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.

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.

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?

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., 1994; Stallknecht et al., 1997;Horowitz and Klein, 2000; Jocken 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., 1997; Enoksson 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,

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.

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.

Can omega6 PUFA be slimming?

I found these studies recently and it has caused me to possibly rethink my stance on how PUFA omega6 may be fattening. More than anything, its important to always remain open minded.

cAMP-dependent signaling regulates the adipogenic effect of n-6 polyunsaturated fatty acids.

This study was set out to simply help resolve the conflicting information coming from various studies about whether omega6 are pro-adipogenic or not.  Linoleic acid is a precursor of arachidonic acid, and it is arachidonic acid that is more the focus of this study.

To cut a long story short, the researchers found that keeping carbohydrates low in the diet was able to turn omega6 from fattening into ( potentially ) slimming. Mice fed a higher protein lower carb diet,  high in PUFA remained quite slim, while the higher carb fed mice became obese.

The way this works is, by keeping carbs low, the glucagon/insulin ratio of the diet is elevated , leading to increased cAMP in adipose tissue ( glucagon elevates cAMP in adipose tissue ). This increased cAMP drives the production of  arachidonic acid towards the prostaglandin F2α, which has been shown to have strong anti-adipogenic functioning.

Below is the important graph in the study imo....

As you can see, prostaglandin F2α is significantly higher on the low carb,  higher protein diet.

The diets fed to the rodents are below...

The starch component is 9.486, not 9 thousand. Dont be confused like I was...

Anyway, some of you may notice that the change was in the sucrose, going from 9% sucrose to 43% sucrose may probably make you obese regardless of the other stuff in the diet......*shrug*

The feed efficiency was strikingly different between the mice, to quote..

In the high protein group, 467.8 kcal were needed to produce a weight gain of 1 g, whereas the high carbohydrate group only needed 67.8 kcal to produce the same weight gain, which almost exclusively represented an increase in adipose tissues.

In still yet another study, researchers were able to show that knockout of the enzyme Akr1b7 which produces prostaglandin F2α, automatically produces obesity ( they noted both hypertrophy and hyperplasia in this model ) . In particular they found increased expression of the lipogenic gene's,  fatty acid synthase and scd1 in the adipose tissue of the knockout group.

Interestingly, in the second study using high-fat-diet, the knockout mice still managed significantly higher fat mass despite slightly reduced food intake.

Lastly, to expand on the function of fatty acid synthase in adipose tissue, another group of researchers have put forward the idea that the function of fatty acid synthase may not exactly be to make fats de novo for storage per se, but rather the function of fatty acid synthase may be to synthesize a ligand for PPARgamma.

It also looks like prostaglandin F2α helps inhibit PPARgamma.

So in conclusion I think, the fattening potential of omega6 PUFA should be considered in context. Anecdotally I noticed especially good weight loss when I combined very low carb with large servings of peanuts, 150g+ per day.