Leptin is a major hormone regulator of fat mass in vertebrates. It's a frequent topic on this blog because I believe it's central to overweight and modern metabolic disorders. Here's how it works. Leptin is secreted by fat tissue, and its blood levels are proportional to fat mass. The more fat tissue, the more leptin. Leptin reduces appetite, increases fat release from fat tissue and increases the metabolic rate. Normally, this creates a "feedback loop" that keeps fat mass within a fairly narrow range. Any increase in fat tissue causes an increase in leptin, which burns fat tissue at an accelerated rate. This continues until fat mass has decreased enough to return leptin to its original level.
Leptin was first identified through research on the "obese" mutant mouse. The obese strain arose by a spontaneous mutation, and is extremely fat. The mutation turned out to be in a protein investigators dubbed leptin. When researchers first discovered leptin, they speculated that it could be the "obesity gene", and supplemental leptin a potential treatment for obesity. They later discovered (to their great chagrin) that obese people produce much more leptin than thin people, so a defeciency of leptin was clearly not the problem, as it was in the obese mouse. They subsequently found that obese people scarcely respond to injected leptin by reducing their food intake, as thin people do. They are leptin resistant. This makes sense if you think about it. The only way a person can gain significant fat mass is if the leptin feedback loop isn't working correctly.
Another rodent model of leptin resistance arose later, the "Zucker fatty" rat. Zucker rats have a mutation in the leptin receptor gene. They secrete leptin just fine, but they don't respond to it because they have no functional receptor. This makes them an excellent model of complete leptin resistance. What happens to Zucker rats? They become obese, hypometabolic, hyperphagic, hypertensive, insulin resistant, and they develop blood lipid disturbances. It should sound familiar; it's the metabolic syndrome and it affects 24% of Americans (CDC NHANES III). Guess what's the first symptom of impending metabolic syndrome in humans, even before insulin resistance and obesity? Leptin resistance. This makes leptin an excellent contender for the keystone position in overweight and other metabolic disorders.
I've mentioned before that the two most commonly used animal models of the metabolic syndrome are both sugar-fed rats. Fructose, which accounts for 50% of table sugar and 55% of high-fructose corn syrup, is probably the culprit. Glucose, which is the remainder of table sugar and high-fructose corn syrup, and the product of starch digestion, does not have the same effects. I think it's also relevant that refined sugar contains no vitamins or minerals whatsoever. Sweetener consumption in the U.S. has increased from virtually nothing in 1850, to 84 pounds per year in 1909, to 119 pounds in 1970, to 142 pounds in 2005 (source).
In a recent paper, Dr. Philip Scarpace's group (in collaboration with Dr. Richard Johnson), showed that a high-fructose diet causes leptin resistance in rats. The diet was 60% fructose, which is extreme by any standards, but it caused a complete resistance to the effect of leptin on food intake. Normally, leptin binds receptors in a brain region called the hypothalamus, which is responsible for food intake behaviors (including in humans). This accounts for leptin's ability to reduce food consumption. Fructose-fed rats did not reduce their food intake at all when injected with leptin, while rats on a normal diet did. When subsequently put on a high-fat diet (60% lard), rats that started off on the fructose diet gained more weight.
I think it's worth mentionong that rodents don't respond to high-fat diets in the same way as humans, as judged by the efficacy of low-carbohydrate diets for weight loss. Industrial lard also has a very poor ratio of omega-6 to omega-3 fats (especially if it's hydrogenated), which may also contribute to the observed weight gain.
Fructose-fed rats had higher cholesterol and twice the triglycerides of control-fed rats. Fructose increases triglycerides because it goes straight to the liver, which makes it into fat that's subsequently exported into the bloodstream. Elevated triglycerides impair leptin transport from the blood to the hypothalamus across the blood-brain barrier, which separates the central nervous system from the rest of the body. Fructose also impaired the response of the hypothalamus to the leptin that did reach it. Both effects may contribute to the leptin resistance Dr. Scarpace's group observed.
Just four weeks of fructose feeding in humans (1.5g per kg body weight) increased leptin levels by 48%. Body weight did not change during the study, indicating that more leptin was required to maintain the same level of fat mass. This may be the beginning of leptin resistance.
25 comments:
Is the implication then that we should avoid fruit all together?
Thanks
sverlyn - note the human study used 1.5 g/kg fructose. So a 150 pound person would get ~100 grams of fructose.
Now look at the fructose content of, say, apples.
http://www.nutritiondata.com/facts/fruits-and-fruit-juices/1809/2
A very large, 1/2 pound (223 gram) apple, contains 15.5 grams of fructose.
So you'd have to eat ~6-7 of those apples to hit 102 grams of fructose.
One apple per day is probably fine, and includes some beneficial phytonutrients (eat the skin!!). 6-7 very large apples per day would be bad for you.
Now, one super-sized coke from McDonalds:
http://www.nutritiondata.com/facts/foods-from-mcdonalds/6298/2
contains around 56 grams of fructose. And no redeeming qualities.
Stephen -- by what mechanism does fructose cause leptin insensitivity ("resistance")? Has anyone figured that out yet?
Secondly, once you get leptin resistance, does it go away if you stop eating fructose?
Also -- when fructose is converted into triglycerides, is there anything interesting about the particular forms they take? Are they short, medium, or long-chain? Saturated? Easily stored in adipose tissue, or ectopically? Are there analogous dietary triglycerides that might have some of the same effects that the fructose-derived triglycerides have?
You say, "Elevated triglycerides impair leptin transport from the blood to the hypothalamus." That prompts a whole line of other questions.. like perhaps that is one way intermittent fasting is good, because maybe it (at least temporarily) lowers triglycerides. (I don't know for sure, just guessing here.) I wonder what else can cause blood triglyceride levels can change.
Sverlyn,
No I don't think so. We've been eating fruit for millions of years, I think it's simply a matter of degree.
Ed,
Impairment of blood-brain barrier transport of leptin and impairment of hypothalamic leptin-responsive pathways are the mechanisms they mentioned in the paper. There may be others. I would bet it's reversible.
The liver makes palmitic acid primarily, a saturated fat. That's true whether it's getting glucose or fructose, I believe. I don't think the palmitic acid itself is the problem, it's just excessive triglyceride in general.
Thanks Stephan for all you hard work and thought provoking posts.
In the last trial I could not see any indication of the calorie intake eg sufficient or greater than metabolic need.
It would have been interesting to know how the fat intake was made up.
The wider interaction of leptin, fructose and insulin set my head spinning.
These are some of my thoughts on wider fructose / Omega 6 related issues.
Fruits are seasonal in the wild. Fruits contains fructose glucose and Omega 6 in their seeds (think bears and berries). Omega 6 indirectly controls breeding behaviour (aggression impulsiveness etc) and through downstream chemicals, the production of sex hormones and steroids.
Omega 6 stores are necessary for future supplies of breast milk, hormones, and necessary to build babies.
It would make sense to have a mechanism to reduce energy production and increase storage when Omega 6 and fructose was available in the food chain, so Omega could be stored along with other fats.
I theorise that fructose combined with Omega 6 may in a situation of excess energy intake push the body to store fat to a greater extent than glucose, and through complimentary mechanisms.
Fructose looks like it is a competition with itself over leptin. Fructose increases leptin and increases a mechanism related to fat production and elongation SCD1. Leptin tries to reduce SCD1.
I guess that fructose ultimately wins the argument.
Insulin joins in as it also tries to increase SCD1. Omega 6 long chain products increase insulin, and insulin increases the production of long chain Omega 6 (uprating desaturase function)so creating a self fuelling loop.
So insulin and fructose by promoting fat production through SCD1 related mechanisms battle against leptin trying to reduce SCD1. Ultimately leptin's attempts to increase metabolism and decrease appetite are overridden by fructose.
Fructose does not compete for insulin, and it seems does not need it to enter the muscles or fat cell.
Fructose unlike glucose and leptin increases hunger.
I think I have read fructose is metabolised much more quickly.
Nature does things for a reason. For me the image is visible in the mist that fructose (with Omega 6) signals the food chain that is abundant, which in an energy surplus situation tells the body to store fat.
In nature if fructose and omega 6 was plentiful it would only be because the environment was fruitful. You would not find high Omega 6 and fructose in a normal low energy scenario.
Fructose and Omega 6 was a message from nature to stuff yourself silly because this glut was surely not going to last. We innocently have overridden the operating parameters with year round excess Omega 6, fructose, and the carbs that come with fructose.
Robert Brown
Author Omega Six The Devils Fat
www.Omegasixthedevilsfat.com
Re the above. Just for clarification - thanks for your patience and possible interest.
I am suggesting that Omega 6 creates a self blocking insulin loop, and that fructose creates a leptin blocking loop because fructose is both instructing directly to increase fat creation, but at the same time by increasing leptin trying to block the same SCD 1 related mechanism.
If ultimately of relevance these self blocking loops may be contributory or causal in metabolic syndrome.
On the topic of rats not responding to high-fat diets, the last study I saw on rats eating a high-fat diet had the rats consuming 25 % more calories than the standard carbohydrate diet rats:
Maternal High-Fat Diet and Fetal Programming: Increased Proliferation of Hypothalamic Peptide-Producing Neurons That Increase Risk for Overeating and Obesity
See Figure 1, Caloric Intake.
Interesting and thought provoking post.
Re. the question about eating fruit, don't forget that in the experiment, the rats were being fed a 60% fructose diet. This was most likely achieved by restricting food sources available to the rats to something that was prepared to have the specific macros and nutrients required for the experiment. Eating apples isn't likely to have an effect, because you're eating the whole apple, getting a load of other nutrients with it, and it's likely to be one food source in your overall diet.
I had a question about fat consumption. If consuming fructose increases blood triglycerides, wouldn't consuming fat also increase them? Or does that get processed through a different mechanism?
Robert wrote:
"Fruits are seasonal in the wild. Fruits contains fructose glucose and Omega 6 in their seeds (think bears and berries)."
Contrary to fruit juices, fruit consumption is associated with reduced risk of diabetes in various epidemiological studies.
I think that it is important to have a sense of proportion. How much omega-6 one actually get by eating one portion of berries or fruits? The seeds of fruits and berries are not a notable source of omega-6 fats.
Juhana
said ---- How much omega-6 one actually get by eating one portion of berries or fruits? The seeds of fruits and berries are not a notable source of omega-6 fats. ----
Yes I agree but bears do not restrict themselves to single portions. The seeds are high in Omega 6 just you need a lot of them.
Sources of Omega Six other than in plant reproductive material are very low if almost everywhere in the plant kingdom, but our gut processing capacity for grass and greens is low (-:.
So as always we are back to balance moderation food value in terms of nutrient density, overall intake, etc. Less sweet apples are probably better and more nutrient dense.
All of which leaves the wider debate do we function better on carbs or fats or both a subject of contention (-:
Here is an article on fructose that cites the trial Stephan refers to
http://www.news.health.ufl.edu/news/story.aspx?ID=5173
Fructose hampers hormone that controls appetite, UF study finds
Robert M
Thank you for that link.
20% of the intake was vegetable oils which would likely be high in Omega 6. Omega 6 increases fat cell capacity in neonate rats.
Extracted fructose is associated with increased risk but not fructose that comes along with whole fruits. Look Bazzano LA et al. Intake of Fruit, Vegetables, and Fruit Juices and Risk of Diabetes in Women. Diabetes Care. 2008 Jul;31(7):1311-7.
Juhana,
Thanks for that trial link it is useful in its confirmation that fruit juices (as against whole fruit and veg )are an issue in the risk of diabetes.
Robert,
Those are interesting ideas. So you think insulin and leptin get caught in positive feedback loops due to superphysiological amounts of fructose and n-6?
We do have unnaturally high insulin and leptin levels in Western industrial nations. Even so-called healthy people typically have higher insulin and leptin than the average Kitavan for example.
Zaphrus,
In my opinion, the main difference between fruit and sugar is that it's difficult to get as much sugar from fruit as you would from a couple of sodas for example. If you only took a quarter can of soda a day, it probably wouldn't be a problem. There's also the matter of nutrient content that may play a role, but the speed of digestion isn't very different whether it's whole fruit or a slice of cake.
I don't know the mechanism, but high-fat diets result in lower fasting blood triglycerides than high-carbohydrate or high-sugar diets. Dietary fat is made of triglycerides, so I'm not clear on why that is, but it's empirically true.
stephan,
this paper doesn't really explain the mechanism but it does say that the body is pretty confused by fructose intake which leads to elevated TG storage in the liver (not a good place to store it) along with the elevated insulin levels (implied) from the body attempting to store more glycogen.
Dietary fructose induces a wide range of genes with distinct shift in carbohydrate and lipid metabolism in fed and fasted rat liver:
http://www.ncbi.nlm.nih.gov/pubmed/18346472?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Hi Stephan,
Wondering what you make of this study showing that saturated and monounsaturated fat lead to greater atherosclerosis than polyunsaturated fat in monkeys (over a 5 year period)?
http://atvb.ahajournals.org/cgi/content/full/15/12/2101
I realize monkeys aren't the same as people, but neither are rats, and the results are interesting...Also interesting is the huge individual variation (4 orders of magnitude) among monkeys that were on the same diet and subject to the same environment...
Hi Stephen,
This is very interesting, however as a human with acquired leptin deficiency (secondary to massive weight loss) I have studied a great deal about it... and I conclude that the obese are NOT leptin resistant.
Resistance indicates that there are no receptors, or insufficient numbers of receptors, to receive the physiologically adequate message from a signaling molecule (e.g. insulin resistance means insufficient functioning insulin receptors). The obese are NOT leptin resistant in this sense.
It is probably more accurate that the effects of leptin are partially blocked by the disease process of obesity. Some research indicates high triglycerides prevent leptin from entering the blood brain barrier. This makes sense since high triglycerides are part of the acute fattening process.
The obese are not leptin resistant because of two reasons. Reason one is that a low carbohydrate diet will result in spontaneous weight loss; if the obese were leptin resistant, NOTHING would work besides starvation (a lack of free access to food). Reason two is that a lot of complications of obesity stem from high levels of leptin. The high rate of sex steroid cancers (especially of the breast) and enlargement of the heart muscle are associated with hyperleptinemia. If there was a resistance to leptin, we wouldn't see excessive leptin action on breast and heart tissue like that.
Rather what is going on is that leptin is not adequately expressed in the BRAIN only and this is related to high triglycerides (i.e. storing fat often).
If leptin were injected directly into the ventricles of someone with high triglycerides, they would most likely respond as any metabolically normal person would.
Think about it... why would people suddenly be able to "see" all of their fat tissue upon going on a low carb diet? Why does appetite drop spontaneously, why do we find it nauseating to over eat, whereas just days ago we were never full? This would not be possible if the obese were truly leptin resistant. Part of that answer is leptin expression is more active in the brain when we are low carbing, because low carbing brings down triglycerides a lot, because insulin comes down a lot.
David,
I just took a look. Very few differences in that paper are statistically significant, and most of them aren't even close. It looks like the only reason atherosclerosis was significantly higher in the saturated group is there was a major outlier in it. It had more than twice as much atherosclerosis as any of the other monkeys in any group. There's no way there would have been a significant difference without that outlier. Of course, that was the one finding they seized on for the title. I think they should have binned the outlier because it was so different from the others in its group, or at least qualified their statistics with an explanation.
I couldn't find the specific composition of the different diets in the paper. How much n-3 was in each diet, was it the same between groups? If n-6 came from canola or soy oil, the n-6 group could have had a better n-6/n-3 ratio than the other groups. Was the saturated group also getting trans fat or sugar (often the case)? They don't say, unless I missed it. Also, what's the natural diet for a green monkey? Maybe it's adapted to seeds and nuts, in which case it would do just fine with n-6. I would have to learn more to be able to interpret that study, and unfortunately they don't provide the information you would need in the paper.
Itsthewoo,
Leptin resistance is just an inability to respond to leptin. In that sense, obese people are leptin resistant in the hypothalamus. Otherwise, they wouldn't be obese. The hypothalamus can't hear the fat tissue, which is screaming 'stop eating'! Leptin receptors are actually upregulated in the hypothalamus, as I think you alluded to, but the leptin isn't getting to them accross the BBB and even if it does, the intracellular response is attenuated (if you believe the mouse study).
As with insulin resistance, leptin resistance isn't necessarily the same in all tissues. There may be varying degrees of sensitivity. But at the most empirical level, it's clear that hypothalamic control of feeding behavior becomes resistant to the action of leptin in the obese.
David
Good find.
The trial raises some really interesting question for me as a proponent of a lower Omega 6 intake.
At the most basic level many western conditions are based in inflammation and oxidative stress. Omega 6 is more prone to oxidation than sat or mono fats. (Omega 3s have less inflammatory products). So more Omega 6 where antioxidant protection (internally produced and or external dietary) is insufficient means more oxidative stress and inflammation.
I guess human are more susceptible to oxidative stress than primates due to our bigger brains creating a higher baseline need.
Primates don't eat human diets high in oxidised fats even in lab trials I guess.
I would like to know more about the basic diet used its Omega 3 content, its antioxidant and macro nutrient content, the level of processing, the forms in which the oils were given (hydrogenated to nay extent?), the antioxidant status of the oil (vit e added? phenols sterols etc).
Did it include chips crisps hydrogenated oils, interestified oils, fat in bakery products, partially oxidised frying oils, oxidised cholesterol, cook chill, etc - Self evidently it is very unlikely primates in labs are fed diets like this. But these products combined with excess carbohydrates are likely to be what starts the oxidative stress, that triggers the oxidation of Omega 6, that increases the downstream Omega 6 inflammatory cascade and the oxidation that accompanies it.
For Omega 6 to do damage it has to be released from the membranes and oxidised. If that does not happen and the Omega 6 fats is burnt effectively in the mitochondria then the consequent damage will not occur.
Are primates less prone to oxidative stress? At an evolutionary level how does a smaller brain impact on antioxidant needs?
Most of the trials 8 9 10 11 12 13 cited were from the 60s and 70s when processed food(oxidised fats) were much less used, stored Omega 6 levels were much lower, what did saturated mean (processed lard?), what was the antioxidant status of the oil used, processed carbohydrate intake was lower, energy intake was lower, obesity was lower etc.
The first trial relates low plasma LA to coronary events but notes as risk factors higher desaturase activity and higher Omega 9s, and lower long chain Omega 6 AA arachidonic acid. Low LA can be due to low dietary intake, but lower intake does not necessarily result in lower membrane AA, as membrane AA may also be dependent on the oxidation rate. High oxidation of AA would be consistent with inflammation, and oxidation. High levels of oxidation and inflammation correlate will with oxidative stress and higher risk of a cardiac event.
Omega 9s reduce susceptibility to oxidation compared with LA which may help account for the positive cardiac effect of the Mediterranean diet.
For me the key is in the relationship between ill health inflammation and oxidation. Excess Omega 6 increases the risk of uncontrolled oxidation and inflammation, so reduction of intake is a good risk reduction strategy.
Yes Omega 3s are inseparable form Omega 6. Omega 3 blocks Omega 6 activity etc, But in nature availability of both 18 carbon fats is low, and trials show we need ½-2% only of calories.
Antioxidants minerals vits A D K etc are key to function and anti oxidation/oxidant balance, but excess dietary Omega 6 is stacking up the eicosanoid (downstream omega 6 chemicals) fuel dump, and all it need is the torch. Modern dietary trends provide the torch to light the Omega 6 fuel of inflammation and oxidative stress.
Robert Brown
Author Omega Six The Devils Fat
www.omegasixthedevilsfat.com
its the woo,
don't forget that there are 5 or 6 different types of leptin receptors including one that is soluble in plasma (ObRe). only one form of the receptors (the long form, ObRb)when activated leads to signal transductionn in cells (hypthalamus, fat cells, macrophages and many other cell types), the uses of the other receptors still remain largely unknown.
interesting note,
i got to hear Dr. friedman (one of the discoverers of leptin) speak this fall-when quoting a study that allowed type one diabetic mice to survive without insulin by giving them leptin-he said that had leptin been discovered before insulin it(leptin treatment) would have been the primary treatment for those who suffer from diabetes
Hi Stephen,
I've read that low melatonin levels have a lot to do with low leptin levels AND leptin resistance. Could this also be a factor we haven't included in all this? Obviously diet is a major part of why things go haywire metabolically, but there are other, subtle things that may do even more damage over time.
Poor sleep, sleeping in well-lit rooms, not enough sleep, alcohol or other drugs before bed, sleep apnea and possibly heavy snoring would all be candidates for melatonin disruption. I have started taking 1mg before bed and it has resulting in MARKED lowered appetite during the day. Raised leptin perhaps?
Can you do a post on melatonin please? It seems to be touted as almost the same kind of "master hormone" as insulin, and also a determinant as to whether the body develops metabolic syndrome or not.
Gunther,
I'm not well enough informed to write about melatonin at this point, but what little I know is interesting. I think I'll put my spotlight on it eventually.
"which burns fat at an accelerated rate."
I'm confused. What do you mean here? Leptin is not known to be lipolytic.
Hi Marnee,
Leptin signaling decreases fat mass both by decreasing appetite/food seeking behaviors and by increasing energy expenditure.
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