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.

Weight regain following weight loss

Biological mechanisms that promote weight regain following weight loss in obese humans.

Great paper here, summarizing the research on why maintaining weight loss is so difficult AND also the foolishness of calorie restriction.

This article discusses research on several factors that may contribute to weight regain following weight loss achieved through behavioural interventions, including adipose cellularity, endocrine function, energy metabolism, neural responsivity, and addiction-like neural mechanisms. All of these mechanisms are engaged prior to weight loss, suggesting that these so called "anti-starvation" mechanisms are activated via reductions in energy intake, rather than depletion of energy stores.

The bolded part is the key part of this paper. The author's are arguing that it is not weight loss per se that sets us up for weight regain, but rather it is the calorie restriction. I posted on another study earlier this year which also seemed to support this idea, here, in that post, we found that mice who lost weight by 40% calorie restriction had a dramatic increase in AgRP, while mice that were allowed to eat ad-lib on a new diet did not increase AgRP but still lost considerable weight. Whats funny is that the author of the above study makes no mention of the AgRP study I blogged about, so unwittingly he is on the right tracks. imo.

 The whole paper is golden so if you can get the full text its well worth a complete read. I tried and failed to paraphrase it, every sentence has useful information. So I just copy paste the beginning of the discussion and the conclusion...

Changes in adipose cellularity and addiction-like neural habituation result from chronic overconsumption and appear irreversible via behavioral weight loss [24,34,122,129]. Thus, these factors are not activated to prevent weight loss but serve to encourage preservation of highest sustained body weight, and may actually promote indefinite increases in energy storage. Alterations in endocrine function (e.g., decreases in leptin and increases in ghrelin), decreases in energy expenditure, and increases in neural responsivity to high-calorie food cues all occur within 24 h of caloric restriction (Table 1) [57,84,132]. 

Regardless of when these mechanisms are activated, each has the potential to exert a [neuro]biological influence that may reduce an obese or formerly obese individual's ability to maintain behavioral weight losses and promote weight regain at least to the individual's highest sustained lifetime weight. These influences also carry the expected weight regain promoting behavioral correlates. 

Weight-reduced vs. never-obese subjects report increased food craving [133], a decreased perception of amount eaten [134], decreased postprandial satiety [135] and an increased preference for calorically dense foods [136].With these additional biological influences encouraging the consumption and storage of energy, it is not surprising that weight regain following behavioral weight loss occurs at a faster rate than initial weight gain [135,137].

These mechanisms appear not to be part of a highly sensitive homeostatic feedback system designed to regulate body weight at any particular “set point,” but mechanisms either acquired via excess weight gain or enacted almost immediately via reduced caloric intake. Importantly, these mechanisms operate irrespective of the adequacy of energy stores. Thus, these mechanisms may be more accurately described as anti-weight loss mechanisms, rather than anti-starvation mechanisms per se.

CONCLUSION

We have presented evidence that the likelihood of weight regain in weight-suppressed obese and formerly obese individuals may be increased by a confluence of biological mechanisms, including adipose hyperplasia, increased metabolic efficiency, changes in neuroendocrine signaling (e.g., decreased satiety signaling), and changes in neural responsivity to both food cues (e.g., increased reward-related or decreased inhibitory anticipatory responsivity) and food intake (e.g., decreased consummatory reward through habituation to the rewarding aspects of palatable food). 

These biological pressures that may undermine weight loss efforts and promote weight regain are almost immediately enacted in obese individuals attempting even modest and healthy weight reduction. Further, these mechanisms operate invariably and appear to defend an individual's highest sustained body weight. Thus, it is the opinion of these authors that these mechanisms would be more accurately described as anti-weight loss mechanisms rather than anti-starvation mechanisms. Regardless, obese individuals face an extreme uphill battle in having to overcome powerful biological drives that appear insurmountable via behavioral interventions, illustrating the critical importance of obesity prevention efforts for normal and overweight individuals. This may be particularly pertinent to parents of overweight children, who are significantly more likely to become obese adults.

p.s. thanks to bill/caloriesproper for the full text.

EDIT -- Added the parts on adipose morphology and leptin

Excess weight gain typically leads to changes in body composition, including significant alterations in adipose cellularity. Although increases in body mass index (BMI) do not directly predict an absolute increase in body fat content [19], elevated body weight is generally associated with an increase in the diameter of fat cells (adipocyte hypertrophy), as well as greater amounts of fat stored within adipocytes [20,21]. Most literature points to adipocyte hypertrophy as the main feature of obesity; however, alterations in adipocyte number may also be important [22,23]. Upon reaching an upward critical limit in fat cell volume, enlarged adipocytes secrete paracrine factors that induce preadipocyte proliferation (hyperplasia) [24–26]. Thus, excess caloric intake* may lead to increases in fat cell size and subsequent increases in fat cell number [20,26,27].

Recent evidence suggests that this increase in fat cell number may occur in overweight individuals [28]. However, the preponderance of evidence suggests that hyperplasia occurs primarily in clinically severely obese individuals [27,29,30]. Thus, if hyperplasia is associated with weight regain, this effect may be relegated to weight regain following weight loss in [formerly] clinically severely obese individuals, for whom returning to a lean bodyweight through behavioral weight loss is exceedingly difficult [31].

With behavioral weight loss, adipocyte hypertrophy decreases; however, the hyperplasia remains [20,29,32–35]. Thus, weight loss dieting may reduce the size but not the number of fat cells. A lack of programmed cell death may be responsible for the failure of reductions in fat mass via nonsurgical means to reduce adipocyte number [20,33]. Therefore, relative to never-obese individuals, weight-suppressed [formerly] obese individuals (particularly clinically severely obese individuals) may be left with a significantly greater number of adipocytes, which cannot be reduced via behavioral weight loss [34]. See Table 1.

Liposuction is the only known treatment able to reduce adipocyte number, but carries high complication rates [36]. It is not yet definitively known whether hyperplasia encourages weight regain in weight-suppressed individuals. There is some evidence to suggest that the presence of smaller adipocytes may encourage weight regain by decreasing the overall rate of fat oxidation and increasing the retention of ingested fuel [37–41]. Normally, during times of energy deprivation, fat stores break down triglycerides into their individuals components, glycerol and free fatty acids [42], which generate energy for the cell. However, the rate of fat breakdown (lipolysis) appears to be related to adipocyte size and cellular surface area [43]; smaller cells exhibit lower rates of basal lipolysis [44]. Therefore, if size-reduced adipocytes are modified to break down less and store more fat, these cells may expand and promote further proliferation. Although still speculative, there is some evidence to suggest that these cells may be predisposed to reach a particular mean size, allowing them to store similar amounts of fat as previously formed adipocytes [25,34].

However, small adipocyte number may be sufficient to observe a clinically significant effect in only a percentage of obese (i.e., clinically severely obese) individuals.An additional line of evidence reports higher levels of insulin in newly size-reduced adipocytes [44,45]. Insulin, which is excreted from pancreatic beta cells in response to rising levels of glucose in the bloodstream, facilitates a preferential utilization of carbohydrates to meet the cell's energy requirements [40,46–48]. Further, insulin inhibits lipolysis [49] and stores triglycerides in adipocytes (lipogenesis) [50].

Interestingly, although insulin sensitivity seems to improve in weight reduced individuals, fat metabolism slows, potentially in an attempt to preserve energy stores [37,38,49,50]. As a result of these changes in carbohydrate and fat utilization, an abnormal accumulation of triglycerides may give rise to a higher net fat cell content and elevations in body weight [37,38,51–53]. Adipocyte size is also correlated with plasma leptin concentrations, which have been shown to affect weight loss maintenance [54]. Relative to control, formerly obese weight-suppressed participants were found to have reduced fat cell volume and serum leptin levels, despite almost identical body fat percentages [35].

Because smaller adipocytes in formerly obese individual smay be secreting less leptin following behavioral weight loss [28,35,37,55], an association between increased number of smaller adipocytes and leptin insufficiency has been proposed
[28,35,37,55,56].

Although leptin levels are not entirely depleted in weight-suppressed formerly obese individuals, their secretions are much more attenuated relative to lean subjects who undergo caloric restriction [35,55]. Thus, with reductions in leptin secretion, heightened appetite and excess food intake may lead to weight regain [28,54]. The potential role of leptin in weight regain is further discussed below.


LEPTIN



Leptin levels are reduced within 24 h of energy restriction [57] and a number of studies report greater reductions of leptin than would be expected for given losses of adipose tissue [34,35,58]. It has been suggested that leptin's primary role is the prevention of starvation, rather than weight regulation per se, questioning the notion of “leptin resistance” [18]. Reductions in leptin levels appear to trigger a starvation defense response, despite the persistence of abundant fat stores [57]. Evidence suggests that there may be a threshold below which the “anti-starvation” action of leptin is enacted, and this threshold is proposed to increase concurrently with increases in adipose tissue [57].

Thus, weight loss dieting in obese individuals may lead to leptin depletion to sub-threshold levels, despite the persistence of relatively high levels of leptin. Sub-threshold leptin levels result in reductions in metabolic rate and physical activity [14], as well as increases in hunger and food intake [59]. Thus, behavioral weight loss and weight loss maintenance are accompanied by physiological attributes that resemble those of a leptin-deficient animal: lower energy expenditure, increased hunger, reduced thyroid metabolism, and diminished sympathetic nervous activity [60,61].

*I think that excess caloric intake quote is very ignorant of the author's. It is much more appropriately stated as excess storage of fat and/or insufficient mobilization of fat.

An easy way to increase testosterone......

During my research into steroids one of the more interesting studies that cropped up was this.....

Pharmacokinetics and dose finding of a potent aromatase inhibitor, aromasin (exemestane), in young males.

Aromasin is an aromatase inhibitor, it works by binding irreversibly to the aromatase enzyme, so that other steroids like testosterone cant bind to it. In this study young males were given 25mg per day ( which is the standard tablet size ) for 10 days.

At the end of the 10 days, total testosterone had increased ~60% but free testosterone ( that is, the testosterone that is actually free to bind the androgen receptor ) increased by 117%. The reason this works is because estrogen is reduced as a result of the aromatase blockage, and estrogen is the main negative feedback signal to the hypothalamus to decrease LH secretion. So with lower estrogen in the system, more LH is secreted and more testosterone is made. Its a double whammy aswell, because with aromatase blockage, less testosterone is lost in the conversion to estrogen.

Infact another recent report even suggested aromatase inhibitors may be of benefit to obese men who suffer from hypogonadism due to the excess estrogen that usually accompanies obesity.

Whether or not this increased testosterone will result in anabolic affects however is up for debate. However if you think your suffering from low testosterone, aromasin could be of some help. Aromasin is actually quite a safe drug, with minimal side affects, but it is slightly pricey.

Note in the first study, estrogen levels returned to normal 3-6 days after aromasin withdrawal, so the drug must be continuously taken to keep the increased levels of testosterone. Bear in mind also, estrogen is actually a very important hormone in men, lower is not necessarily better. Low estrogen will absolutely murder your sex drive and ability to get an erection, in a similar way low testosterone will.

Insulin "turbocharges" conversion of testosterone to estrogen

This may be old news to many.....

So aromatase converts testosterone to estrogen, and aromatase activity is greatly increased by insulin, something of which we all seem to have too much of in our modern society. ( insulin that is )

Here is an interesting passage from this paper.....

The physical effects of illness and inflammation, and the psychological stress associated with concern about being loved and accepted by family and peers, compounded by work pressure, financial stress and the perceived urgency of daily living, all contribute to effectively increase corticotropin releasing hormone (CRH) Foster et al., 2009. The resultant pituitary adrenocorticotrophic hormone (ACTH) and corticosterone output stimulate the increased consumption of sweet and palatable carbohydrates (Dallman et al., 2007), including foods that contain 30% sucrose (like many breakfast cereals, cakes, biscuits, and confectionary), that stimulate a normal reactive insulin response.

Unfortunately, the increased insulin output,

• upregulates P450 aromatase 6-fold (Samad, 2007),
•  increases leptin output (Thomas et al., 2000; Falconnier et al.,
• 2003; Manderson et al., 2003; Lindsay et al., 2004),
•  increases estrogen-receptor-alpha number and activity (Kaaks, 2008),  
• induces hypertriglyceridemia, sodium retention and hypertension (Biddinger and Kahn, 2006),
•  increases subcutaneous fat deposition (Shin et al., 2007),

Further from the author.....

In summary, continuing exposure to stress, compensatory eating, xeno-oestrogens, the pill, pesticides, oestrogenic chemicals, fast foods, soft drinks and poor quality carbohydrate diets, cyclically amplify aromatase to TURBOCHARGE the production of even more oestradiol. . .until overweight becomes obesity, stress becomes depression, glucose intolerance becomes type two diabetes, benign prostate and breast changes turn into prostate cancer and breast cancer, and acceptable forgetfulness progresses toward Alzheimer’s disease.

In reference to the bolded part, the author recognizes that it is the carbohydrates in the diet that need to be scrutinized, not the dietary fats. Personally I think the cause of gyno in people taking high doses of steroids/androgens actually comes from the "bulking" aspect of their diet that generally involves extremely high amounts of calories/carbohydrates/refined carbohydrates. All the insulin that follows such a diet no doubt "turbochargers" aromastase to convert all that testosterone your injecting into estrogen.

There is also the link between increased levels of stress and increased carbohydrate consumption that has been reported many times before. To be honest, unless you are financially well off, modern life is almost 24/7 stress.

IF your still on the fence to the eternal chicken and egg question of what comes first, insulin hyper-secretion or insulin resistance, but still want to reduce your aromatase activity. You can do either one of two things, reduce your insulin resistance, or reduce your insulin secretion. ( or both obviously ). Reducing insulin resistance is not something that can be done in an obvious way, otherwise we'd have a cure for type 2 diabetes. HOWEVER, reducing your insulin secretion is easily done by reducing carbohydrates in your diet.