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What Caused the Setpoint to Change?
We have two criteria to narrow our search for the cause of modern fat gain:
- It has to be new to the human environment
- It has to cause leptin resistance or otherwise disturb the setpoint
Although I believe that exercise is part of a healthy lifestyle, it probably can’t explain the increase in fat mass in modern nations. I’ve written about that here and here. There are various other possible explanations, such as industrial pollutants, a lack of sleep and psychological stress, which may play a role. But I feel that diet is likely to be the primary cause. When you’re drinking 20 oz Cokes, bisphenol-A contamination is the least of your worries.
In the last post, I described two mechanisms that may contribute to elevating the body fat set point by causing leptin resistance: inflammation in the hypothalamus, and impaired leptin transport into the brain due to elevated triglycerides. After more reading and discussing it with my mentor, I’ve decided that the triglyceride hypothesis is on shaky ground*. Nevertheless, it is consistent with certain observations:
- Fibrate drugs that lower triglycerides can lower fat mass in rodents and humans
- Low-carbohydrate diets are effective for fat loss and lower triglycerides
- Fructose can cause leptin resistance in rodents and it elevates triglycerides (1)
- Fish oil reduces triglycerides. Some but not all studies have shown that fish oil aids fat loss (2)
Inflammation in the hypothalamus, with accompanying resistance to leptin signaling, has been reported in a number of animal studies of diet-induced obesity. I feel it’s likely to occur in humans as well, although the dietary causes are probably different for humans. The hypothalamus is the primary site where leptin acts to regulate fat mass (3). Importantly, preventing inflammation in the brain prevents leptin resistance and obesity in diet-induced obese mice (3.1). The hypothalamus is likely to be the most important site of action. Research is underway on this.
The Role of Digestive Health
What causes inflammation in the hypothalamus? One of the most interesting hypotheses is that increased intestinal permeability allows inflammatory substances to cross into the circulation from the gut, irritating a number of tissues including the hypothalamus.
Dr. Remy Burcelin and his group have spearheaded this research. They’ve shown that high-fat diets cause obesity in mice, and that they also increase the level of an inflammatory substance called lipopolysaccharide (LPS) in the blood. LPS is produced by gram-negative bacteria in the gut and is one of the main factors that activates the immune system during an infection. Antibiotics that kill gram-negative bacteria in the gut prevent the negative consequences of high-fat feeding in mice.
Burcelin’s group showed that infusing LPS into mice on a low-fat chow diet causes them to become obese and insulin resistant just like high-fat fed mice (4). Furthermore, adding 10% of the soluble fiber oligofructose to the high-fat diet prevented the increase in intestinal permeability and also largely prevented the body fat gain and insulin resistance from high-fat feeding (5). Oligofructose is food for friendly gut bacteria and ends up being converted to butyrate and other short-chain fatty acids in the colon. This results in lower intestinal permeability to toxins such as LPS. This is particularly interesting because oligofructose supplements cause fat loss in humans (6).
A recent study showed that blood LPS levels are correlated with body fat, elevated cholesterol and triglycerides, and insulin resistance in humans (7). However, a separate study didn’t come to the same conclusion (8). The discrepancy may be due to the fact that LPS isn’t the only inflammatory substance to cross the gut lining– other substances may also be involved. Anything in the blood that shouldn’t be there is potentially inflammatory.
Overall, I think gut dysfunction probably plays a major role in obesity and other modern metabolic problems. Insufficient dietary fiber, micronutrient deficiencies, excessive gut irritating substances such as gluten, abnormal bacterial growth due to refined carbohydrates (particularly sugar), and omega-6:3 imbalance may all contribute to abnormal gut bacteria and increased gut permeability.
The Role of Fatty Acids and Micronutrients
Any time a disease involves inflammation, the first thing that comes to my mind is the balance between omega-6 and omega-3 fats. The modern Western diet is heavily weighted toward omega-6, which are the precursors to some very inflammatory substances (as well as a few that are anti-inflammatory). These substances are essential for health in the correct amounts, but they need to be balanced with omega-3 to prevent excessive and uncontrolled inflammatory responses. Animal models have repeatedly shown that omega-3 deficiency contributes to the fat gain and insulin resistance they develop when fed high-fat diets (9, 10, 11).
As a matter of fact, most of the papers claiming “saturated fat causes this or that in rodents” are actually studying omega-3 deficiency. The “saturated fats” that are typically used in high-fat rodent diets are refined fats from conventionally raised animals, which are very low in omega-3. If you add a bit of omega-3 to these diets, suddenly they don’t cause the same metabolic problems, and are generally superior to refined seed oils, even in rodents (12, 13).
I believe that micronutrient deficiency also plays a role. Inadequate vitamin and mineral status can contribute to inflammation and weight gain. Obese people typically show deficiencies in several vitamins and minerals. The problem is that we don’t know whether the deficiencies caused the obesity or vice versa. Refined carbohydrates and refined oils are the worst offenders because they’re almost completely devoid of micronutrients.
Vitamin D in particular plays an important role in immune responses (including inflammation), and also appears to influence body fat mass. Vitamin D status is associated with body fat and insulin sensitivity in humans (14, 15, 16). More convincingly, genetic differences in the vitamin D receptor gene are also associated with body fat mass (17, 18), and vitamin D intake predicts future fat gain (19).
Exiting the Niche
I believe that we have strayed too far from our species’ ecological niche, and our health is suffering. One manifestation of that is body fat gain. Many factors probably contribute, but I believe that diet is the most important. A diet heavy in nutrient-poor refined carbohydrates and industrial omega-6 oils, high in gut irritating substances such as gluten and sugar, and a lack of direct sunlight, have caused us to lose the robust digestion and good micronutrient status that characterized our distant ancestors. I believe that one consequence has been the dysregulation of the system that maintains the fat mass “setpoint”. This has resulted in an increase in body fat in 20th century affluent nations, and other cultures eating our industrial food products.
In the next post, I’ll discuss my thoughts on how to reset the body fat setpoint.
* The ratio of leptin in the serum to leptin in the brain is diminished in obesity, but given that serum leptin is very high in the obese, the absolute level of leptin in the brain is typically not lower than a lean person. Leptin is transported into the brain by a transport mechanism that saturates when serum leptin is not that much higher than the normal level for a lean person. Therefore, the fact that the ratio of serum to brain leptin is higher in the obese does not necessarily reflect a defect in transport, but rather the fact that the mechanism that transports leptin is already at full capacity.
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lots of good comments by people. I was thinking when reading about sleep, I think we have it backwards people sleep poorly because they are sick not sick because of poor sleep.
healthy people naturally sleep enough and properly for the most part.tho the number of truly healthy people seems to be falling.
also if a persons fat cells are insulin resistant that cell cannot make enough leptin (how do the doctors know what amount you should have in blood based on fat cells status?)it needs glucose to stimulate leptin prodution.
high leptin levels means your leptin resistant in that the leptin is remaining in the blood and not reaching the brain, otherwise you leptin levels would rise and fall in a normal fashion.
wonder what affects this high leptin has on the organs like liver and adrenals and heart if they remain too high, like high insulin does when it remains in the blood at high levels too long.
anything in excess can cause harm to the organs I am sure, just like high adrenalin for too long causes diseases too. high cortisol too these hormones must remain in a flux to avoid poisening itself.
poor liver ends up being overloaded with detoxifying these hormones not to mention all the poisens in our enviroment too.
no wonder we are all having hard time getting and maintaining good vibrant health.
isn't our skin the biggest immune organ? doesn't it protect us first, then our gut? then our sinus or sinus first then gut?
when I used to read about leaky gut I thought ridiculous. not I understand what they meant.
as for omega 6, I don't think it is totally the culprit here, I think it the fact people are eating rancid rotted oils, those oils on the shelf have been burned and are dead oil that is rotting, like eating rotten meat that has been spiced to cover over the bad taste and smell. oxidized oils as it were, polyunsaturated fats cannot be cooked or burned or heated, after all healthy omega polys come from cold water fish cold climate nuts, that won't freeze in winter and have mild summers.
if you look at hot weather fats they get more saturated as the climate gets warmer. saturated fats are stable in hot weather where polyunsaturated fats break down. moderate climate that don't get very cold are the monos like peanuts grown in georgia, or olives grown in semi tropical climiates.
so it's type of fat is determined by the climate it grows in. so maybe if we all live in tropical we should only consume saturated fats that are natural not the processed hydrogenated crap they try to pass off as saturated fats or confused with sat fats from natural sources.
by the way dr oz and his brother, are just in it for the money. they advocate whatever they are paid for, after all they are probably making more money doing a tv show then being real doctors at a hospital.
I saw them slamming saturated fat as causing heart disease, if they are reading the same stuff I am then they know that aint true, but who is paying them to say that? if they are talking about manmade sat fat from oils and don't tell others that is what they mean they are guilty of fraudulent concealment.
he has right to say what he wants, but he must take responsiblity for how it affects others, he has a md by his name and people put faith in him, so he has a higher responsiblity to watch what he says. regular joe says the same things they won't take it as seriously guess that is why they are willing to pay these doctors so much to say what they want to give the info strong credibility.
wonder how many people have died of heart disease because they replaced good sat fat with rancid veggies oils touted as better than sat fats per doctors recommendations? or ate low fat and more carbs, that died from same?
RRR
Hi everyone,
A new study was just published in Science linking intestinal bacteria to obesity. The researchers found that Increased appetite and insulin resistance can be transferred from one mouse to another via intestinal bacteria.
Looks like the theory that gut dysbiosis is at least partially responsible for obesity is gaining ground.
Chris
Stephen I've been following your blog for a while and find it very interesting.
I've noticed that recently you've changed your stance on dietary fiber and now recommend prebiotic fiber such as FOS, inulin and resistant starch as important for modifying the gut flora.
I followed this approach a couple of years ago and my health declined.
Recently, having heard the new wave of buzz about inulin, started taking 10 grams a day, and then upped to 15.
I felt fine and my digestion may have slightly improved but my sex drive, which is normally high, dropped way down.
It's well known that high soluble fibre diets reduce testosterone levels and I believe a high dose of inulin will do the same.
Given low T levels correlate with low insulin sensitivity is it really a great idea to increase fiber greatly?
Also it's worth noting that low amounts of inulin, like 1 gram, which you can get from one half onion have been shown to positively alter gut flora, and this amount would not lower sex hormone levels.
This amount probably would not reduce the ph of the colon like high doses would though and would not create very high levels of butyrate.
In previous posts you note that the Japanese only eat small amounts of fibre but are very healthy. Clearly these people dont have high levels of butyrate yet are still healthy?
I'm interested in this because I can see all the potential benefits to taking inulin but am not sure that it will help everyone's health…
Dony
No defense required.
I am totally green as far as most of this is concerned, but fascinated.
This is interesting. Prolactin was expressed in early peradipocyte differentiation.
http://www.ncbi.nlm.nih.gov/pubmed/16630538
And in adipose and visceral tissue,
"In addition to being a circulating hormone of pituitary origin, PRL in humans is produced by nonpituitary sites, including the endometrium, decidua, lymphocytes, brain, breast, and prostate, where it acts as a cytokine"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579649/?tool=pubmed
Okay, this is why you shouldn't just read the first line of a study. In my own defense,
"Hyperprolactinemia is associated with obesity. Furthermore, in human adipose tissue cultured in vitro, prolactin (PRL) inhibited lipoprotein lipase (LPL) activity via functional PRL receptors."
I assumed the inhibition of lpl activity was within the cell, decreasing breakdown of already stored fat. I guess I have to read up on how fat is broken down in the fat cell itself, I only assumed lpl was involved because of the context of that quote.
===========================
Insulin is the primary hormone acting by increasing lipogenesis. Both insulin and PRL (36) enhance the differentiation of fibroblasts and preadipocytes into mature adipocytes. Therefore, the reduction in PRL plasma levels is likely dependent on the lowering of insulin plasma concentration which, in turn, produces the reduction in LPL adipose tissue expression. On the other hand, the large increase in insulin sensitivity did not influence PRL secretion, whereas insulin secretion did.
In conclusion, lipid malabsorption but normal calorie intake rather than reduced calorie intake in severe obesity might be related to the net improvement in PRL secretion after weight loss, which became similar to the values reported in the literature for healthy women (15), even in the face of persistence of a frank obesity. Furthermore, the reduced expression of LPL in the adipose tissue observed after bariatric surgery, being significantly correlated with the decrease in insulin and PRL, suggests a role of hyperinsulinemia and hyperprolactinemia in inducing and maintaining obesity
==================================
At this point, although I'm as green as it gets when it comes to prolactin, my guess is that the drop in insulin is the obvious cause of the drop in lipoprotein lipase.
The subjects in this study went through bilio-pancreatic surgery, a more severe form of gastric bypass causing extreme malabsorption of fat.
"Discussion: The restriction of lipid metabolizable energy rather than weight loss seems to be responsible for both reduction in PRL circulating levels and normalization of its secretion rhythm after bariatric surgery."
The other study you posted, Robert, may have involved a gentler form of bariatric surgery more friendly to fat absorption.
^ Thanks Dony
Conflicting results ?
Any thoughts ?
http://www.nature.com/oby/journal/v16/n8/full/oby2008297a.html
"In this study we found that severely obese women, following major weight reduction as a consequence of malabsorptive bariatric surgery, had a significant lowering of plasma PRL levels during the whole day."
http://www.springerlink.com/content/un4767k86p754486/
Basal PRL levels were neither significantly correlated with the BMI of the subjects (r = −0.05, P = 0.77) nor with any other of the assessed variables (all r < 0.16, P > 0.06) even after adjusting for the influence of sex. After massive surgically induced weight loss that on average almost approached 50 kg, basal serum PRL levels remained completely unchanged (before vs. after, 9.1 ± 6.0 vs. 9.2 ± 4.6 μg/l, P = 0.86).
http://www.nature.com/oby/journal/v16/n8/full/oby2008297a.html
For full disclosure, all I've read is the first line;
"Background: Hyperprolactinemia is associated with obesity. Furthermore, in human adipose tissue cultured in vitro, prolactin (PRL) inhibited lipoprotein lipase (LPL) activity via functional PRL receptors."
Lipolysis inhibits leptin secretion. Prolactin decreases lipolysis in adipose tissue. This should increase leptin levels. If the hyperprolactin state is chronic, body fat might increase. Anything that chronically shuts down lipolysis should increase both leptin levels and fat levels. This would tend to cause increased levels of leptin with obesity, is this necessarily leptin resistance?
The rat pseudopregnancy study;
"Central icv injection of leptin had no effect on food intake in pseudopregnant rats receiving chronic ovine prolactin. These results suggest that chronically high lactogen levels, secreted by the placenta during the second half of pregnancy, induce central leptin resistance."
The assumption there is that non-central administration of prolactin caused central leptin resistance. Communication between the hypothalamus and the rest of the body is hardly one-way.
Induced hyperleptinism in non-obese rats causes decrease in appetite, and depletion in fat mass. Once the fat is gone, leptin's affect on appetite decreases. The rats continue to have little desire for carbohydrate, but the appetite for protein increases.
http://ajpregu.physiology.org/cgi/content/full/293/4/R1468
This is when the rats are offered self-selected diets of carb, protein, fat. How could they prefer protein over carb if their food is offered in pellet-form? For some, butter and potatoes– to taste– might not be fattening, where french fries might. Any study of leptin "resistance" where the subjects can't self-select among the macronutrients is highly suspect.
"Leptin rats exhibited a dramatic increase in protein intake, whereas controls exhibited a strong carbohydrate preference. Fat intake did not differ between groups at any time during the 8-day test. Despite these dramatic differences in macronutrient selection, total daily caloric intake did not differ between groups except on day 2. Thus controls of food intake related to ongoing metabolic and nutritional requirements may supersede the negative feedback signals related to body fat stores."
That last part is what makes me suspect that the more important work done by leptin is permissive, rather than prohibitive; encouraging the use of fat for energy rather than inhibiting its storage. Rather than inhibiting hunger, satisfying it.
I just found your blog, and I like it very much. I'm a celiac that eats paleo, and was a biochemisty/genetics student for a few years. rock on!
That gut bacteria thing… I can't imagine a change in diet that wouldn't have profound effects on gut bacteria. Resveratrol, extra glycine, potassium, sodium, high fat, low fat…olestra, polyunsaturated fat (bacteria that cope well with omega 6 might be nastier than those that cope well with omega 3…)
Bitter compounds might cause rodents to eat less… or it might make their bacteria behave.
I thought I'd read a full article on that tryptophan/serotonin thing, but all I can find now are abstracts.
——————————–
Growth-retarded rats fed a tryptophan deficient diet at 21 days for periods of 6-22 months were shown to reach normal body weight when subsequently fed Purina Rat Chow. They demonstrated an increased ability over similar aged controls to recover from hypothermia induced by 3-minute whole-body ice water immersion, were able to bear litters at 17–28 months of age, showed a delay in the age of onset of visible tumors, and indicated an increase in their average lifespan at late ages. Animals fed on this diet from 3 months of age revealed a similar ability to reproduce at advanced ages, but not as marked as those placed on the diet earlier. The average lifespan (in months +/- the standard error of the mean) of the rats recovering from the long-term tryptophan-deficient diets was 36.31 +/- 2.26 while the control rats survived an average of 30.5 +/- 1.90 months. The last of 8 rats surviving the period of tryptophan-deficiency died at 45.50 months (1387 days) while the last of 14 control rats died at 41.75 months (1266 days). It is hypothesized that some kind of subtle mechanism exerts its influence on the rats during the period of tryptophan deficiency which caused an accelerated morbidity and mortality as they approached senescence approximately 1 to 2 years after refeeding. This is parallel to the situation with immature animals subjected to long-term caloric restriction and then fed on normal diets.
———————————
http://www.ncbi.nlm.nih.gov/pubmed/22255
I was just reading an excerpt on googlebooks that claimed that tryptophan restriction caused voluntary calorie restriction in rats, and that it was this rather than any effect on serotonin that was the cause of the longevity. I think you get in trouble looking for first causes. If serotonin is involved in the pleasure received when eating carbohydrate, tryptophan restriction might decrease appetite, especially for carbohydrate. Methionine might have a similar effect; after eating glucose, protein synthesis increases, pulling competing amino acids out of the blood stream, which increases the transport of tryptophan across the blood brain barrier. Restricting a growth-limiting amino acid such as methionine might leave a greater ratio of these competing amino acids in the bloodstream, decreasing tryptophan transport in a manner similar to tryptophan restriction itself. I can't seem to find much about that last so far, although there is a case study of serotonin syndrome involving a serotonin reuptake blocker used in conjunction with SAMe– but that could be caused by the reuptake blocker by itself.
^
I said
"You were pondering why nature would want an insulin resistance mechanism."
I meant to say leptin not insulin. (-:
Indeed I do not recall you pondering on insulin resistance, but do recall a comment on leptin resistance.
Is leptin resistance in pregnancy not a form of leptin resistance? Does it not depend how you define leptin resistance? (-:
How do you define leptin resistance, or perceive other define it.
RA Brown
Hi, I never pondered why nature would create an insulin resistance mechanism.
From my point of view, most forms of insulin resistance fall into one of two categories. "Physiological" insulin resistance, the sort that happens during stress, starvation, and seasonal weight gain… and "pathological" insulin resistance, the sort inducted by damage to mitochondria, major mitochondrial genetic defects, or genetic/inducted defects in secondary systems (e.g. profound hypoleptinemia secondary to fat cell depletion will cause pathological insulin resistance, diabetes, very high cholesterol and such).
The relationship between impaired leptin signaling and prolactin is expected, and it is not leptin resistance. This is physiological and corrected when prolactin is adjusted to a normal range (sufficient dopamine, no excess of serotonin, not post partum).
ItsTheWoo
You were pondering why nature would want an insulin resistance mechanism.
I found this as usual looking for something else.
In pregnancy prolactin appears to block the effect of leptin in the brain.
This makes sense as women ideally need to put no weight in pregnancy to provide an insurance reserve and prepare for the energy demands of lactation.
And at the same time there is a make more leptin message, which if leptin is essential to pregnancy would make sense too.
Induction of Central Leptin Resistance in Hyperphagic Pseudopregnant Rats by Chronic Prolactin Infusion
http://endo.endojournals.org/cgi/content/full/149/3/1049
But at the same time may increase letpin secretion by adipose tissue
Prolactin Stimulates Leptin Secretion by Rat White Adipose Tissue
http://endo.endojournals.org/cgi/content/abstract/140/11/5149
I'm disappointed awriter never returned. I was curious as to what her leptin level actually was.
I suspect it is probably between 10-15, which isn't terribly high at all, and is actually rather low for a 145 pound woman.
Reading more about awriter's experiments, it seems as if she is taking pure T3, which thereby resulted in improved energy and reduced cholesterol levels. For some reason she thinks this is becuase of reduced leptin resistance, which makes very little sense, as it is well known low energy and high cholesterol are a result of low thyroid function.
Her low thyroid may be because of leptin resistance, but it could be many things. It might even be hypoleptinemia (awriter seems to think that a leptin >10 is high, this is very false when applied to females, and for a female, a leptin of 10 is actually on the low end of normal).
Or, the thyroid thing might not have anything to do with leptin. Eating an extremely low carb/calorie diet can also cause functional hypothyroidism (decreased conversion of t4 to t3).
Lots of leaps of logic going on here.
^ Re the above on leptin cell migration and cancer.
Delicate and complex dances of intertwined paths we tread it seems.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804604/?tool=pubmed
"Additionally, epidemiological studies underline that obesity represents a significant risk factor for the development of cancer, although the exact mechanism of this relationship remains to be determined."
"Functional leptin receptors are found to be expressed on diverse cancer cells derived from different tissues such as breast, colon or prostate [26-30]. The breast cancer cell lines HTB-26 and ZR75-1 [27], the prostate cancer cell lines DU145 and PC-3 [30], and various colon carcinoma cell lines such as LS174T and HM7 [29] as well as SW480, SW620 and HCT116 [26] all express OB-Ra and OB-Rb. In breast cancer cell lines and in human primary breast carcinoma leptin receptor has been demonstrated to occur in combination with leptin. Therein, leptin is able to induce the growth of these cells via different pathways, can mediate angiogenesis by inducing the expression of VEGF, and promotes invasion and migration by transactivation of the epidermal growth factor receptor (EGFR) [15]. A bidirectional crosstalk between leptin and insulin-like growth factor-I (IGF-I) signaling was also shown to stimulate invasion and migration of breast cancer cells [31]."
^
Re the melatonin trial above Fig 3 suggests leptin rises with age, and melatonin supplementation is associated with a significant reduction in leptin levels back down towards the leptin levels of youthful rats.
Dony
Thanks for those thoughts.
Do you have a link for the rat / tryptophan trial.
In terms of puberty signalling I am not sure that you can equate animals and humans.
I suspect melatonin is involved here some where, and it seems that there are interesting differences between species.
http://www.reproduction-online.org/cgi/reprint/94/1/97
Nocturnal activity is going to complicate comparisons.
Ted
Thanks for the link, that was useful and interesting.
On weight and sleep there are a number of factors that could explain the links between sleep and obesity.
Thanks to a thought provoked by your comment I just found this which helps add to the argument.
Visceral fat content has been suggested to link to a number of western conditions.
A trial suggests melatonin administration in middle aged rates suppressed visceral fat accumulation.
http://endo.endojournals.org/cgi/content/abstract/140/2/1009?ijkey=38afe48d213a244995e70de4cb3682e5f05be928&keytype2=tf_ipsecsha
Every thing it seems is interlinked at some level.
Hi Helen,
I think it's entirely possible.
Speaking of leptin and melatonin…
"Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity."
http://www.ncbi.nlm.nih.gov/pubmed/19117547
Orexin is sort of an alert-making hormone, helpful in consolidating the sleep and awake periods. People with narcolepsy have disrupted orexin, rodents bred to lack orexin are narcoleptic.
Tryptophan restriction increases rat lifespan, and delays sexual maturity. Refed tryptophan, rats breed at an age at which they would normally be dead. One theory is that low serotonin levels explain both the delayed maturation and longevity.
"Differential effect of orexins (hypocretins) on serotonin release in the dorsal and median raphe nuclei of freely behaving rats"
http://cat.inist.fr/?aModele=afficheN&cpsidt=18027120
Mice that over-produce orexin generate lots of amyloid plaque and end up with mouse-alzheimer's.
One more thing… fasting and long term calorie restriction decrease leptin levels, but increase orexin.
Malpaz, this may be a long shot, but what are your sleep patterns like?
@ Mark
sleep is important, but I think the notion that a lack of it causes obesity is a bit far fetched.
& Helen
affected by disturbances in normal patterns of light/dark/sleep,
interesting series of 30minute talks here
enter MELATONIN in searchbar and you'll find
Basic science of circadian rhythms, melatonin and melatonin receptors
Pancreatic Melatonin Receptors: From Fiction to Function
The genetics of the melatonin receptor 1B in type 2 diabetes
Stephan,
If you're still reading…
I know you aren't considering environmental toxins a big player in the rise in obesity, but from bits and pieces I've read, they seem to have a measurable impact. Do you think a possible scenario could be a synergistic effect?
For instance, an animal could be somewhat affected by bromides/phthalates/BPA, and somewhat affected by refined fructose and vegetable seed oils, and somewhat affected by gut-disrupting substances (BTW – have you checked sucralose?), and somewhat affected by disturbances in normal patterns of light/dark/sleep, but put two to four of these factors together and you have a perfect storm?
It seems that we live in a metabolic chamber of horrors.
Great information. Looking forward your next post
great post!
^
So many questions
http://cat.inist.fr/?aModele=afficheN&cpsidt=17616849
"Leptin and Ob-Rb were expressed in hyperplastic polyps, adenoma, and adenocarcinoma. In the gastric adenocarcinoma, leptin was expressed significantly less in the poorly differentiated and diffuse-type groups than in the well-differentiated and moderately differentiated groups or in the intestinal type. Based upon our findings, we suggest the possibility that leptin expression can have a pathophysiologic role about the differentiation or growth pattern of gastric adenocarcinoma. A further series of experiments is necessary to elucidate the pathophysiological role of leptin in the differentiation of gastric adenocarcinoma."