Tuesday, 29 November 2011

New GLP-1 stuff

Understanding the Cardiovascular Effects of Incretin.

Cardiovascular disease (CVD), a leading cause of death in patients with diabetes mellitus, has several pathogenic mechanisms that are well established. However, the traditional hypoglycemic agents do not have proven positive effects on macrovascular disease. Novel therapeutic agents target the incretin pathway including the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonists and the dipeptidyl peptidase-4 inhibitors. The glucose-regulatory actions of these agents function by increasing insulin secretion and suppressing glucagon. They also act to increase weight loss not only by inhibiting gastric emptying, but also by reducing appetite.

Although GLP-1 and GLP-1R agonists have demonstrated beneficial effects on myocardium and vascular endothelium including coronary and peripheral mouse vessels, they also have anti-inflammatory and anti-atherogenic actions. These agents also have positive effects on the lipid profile and blood pressure. Although these cardioprotective actions seem to be beyond the effects of glucose control and weight loss, they are mediated through GLP-1R- or GLP-1R-independent actions of cleaved GLP-1 (9-36). Larger randomized controlled trials are necessary to elucidate the clinical promise of these beneficial CVD effects.

Combined stimulation of glucagon-like peptide-1 receptor and inhibition of cannabinoid CB1 receptor act synergistically to reduce food intake and body weight in the rat.

Acute activation of central Glp1 receptors enhances hepatic insulin action and insulin secretion in high fat-fed, insulin resistant mice.

The Gut Hormones PYY(3-36) and GLP-1(7-36 amide) Reduce Food Intake and Modulate Brain Activity in Appetite Centers in Humans.

Ketogenic Diet to help supress cancer?


Couldnt help, had to post this here.
Over the last years, evidence has accumulated suggesting that by systematically reducing the
amount of dietary carbohydrates (CHO) one could suppress, or at least delay, the emergence
of cancer, and that proliferation of already existing tumor cells could be slowed down. This
hypothesis is supported by the association between modern chronic diseases like the
metabolic syndrome and the risk of developing or dying from cancer. CHOs or glucose, to
which more complex carbohydrates are ultimately digested, can have direct and indirect
effects on tumor cell proliferation: first, contrary to normal cells, most malignant cells depend
on steady glucose availability in the blood for their energy and biomass generating demands
and are not able to metabolize significant amounts of fatty acids or ketone bodies due to
mitochondrial dysfunction. Second, high insulin and insulin-like growth factor (IGF)-1 levels
resulting from chronic ingestion of CHO-rich Western diet meals, can directly promote tumor
cell proliferation via the insulin/IGF-1 signaling pathway. Third, ketone bodies that are
elevated when insulin and blood glucose levels are low, have been found to negatively affect
proliferation of different malignant cells in vitro or not to be usable by tumor cells for
metabolic demands, and a multitude of mouse models have shown anti-tumorigenic properties
of very low-CHO ketogenic diets. In addition, many cancer patients exhibit an altered glucose
metabolism characterized by insulin resistance and may profit from an increased protein and
fat intake.
In this review, we address the possible beneficial effects of low CHO diets on cancer
prevention and treatment. Emphasis will be placed on the role of insulin and IGF-1 signaling
in tumorigenesis as well as altered dietary needs of cancer patients.

Saturday, 29 October 2011

You can always find a reason why a trade was "wrong"

It took a while to sink in but what I have learnt about trading is that backtesting is very naive, and whenever you make a loosing trade, you can ALWAYS find a reason why it went wrong by backtesting.

The biggest dilemma is that of support/resistance vs the trend. If you make a losing trade on S/R, then the guru will always say "you went against the trend",

If you make a losing trade going with the trend, the guru will just say you bought/sold into S/R!

Having said that, trading on S/R is really the only way to trade I feel, you need to go into profit asap and have a very very tight stop, for when you enter a trade with the trend but go into negative territory your faced with the hard decision, do you hold the trade and wait for price to come back and put you into profit? Or do you exit the trade NOW and take the loss, only to watch price come back to your level and go your way later?

Trying to make an active decision here always puts you at a loss. I nearly always made the "wrong" decision, exiting a losing position too early , or hanging onto trades that went hundreds of pips against me since last time it "came back".

You have to trade like a robot, and be very mechanical with your system. Never use intuition, just go with price and what the chart is saying.

This also brings me to the subject of following so called "experts" and analysts through various websites, countless predictions are made which almost always turn out to be wrong. Yet I still find myself looking at their opinions and it always sways my own judgement.

if guru X says the market is going to fall, then that affects my own opinion and affects how I trade. Indeed, following the news and listening to others is probably the worst thing I am doing, its just "noise", only the price and chart is the "signal".

Trading is the hardest thing I have ever done, its no surprise the vast majority lose their money, whenever you enter a trade, you always have at least a 50% chance of being right, but emotion is so powerful it always make you trade too defensively.

One thing that is clearly so deeply rooted into human psychology is the urge to always gamble the loser and accept the small winner.

When faced with the proposition of definitely accepting a small loss, or taking a gamble between losing nothing or accepting an even bigger loss, we ALWAYS gamble.

Wednesday, 7 September 2011

K(ATP) channels and fat cell multiplication

Involvement of ATP-sensitive potassium channels in proliferation and differentiation of rat preadipocytes.

These results suggest that when ATP-sensitive potassium channel expression decreases, preadipocyte proliferation is promoted, but when the expression of the channels increases, preadipocyte proliferation is inhibited.

It is to be confirmed whether the development of obesity has relation to excessive inhibition of ATP-sensitive potassium channels in preadipocytes or not.

hhhmmmm, inhibition of KATP channels, where have we seen that before? Oh yeh, here, this is what they say.....

"increased intracellular glucose, resulted from hyperglycemia, increases cytosolic ATP through glucose metabolism. This leads to closure of ATP-sensitive potassium ion channels (KATP channels) "

So how do we get increased intracellular glucose?, Yup, INSULIN.

No wonder the KATP knockout mice cannot get fat, they have no KATP channels to close in the first place! And so the downstream signalling cascade from the closure of the KATP never happens!

Tuesday, 16 August 2011

GABA also plays a role in body-fat regulation

GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism.

"AgRP neurons, also co-release neuropeptide Y (NPY) and γ-aminobutyric acid (GABA) to promote feeding and inhibit metabolism"

So the AgRP neurons also secret NPY and GABA, and this helps make you fat by suppressing the action of the POMC neurons, infact AgRP blocks the melanocortin 4 receptors, which is VERY bad news because blocking those receptors is a strong factor for bodyfat gain.

According to the abstract, removing the AgRP neurons essentially makes you stop eating and you die of starvation. So clearly the AgRP neurons are what makes you "hungry"

However, even if you delete the AgRP neurons, feeding behaviour can be restored by the administration of bretazenil, which is a GABA agonist. Interesting! So GABA receptor binding in the parabrachial nucleus plays a massive part in food intake.

Monday, 15 August 2011

Melanocortin 4 Receptor and Roux-en-Y Surgery

I rememberd reading on Stephen Guyenet's blog here about how weight loss surgery has no effect on those poor people with Melanocortin 4 receptor ( MC4R ) mutations, the link that Stephen gives in his blog is to a study that that looked at gastric banding surgery, which is actually significantly different from Roux-en-Y surgery.

In Roux-en-Y surgery, the ileum l-cell rich part of the intestine is moved right next to the entrance of the new stomach, but also, bile acids secreted from the gall bladder are given direct access to the rest of the ileum, which seems to cause hypersecretion of GLP-1 and results in intense stimulation of the POMC neurons.

I recently came across this study here that suggests that in actuality, even those people with MC4R receptor mutations may benefit from surgery aslong as it is Roux-en-Y.

I think this could be one of the strongest arguments yet for the power that incretins and bile acids play in bodyfat balance. Is it so powerful that it can even go someway as to help alleviate some the dreaded MC4R mutation effect of morbid obesity?

Sunday, 14 August 2011

Neuropeptide Y - Insight into what it does

Moderate long-term modulation of neuropeptide y in hypothalamic arcuate nucleus induces energy balance alterations in adult rats.

Administration of leptin or insulin suppresses the expression of NPY (about 0.5 to 1.5-fold decrease of ARC NPY levels) and reduces food intake in lean rats and in rodent models with elevated NPY expression, such as ob/ob mice, fasted rats or diabetic rats.

NPY production is stimulated by negative energy conditions, such that food deprivation induces a potent up-regulation in the expression of NPY and AGRP (5–10 fold increase as compared to basal).

Furthermore, NPY levels return to initial values within 6 to 24 hours after re-feeding. (well that is good to know,)

In addition, some studies also report elevated levels of hypothalamic NPY (30%, in average) in diet-induced obese mice (DIO). However, other studies show a compensatory down-regulation of NPY expression in the ARC and immunoreactivity in the PVN in rats fed with high-fat diet for variable periods of time which was related to the inhibitor effect of elevated leptin concentrations.

Overall this study shows that a forced increase in basal NPY leads to extreme over-eating and extreme fat gain.


Reducing NPY strangely leads to normal feeding under basal circumstances, BUT, the mice did not increase thier food intake after a period of calorie restriction!

This suggests that the upregulation of NPY after calorie restriction is an essential survival mechanism. This is direct evidence that your body attempts to maintain a "bodyfat set-point", atleast with regards to under-feeding and forced adipose mass depletion.

Saturday, 13 August 2011

Leucine deprivation decreases fat cell volume

Unfortunately these studies did not show a reduction in fat cell number by apoptosis but they did show a marked reduction in fat cell volume, generally speaking it is fat cell number reductions that we want, but still these studies are interesting nonetheless.

Leucine deprivation decreases fat mass by stimulation of lipolysis in white adipose tissue and upregulation of uncoupling protein 1 (UCP1) in brown adipose tissue.

As we recently reported, mice maintained on a leucine-deficient diet for 7 days experienced a dramatic reduction in abdominal fat mass (9).

In our current study, we observed increases in lipolysis and expression of β-oxidation genes and decreases in expression of lipogenic genes and activity of fatty acid synthase (FAS) in WAT,

In addition, we observed for the first time that leucine deprivation increases expression of uncoupling protein (UCP)-1 in brown adipose tissue (BAT), suggesting increased thermogenesis.

The rapid fat loss induced by leucine deprivation suggested a possible increase in energy expenditure.

Serum free fatty acid (FFA) and glycerol levels were much lower in leucine-deprived mice than in pair-fed and control diet–fed groups

Consistent with these findings, no apoptosis was detected by Tdt-mediated dUTP nick end labeling (TUNEL) staining in mice maintained on a leucine-deficient diet

the results of the present study show that leucine deprivation significantly reduces body weight and abdominal adipose mass without affecting proportion of lean body mass

Mice maintained on a leucine-deficient diet, however, reduced their food intake by 15%. These results are consistent with previous studies showing that mice consume less food when provided with a diet deficient in essential amino acids

Fat mobilization in response to increased energy requirements is normally mediated via increased activities of the sympathetic nerve system

Leucine Deprivation Stimulates Fat Loss via Increasing CRH Expression in The Hypothalamus and Activating The Sympathetic Nervous System.

leucine deprivation stimulates fat loss by increasing expression of corticotrophin-releasing hormone in the hypothalamus

the effect of leucine deprivation on fat loss is mediated by activation of the sympathetic nervous system.

Friday, 12 August 2011

Cutting calories to loose weight changes your brain

Obese reversal by a chronic energy restricted diet leaves an increased Arc NPY/AgRP, but no alteration in POMC/CART, mRNA expression in diet-induced obese mice.

"Arc neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expression in DIO mice after obesity reversal were significantly higher than DIO mice without obesity reversal (17%, 47%, both p<0.05),"

This means that post obese mice will have lower energy expenditure, increased hunger, and an increased tendency to store fat mass.

"while the Arc pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA showed no difference."

" Both NPY and AgRP expression in DIO mice were negatively correlated with plasma leptin (R=-0.78, p<0.05; R=-0.72, p<0.05)."

" In conclusion, while chronic energy restriction will lead to weight loss, it can up-regulate hypothalamic orexigenic peptides, which may be an important contributing factor to weight regain after a weight loss program from an energy restricted diet."

Thursday, 11 August 2011

GLP-1 strikes again!

A novel human-based receptor antagonist of sustained action reveals body weight control by endogenous GLP-1.

"Daily administration of this antagonist by subcutaneous injection to diet-induced obese mice for 1 week caused a significant increase in food intake, body weight, and glucose intolerance, demonstrating endogenous GLP-1 as a relevant hormone in mammalian energy balance in the obese state."

Wednesday, 10 August 2011

Strength Training Research Summarised....


Really good review of the clinical studies involving strength training, below the summary and recommendations from the article.....

*All credit goes to the authors of the above linked article ofcourse.

Persons should train until momentary muscular failure to actively recruit all of the available motor units and muscle fibres, as opposed to a pre-determined number of repetitions.

Load and Repetition Range
Persons should self-select a weight >80% 1RM and perform repetitions to failure. Evidence suggests this is optimal for maximising strength and muscular endurance gains, whilst helping to improve bone mineral density.

Resistance Type
Persons should select resistance type based on personal choice, although evidence appears to suggest that resistance machines might have a lower risk of injury than free-weights.There appears to be no difference in strength gains between using free-weights, machines or other resistance types.Free weights and sport specific movements show no enhancement in sporting performance or force throughout that movement.

Repetition Duration
Persons should maintain steady force production throughout a range of motion, and reduce external forces such as momentum; movements should be of a pace that maintains muscular tension, not ballistic or explosive in nature.Faster movements cause greater peaks in both muscular and ground reaction forces which likely transfer through joints and connective tissue, potentially causing injury.

Volume of Exercise, Frequency and Periodization
Persons can obtain appreciably the same strength gains by performing only a single set of each exercise 1 x / 2 x week, compared to higher volume workouts.Persons should train when they feel physically and mentally ready to do so. Both physical and mental fatigue have the potential to negatively affect a workout and/or muscular growth and development.No specific periodized routine is unequivocally supported within the literature.

Persons should consider their somatotype and that their genetics will dictate their muscular growth and development. Previous success with a routine is not evidence that it is optimal, genetic differences might dictate interpersonal differences in volume and frequency.

Sunday, 7 August 2011

Brain control of fat metabolism

Brain insulin controls adipose tissue lipolysis and lipogenesis.

"Here, we show that insulin infused into the mediobasal hypothalamus (MBH) of Sprague-Dawley rats increases WAT lipogenic protein expression, inactivates hormone-sensitive lipase (Hsl), and suppresses lipolysis"

"Conversely, mice that lack the neuronal insulin receptor exhibit unrestrained lipolysis and decreased de novo lipogenesis in WAT. Thus, brain and, in particular, hypothalamic insulin action play a pivotal role in WAT functionality."

Hypothalamic control of lipid metabolism: focus on leptin, ghrelin and melanocortins.

"In mammals, neurons, particularly in the arcuate nucleus of the hypothalamus (ARC), are involved in the regulation of energy homeostasis. One regulatory pathway consists of neurons co-expressing neuropeptide Y (NPY) and agouti-related protein (AgRP), both potent stimulators of food intake, and an adjacent set of ARC neurons co-express proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), which suppress food intake."

"The anorectic effect of these drugs requires the accumulation of malonyl-CoA in the hypothalamus, which may be sensed as a signal of nutrient abundance by critical neurons regulating food intake (‘malonyl-CoA hypothesis’) and decreased expression of orexigenic (AgRP and NPY) and elevated expression of anorexigenic (CART, POMC) neuropeptides in the ARC"

"Leptin induces opposite effects on two ARC neuronal subpopulations: it directly inhibits the orexigenic NPY/AgRP-containing neurons and it stimulates the electrical activity of anorexigenic POMC neurons"

"One of the factors required by leptin to exert its anorectic effect is hypothalamic AMPK"

"suppression of AMPK activity in the medial hypothalamus is necessary for leptin’s anorexic and weight loss effects and that lack of suppression causes leptin resistance"

"The most relevant receptors in terms of energy balance regulation are MC3R and MC4R. Receptor agonist delivery into the hypothalamus reduces food intake, body weight and fat mass"

"Anatomical studies have demonstrated that central WAT sympathetic outflow neurons express MC4R"

" Central melanocortins modulate the norepinephrine turnover, which is the principal initiator of lipolysis in mammals. Norepinephrine is released from the sympathetic nerves innervating WAT, and the central injection of a MC3/4R agonist increased the norepinephrine turnover in specific fat depots"

Overall this is a very good study and needs to read in its entirety.

Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function.

More evidence for the power of GLP-1 in obesity.

"Collectively, these data provide the strongest evidence to date that CNS GLP-1 plays a physiologic role in the long-term regulation of energy balance. Moreover, they suggest that this role is distinct from that of circulating GLP-1 as a short-term satiation signal."

Saturday, 6 August 2011

Cross-talk between adipose and gastric leptins

Cross-talk between adipose and gastric leptins for the control of food intake and energy metabolism.

" In accordance with the lipostatic theory stated by Kennedy in 1953, leptin was originally discovered in white adipose tissue. Its expression by other tissues was later established."

"Among them, the gastric mucosa has been shown to secrete large amounts of leptin."

" However while adipose tissue secretes leptin in a slow constitutive endocrine way, the gastric mucosa releases leptin in a rapid regulated exocrine fashion into the gastric juice."

"Scrutiny into transport mechanisms revealed that a significant amount of the exocrine leptin crosses the intestinal wall by active transcytosis."

" Exocrine-secreted gastric leptin thus participates in a physiological axis independent in terms of time and regulation from that of adipose tissue to rapidly control food intake and nutrient absorption."

Insulin responsible for poor incretin response?

Insulin-dependent suppression of cholesterol 7α-hydroxlase is a possible link between glucose and cholesterol metabolisms.

cholesterol 7a-hydroxlase is the rate-limiting step for the synthesis of bile acids from cholesterol.

Is this why obese people have high cholesterol and poor postprandial bile acid/incretin responses?

Food for thought anyway.

Friday, 5 August 2011

Incretin's continued......

Role of incretins in the regulation of bone metabolism

"GIP has anabolic effects on bone mainly by stimulating osteoblastic bone formation through intermittent elevation of intracellular cAMP levels. On the other hand, GLP-1 is suggested to regulate bone resorption indirectly through the thyroid C cell."

Effects of GIP receptor antagonist for treatment of obesity

"GIP receptor antagonists possess favorable effects such as, decreased body adiposity or improvement of glucose intolerance through change of fat metabolism in high-fat diet induced or genetically induced obese experimental animals.

Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes.

Good review and free article.

Reversal of obesity and insulin resistance by a non-peptidic glucagon-like peptide-1 receptor agonist in diet-induced obese mice.

"Different from Boc5 treatment, caloric restriction did not affect adiposity significantly and circulating adipocytokines levels remained abnormal"

"These apparent differences imply that the regulatory role exerted by Boc5 (and hence, incretin mimetics in general) on lipid metabolism is independent of its inhibition on food intake."

Well well well, so much for the whole calorie restriction thing.

"Our results indicate that the basal glucose incorporation was significantly elevated in adipocytes isolated from obese mice while their response to insulin stimulation was severely impaired"

"the role of caloric restriction (pair-feeding) in modifying fat cell lipogenesis and lipolysis was minimal"

Wednesday, 3 August 2011

Bile acid signalling, how important is it?

Bile-induced secretion of glucagon-like peptide-1: pathophysiological implications in type 2 diabetes?

"it has become clear that bile acids not only act as simple fat solubilizers, but additionally represent complex hormonal metabolic integrators."

"bile acids are ligands for the nuclear receptor FXR controlling transcription of genes involved in, for example, bile acid, cholesterol, and glucose metabolism"

"Bile acid activation of TGR5 results in increased intracellular cAMP levels, which in brown adipose tissue and muscle cells modulates energy expenditure by activating type 2 iodothyronine deiodinase, which in turn deiodinates thyroxine to the active thyroid hormone triiodothyronine"

"The reason for these limitations may be due to the fact that current GLP-1-based drugs exert their effects via elevated plasma levels of “GLP-1 receptor agonists”, and therefore, allegedly, may not elicit the local effects that endogenous secreted GLP-1 might have."

"Roux-en-Y gastric bypass (RYGB) surgery incurs remission of type 2 diabetes in the majority of patients (4), a “cure” of type 2 diabetes that has been linked to increased endogenous GLP-1 secretion"

"recent studies provide evidence for L cell expression of several G protein-coupled receptors (for example GPR120), which can be activated by long-chain fatty acids and, hence, result in GLP-1 secretion"

"Recently, the G protein-coupled receptor TGR5 was found in the enteroendocrine GLP-1-secreting cell line STC-1 (17) and in primary L cells from mice"

"These findings suggest that postprandial gall bladder contraction and increased flow of bile acids to the intestine potentiate nutrient-induced GLP-1 secretion from the L cells via TGR5 activation. "

"The newly described role of bile-induced TGR5 activation in L cell secretion combined with findings of reduced postprandial gall bladder emptying in type 2 diabetes (38, 39) [worsened by diabetic neuropathy typical for patients with long-standing disease (39)] suggests that reduced postprandial GLP-1 responses in patients with type 2 diabetes may, hypothetically, arise as a consequence of diabetic gall bladder dysmotility, which in turn might reduce postprandial bile flow to the intestine and, thereby, TGR5 activation in the L cells."

"Last, serum bile acids have been found to increase following RYGB (positively correlated with GLP-1 and negatively correlated with thyrotropic hormone) (33). As direct access of bile acids to L cell-rich parts of the small intestine is established following RYGB"

The Changes of Pro-opiomelanocortin Neurons in Type 2 Diabetes Mellitus Rats After Ileal Transposition: The Role of POMC Neurons.

"The Ileal transposition group demonstrated significantly improved plasma glucose homeostasis with increased glucagon-like peptide 1 secretion.

"associated with increased central neuronal activity with increased pro-opiomelanocortin and derivative gene expression in the hypothalamus and increased protein expression in the pituitary gland."

"More pro-opiomelanocortin neurons in the hypothalamus of diabetes rats were activated after ileal transposition. "

Dairy pwns

Dairy attentuates oxidative and inflammatory stress in metabolic syndrome.

adequate-dairy decreased malondialdehyde and oxidized LDL at 7 d (35% and 11%, respectively; P < 0.01), with further decreases by 12 wk. Inflammatory markers were suppressed with intake of adequate-dairy, with decreases in tumor necrosis factor-α at 7 d and further reductions through 12 wk (35%; P < 0.05);

and a corresponding 55% increase in adiponectin at 12 wk (P < 0.01).

adequate-dairy significantly reduced waist circumference and trunk fat (P < 0.01 for both)

Sunday, 31 July 2011

Gastric Bypass Surgery And Gut Peptides

Changes in Glucose Homeostasis after Roux-en-Y Gastric Bypass Surgery for Obesity at Day Three, Two Months, and One Year after Surgery: Role of Gut Peptides.

"Endocrine effects of gastric bypass (GBP) surgery for obesity on glucose homeostasis are not fully understood."

"Both enhanced insulin sensitivity and incretin hormones, such as GLP-1, contribute to the early control of glucose homeostasis. Progressively increasing postprandial levels of enteroglucagon (oxyntomodulin) and GLP-1 facilitate weight loss and enhance insulin effectiveness."

Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism.

It has also been suggested that poor and slow bile acid secretion in obese people is responsible for poor GLP-1 secretions.

In this study the authors speculate that the higher concentration of blood bile acids is enforced by increased bile acid uptake by the ileum because it is moved closer to the entrance from the stomach.

"Post-GB anatomic or functional adaptive changes, including altered dietary patterns, intestinal motility, mucosal hyperplasia, or gut flora, could each contribute to increased postprandial bile acid absorption."

liraglutide - new weight loss, GLP-1 agonist drug

The contribution of serotonin 5-HT2C and melanocortin-4 receptors to the satiety signaling of glucagon-like peptide 1 and liragultide, a glucagon-like peptide 1 receptor agonist, in mice.

"liraglutide, a GLP-1 receptor (GLP-1R) agonist, induces satiety."

" The serotonin 5-HT2C receptor (5-HT2CR) and melanoroctin-4 receptor (MC4R) are involved in the regulation of food intake."

The above study is able to show that the anorexia effects of GLP-1 is diminished in mice with 5-HT2C and MC4R receptor abnormalities, which would suggest some of the downstream effects of GLP-1 binding acts on those receptors.

However, strangely, the new drug liraglutide is still able to mimic the anorexia effects of GLP-1 in mice with those same receptor abnormalities. Clearly liraglutide is doing more than what it says on the tin.

Comparative Effects of the Long-Acting GLP-1 Receptor Ligands, Liraglutide and Exendin-4, on Food Intake and Body Weight Suppression in Rats.

"liraglutide reduced 24 and 48 h body weight in nonobese, chow-maintained rats"

"Chow intake and body weight suppression by liraglutide were of greater magnitude and shorter latency following intraperitoneal compared to subcutaneous delivery,"

"Both drugs regimens yielded marked weight loss over the 7-day period. The weight loss effect of liraglutide was achieved in the first 2 days and remained stable for the duration of the experiment; weight loss with exendin-4 appeared more linear over the 7-day period."

Liraglutide Prevents Hypoadiponectinemia-Induced Insulin Resistance and Alterations of Gene Expression Involved in Glucose and Lipid Metabolism.

"Administration of liraglutide prevented hypoadiponectinemia-induced increases in plasma insulin, free fatty acids, triglycerides and total cholesterol. Liraglutide also attenuated hypoadiponectinemia-induced deterioration in peripheral and hepatic insulin sensitivity and alterations in key regulatory factors implicated in glucose and lipid metabolism. "

"These findings demonstrated for the first time that liraglutide could be used to rescue insulin resistance induced by hypoadiponectinemia and HFD via regulating gene and protein expression involved in glucose and lipid metabolism."

Wow, this drug sounds too good to be true.........

Insulin and Leptin is needed for Fertility

Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility.

" the physiological significance of concomitant leptin and insulin action on POMC neurons remains to be established"

"Here, we show that mice lacking both leptin and insulin receptors in POMC neurons display systemic insulin resistance, which is distinct from the single deletion of either receptor."

"We conclude that direct action of insulin and leptin on POMC neurons is required to maintain normal glucose homeostasis and reproductive function"

Friday, 29 July 2011

Smoking ( Nicotine ) really does help you stay thin

Nicotine decreases food intake through activation of POMC neurons.

"This study demonstrates that nicotine decreases food intake and body weight by influencing the hypothalamic melanocortin system and identifies critical molecular and synaptic mechanisms involved in nicotine-induced decreases in appetite."

Carbs may sabotage your GLP-1 response

The effect on glucagon, glucagon-like peptide-1, total and acyl-ghrelin of dietary fats ingested with and without potato

In this study we see that, lard produces a strong and somewhat delayed spike in GLP-1, you get the spike about 2.5hours after ingestion.

Olive oil gives you a GLP-1 increase that happens sooner than lard but doesnt reach as high a concentration, the increase also remains elevated for longer than lard.

Ingestion of carbs ( potato ) with the fats listed above completely blunts up the GLP-1 response.

Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity

Funny Stuff

" We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes."

"The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production."

"UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing,"

Thursday, 28 July 2011

Over-eat but dont get fat?

ATP-Sensitive Potassium Channel-Deficient Mice Show Hyperphagia but Are Resistant to Obesity.

"Body weight homeostasis is maintained through the balance between energy expenditure and energy intake, and these processes are controlled in the hypothalamus - the center for body weight regulation."

"When anorexigenic peptide is elevated, melanocortin receptor 3/4 in the paraventricular nucleus of the hypothalamus is activated and satiation and thermogenesis are induced. Increased orexigenic peptide activates the Y1/5 receptor in the paraventricular nucleus of the hypothalamus, induces a sense of hunger, and halts thermogenesis"

"This study demonstrated that Kir6.2-deficient mice showed increased hypothalamic NPY expression accompanied with increased caloric intake, decreased visceral fat mass, and resistance to the induction of obesity by a high fat diet compared to the levels in C57BL/6 mice."

Glucose regulates the effects of leptin on hypothalamic POMC neurons.

The body works on thresholds.

Some may not be better than none.

More may not be better than some.

Insulin resistance is a cellular antioxidant defense mechanism

Theres no ends to wierd stuff you can find when you dig deep enough in pubmed.


Metformin increases leptin sensitivity

The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression.

"These data identify the hypothalamic ObRb as a gene modulated after metformin treatment and suggest that the anorectic effects of the drug are potentially mediated via an increase in the central sensitivity to leptin."

Artificial sweeteners

Effects of carbohydrate sugars and artificial sweeteners on appetite and the secretion of gastrointestinal satiety peptides.

Study showing that artificial sweeteners have no effect on your physiological hormones in your gut, contrary to popular belief.

Think your in control? Well, Your not

Relation of addiction genes to hypothalamic gene changes subserving genesis and gratification of a classic instinct, sodium appetite.

This study was a true eye opener for me. The idea of "free will" and "choice" is thrown into complete disarray here.

Basically, what this study shows is that the unconcious part of your brain will use dopamine signalling and other feel good reward chemistry in your brain in an attempt to control your behaviour in such a way so that you do what *it* thinks is ultimately best for your survival or prosperity.

Notice however, that whether or not the action your unconciousness is encouraging you to do REALLY IS in your best benefits is a different matter. That is to say, your unconciousness is not always RIGHT.

Free will and choice can only exsist in a situation where the outcomes of any of your actions are negligible to your survival and/or prosperity.

Glucagon-like peptide 1 stimulates hypothalamic proopiomelanocortin neurons.

Interesting study

Friday, 15 July 2011

Adipocyte Apoptosis and Resveratrol

Effect of resveratrol on fat mobilization.

"Moreover, dietary supplementation of aged ovariectomized rats with a combination of resveratrol and vitamin D, quercetin, and genistein not only decreased weight gain but also inhibited bone loss."

"Combining several phytochemicals, including resveratrol, or using them as templates for synthesizing new drugs, provides a large potential for using phytochemicals to target adipocyte adipogenesis, apoptosis, and lipolysis."

Enhanced inhibition of adipogenesis and induction of apoptosis in 3T3-L1 adipocytes with combinations of resveratrol and quercetin.

" Taken together, our data indicate that combinations of resveratrol and quercetin can exert potential anti-obesity effects by inhibiting differentiation of preadipocytes and inducing apoptosis of mature adipocytes."

Thursday, 14 July 2011

More Neuropeptide Y stuff

Short-term cold exposure may cause a local decrease of neuropeptide Y in the rat hypothalamus.

Leptin inhibits hypothalamic Npy and Agrp gene expression via a mechanism that requires phosphatidylinositol 3-OH-kinase signaling.

NPY receptors as drug targets for the central regulation of body weight.

Hyperprolactinemia suppresses the luteinizing hormone responses to N-methyl-D-aspartate, epinephrine, and neuropeptide-Y in male rats.

Neuropeptide Y in relation to carbohydrate intake, corticosterone and dietary obesity.

Neuropeptide Y projection from arcuate nucleus to parvocellular division of paraventricular nucleus: specific relation to the ingestion of carbohydrate.

NPY in the coordination of bone mass to body weight

Neuropeptide Y knockout mice reveal a central role of NPY in the coordination of bone mass to body weight.

Basically, high NPY = low bone density, and low NPY = high bone mass

NPY is another starvation hormone, it basically tells your body that your starving and that all ingested calories should go towards storage.

Stopping Coconut Oil for a Bit - Mind in OVERDRIVE

Been taking 40g coconut oil in mornings last few days and ive noticed ever increaseing duration in the nausea it produces afterwards,

Its got so bad that my thoughts are just racing like mad constantly and its impacting my ability to sleep, been waking up at 3am last few nights and this morning I wasnt even able to get back to sleep.

Whats interesting is that I dont even feel that tired, I just have this constant hyper caffeine high.

Will give it a rest for a few days.

Wednesday, 13 July 2011

Ketone bodies modulates body weight and hepatic insulin sensitivity

Central infusion of ketone bodies modulates body weight and hepatic insulin sensitivity by modifying hypothalamic leptin and insulin signaling pathways in type 2 diabetic rat


"In conclusion, mild ketosis by central infusion of ketones improves energy and glucose metabolism through the potentiation of leptin and insulin signaling in the hypothalamus of diabetic rats."

Obesity and more.....

Well it seems as ever you learn far more from reading the comments section of aritcles than the actual articles themselves.

This post is just a summation of some interesting information and to serve as a bookmark.

Brain dopamine and obesity.

"The availability of dopamine D2 receptor was decreased in obese individuals in proportion to their BMI."

Dopamine signalling is an important way for your brain to decide if ingested calories go towards energy and reproduction or if its just going to be stored in fat cells. There is some evidence that dopamine agonists ( i.e. dopamine receptor activators ) can help with keeping metabolsim high and helping partition calories towards energy production instead of storage. Drugs such as Bromocriptine and Cabergoline and Pergolide have been implicated.

Activation of dopamine D2 receptors simultaneously ameliorates various metabolic features of obese women.

"Thus these results imply that short-term bromocriptine treatment ameliorates various components of the metabolic syndrome while it shifts energy balance away from lipogenesis in obese humans."

Childhood obesity: behavioral aberration or biochemical drive? Reinterpreting the First Law of Thermodynamics.

Interesting paper by Lustig.

Attenuated GLP-1 secretion in obesity: cause or consequence?

"Postprandial GLP-1 secretion in response to oral carbohydrate is considerably attenuated in obese subjects. The cause of this attenuation of GLP-1 secretion is not known although we suggest that both this fall and the overall reduction in GLP-1 values in obese subjects may be related to an increase in plasma non-esterified fatty acids."

Thanks to Itsthewoo for pointing this paper out.

Diet high in oat β-glucan activates the gut-hypothalamic (PYY(3-36) -NPY) axis and increases satiety in diet-induced obesity in mice

Just throwing it out there. Will read up on it more when I get time.

Saturday, 2 July 2011

Another take at muscle building

I had this idea the other day that I may have overlooked in my research on muscle building. The golden rule of biology is that, in all circumstances, cells always seek to adapt to thier environment in such a way so as to maintain homeostasis with that environment.

In light of this, it may not be wise to complete strength training sets to failure or near failure. Going to failure surely creates an environment for the cell that ultimately favours aerobic respiration, i.e, high endurance. So this is what the cell adapts to, endurance, i.e. lots of type I fibres with densely packed mitochondria.

It could therefore be alot more beneifical to not go anywhere near failure when performing a set, giving us the stimulation for type II fibre hypertrophy WITHOUT the stimulation for many high endurance type I fibres.

This is just another theory, I will test it on myself in the coming months by only performing enough reps in a set to take me to about ~70% close to failure.

For example, if for a given weight I can only perform 12 reps of bicep curls before I hit failure, ( so I cannot complete the 13th rep ), then I will pick that weight and only do sets of 8 reps.

To compensate for the reduced volume this would bring ( and we know that volume is one of the important things for building muscle ), I will increase the total number of sets I do for a given exercise , 1-2 or something, depending on how I feel the muscle is coping.

Wednesday, 29 June 2011

Cooling the brain and insomnia

Cooling the Brain During Sleep May Be a Natural and Effective Treatment for Insomnia


Monday, 27 June 2011

β-Hydroxybutyrate is the preferred substrate for GABA

β-Hydroxybutyrate is the preferred substrate for GABA and glutamate synthesis while glucose is indispensable during depolarization in cultured GABAergic neurons.


Tuesday, 7 June 2011

Mitochondrial Uncoupling

The ketogenic diet increases mitochondrial glutathione levels.

"Together, the results demonstrate that the KD up-regulates GSH biosynthesis, enhances mitochondrial antioxidant status, and protects mtDNA from oxidant-induced damage."

I also found this study recently which was interesting.....

Glutathionylation acts as a control switch for uncoupling proteins UCP2 and UCP3.

The two are related it seems, i think it presents a novel explanation for uncoupling protein increase on a ketogenic diet.

Saturday, 21 May 2011

Advice and Confidence - Dan Ariely

Dan Ariely has some truely amazing and shocking revelations on his site here, but since I have spent the last few months trading I was particularly interested in these 2 articles,



The bottom line is, advice from sources we presume to be more informed than us pretty much shuts down our brains own decision making machinery.

Also, we find confidence far more seducing than expertise.

Wednesday, 18 May 2011

Thigh, Bum and Belly Fat Differentials


This study suggests that overall flux of fat into thigh/bum area is less easily done as compared into the belly area, and the belly area more easily takes up dietary fat compared to thigh/bum fat.