication, not calories.

With this in mind aswell as what we know about leptin signalling in the brain it would be very easy to blame obesity on "leptin resistance" since clearly leptin is suppose to function within a negative feedback loop to keep bodyweight stable.








Wednesday, 2 April 2014

Defective adipocytes in obesity

:Back to this paper....

First, you have to harvest some (pre)adipocytes from obese and lean people. You then grow them like this....

Growth for 24–48 h in preadipocyte media (PM-1; Zen-Bio) contained Dulbecco's modified Eagle's medium F12 (DMEM/F12 [1:1, v/v]), HEPES (pH 7.4), 10% FBS, and antibiotics.
Cells were differentiated for 7 days in media containing DMEM/F12 (1:1; v/v), HEPES (pH 7.4), 10% FBS, biotin, pantothenate, insulin, dexamethasone, isobutylmethylxanthine (IBMX), and a nonthiazolidinedione peroxisome proliferator–activated receptor (PPAR)-γ agonist (DM-2; Zen-Bio),
followed by an additional week in adipocyte maintenance media (DM-2 without IBMX and PPARγ agonist

You then add the mitochondrial uncoupler FCCP to the mix and measure the increase in the oxygen consumption rate ( as compared to basal ) of those cells from obese people vs lean people, and you wind up with this graph....



Which tells you that under equal conditions, adipocytes from lean people have greater ability to oxidize fuels ( fats?) compared to adipocytes from obese people. The authors of the paper have no explanation for this particular finding with FCCP. I think it suggests an intrinsic defect in the adipocytes of obese people.

Isoproterenol induced increase in oxygen consumption was also impaired in adipocytes from obese people.



So whats responsible for the reduction in oxygen consumption in Isoproterenol? And is it the same defect responsible for the FCCP deficit? Again this remains unknown.

However, they did determine that the reduction in Isoproterenol induced oxygen consumption was NOT due to....

  • impaired differentiation of the adipocytes
  • differences in mitochondrial mass
  • differences in gene expression of mitochondrial proteins 
  • a reduction in Isoproterenol-stimulated lipolysis 
  • PKA activity
  • initial differences in basal oxygen consumption
  • Beta-receptor subtype expression

So we are left scratching our heads. We know that obese people store too many calories......in adipocytes. And here we have found that adipocytes from obese people have an intrinsic defect in oxygen consumption when exposed to stimuli that increase energy expenditure. Alas, the penny hasnt dropped yet.

Although this isnt proof of a cause of obesity, a burning question is, how easy is it to stay lean when your body is infested with these "lazy" fat cells?







Sunday, 23 March 2014

Catecholamine resistance in obesity

Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKK{varepsilon} and TBK1.
Decreased sympathetic activation of adipose tissue due to impaired catecholamine synthesis or sensitivity has been observed in obese patients (Reynisdottir et al., 1994Stallknecht et al., 1997;Horowitz and Klein, 2000Jocken et al., 2008). Obesity is commonly associated with blunted whole-body catecholamine-induced lipolysis (Horowitz and Klein, 2000). This is thought to occur through a number of mechanisms, including leptin resistance (Myers et al., 2010), as well as the reduced expression of β-adrenergic receptors (Reynisdottir et al., 1994) or increased expression of α2-adrenergic receptors (Stich et al., 2002). White adipose tissue and cultured isolated adipocytes from obese human and mouse models exhibit decreased cAMP-stimulated lipolysis and fat oxidation, due to reduced energy expenditure from decreased mitochondrial uncoupling (Yehuda-Shnaidman et al., 2010). This desensitization to adrenergic activation is also a feature of childhood onset obesity (Bougneres et al., 1997Enoksson et al., 2000), and has been observed in adipocytes from first-degree relatives of obese subjects (Hellstrom et al., 1996).


Acute stimulation of white adipocyte respiration by PKA-induced lipolysis.



we present evidence that human white adipocytes can acutely increase aerobic and anaerobic respiration in response to βAR and protein kinase A (PKA)-dependent stimulation of lipolysis.


Lipolysis stimulated by βAR activation or other maneuvers that increase cAMP levels in white adipocytes acutely induces mitochondrial uncoupling and cellular energetics,

Wednesday, 12 March 2014

Insulin hypersecretion in islets from diet-induced obese mice

Insulin hypersecretion in islets from diet-induced hyperinsulinemic obese female mice is associated with several functional adaptations in individual β-cells.

Abstract

Insulin resistance and hyperinsulinemia are generally associated with obesity. Obese nondiabetic individuals develop a compensatory β-cell response to adjust insulin levels to the increased demand, maintaining euglycemia. Although several studies indicate that this compensation relies on structural changes, the existence of β-cell functional adaptations is incompletely understood. Here, we fed female mice with a high-fat diet (HFD) for 12 weeks. These animals became obese, hyperinsulinemic, insulin-resistant, and mildly glucose-intolerant while fed, and fasting glycemia was comparable in HFD and control mice. Islets from HFD animals exhibited increased β-cell mass and hypertrophy.

Additionally, they had enhanced insulin gene expression and content and augmented glucose-induced insulin secretion. Electrophysiological examination of β-cells from both groups showed no differences in KATP channel open probability and conductance. However, action potentials elicited by glucose had larger amplitude in obese mice. Glucose-induced Ca²⁺ signals in intact islets, in isolated β-cells, and individual β-cells within islets were also increased in HFD mice. Additionally, a higher proportion of glucose-responsive cells was present in obese mice. In contrast, whole-cell Ca²⁺ current densities were similar in both groups.

Capacitance measurements showed that depolarization-evoked exocytosis was enhanced in HFD β-cells compared with controls. Although this augment was not significant when capacitance increases of the whole β-cell population were normalized to cell size, the exocytotic output varied significantly when β-cells were distributed by size ranges. All these findings indicate that β-cell functional adaptations are present in the islet compensatory response to obesity.

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Found this in a related link to JJ's 2012 paper on hyperinsulinemia, very interesting that obese islets are programmed to secrete large amounts of insulin for a given amount of glucose?

Is this an "adaption" to insulin resistance? I dont believe so. If we go back to JJ's paper we remember that insulin feed's back positively to beta islets via the autocrine loop to cause growth. Possibly also to cause these morphological changes. I think a reasonable assumption is that anything that causes intense insulin secretion will serve to induce these morphological changes and obesity may follow.





Friday, 10 January 2014

Sleep apnea and snoring

Some months back I went to a private clinic to seek help for my growing sleep apnea and snoring issues. They wanted £250 JUST for consultation. Revolted, I left and decided to do what should always been done these days when you have a health problem - research it yourself on pubmed and get your own cure.

You see, doctors are not there too help you, they are there to make money. The only person who really wants to help you is YOU.

Anyway, a few searches later and it had become quite clear that sleep apnea was very strongly "associated" with metabolic syndrome. Which in turn is strongly associated with insulin resistance and carbohydrate consumption. During my snoring troubles I had been on and off high-carb, as I usually am, and was probably more on high-carb than I wanted to admit to myself.

So I went back to zero-carb, which I know I can always count on. I know zero-carb rapidly resolves insulin resistance and metabolic syndrome, which I had hoped would also resolve my snoring. It took only a few days, but zero-carb did a fantastic job of alleviating both my sleep apnea and snoring. Within as little as a week there were substantial improvements, And within 2 weeks almost complete remission. This was accompanied by only mild weight loss.

The moral of the story is that, I firmly believe that for whatever reason, sleep apnea and snoring is caused by insulin resistance.