Now, when you stop to think about it, hindsight being 20/20, it makes a great deal of sense that adipose tissue needs to communicate with the rest of the body in order to convey long term energy status to the organism. On my laptop, I can press a button, even when my computer is off, and an led graph display on the side will indicate battery levels. In addition, there is an icon in my menu bar that shows me whether I am running off mains power, or battery power, as well as the current charge level, assuming that I’m running from the battery. If the battery ever gets critically low, I get a warning dialog, and my laptop preemptively shuts down to prevent data loss.
Compared to human metabolism, my laptop is ridiculously simple, so, if my laptop battery has this many systems in place to communicate with the user ( the overall brains of the operation ) about energy status, imagine how many equivalents there must be for the biological battery that is adipose tissue to achieve the same thing in an organism. And, of course, it turns out that leptin is merely one of many secretagogues that come from adipose tissue. These adipose secretions that seem to function as the body’s fuel gauge vary directly with the amount of fat the organism is carrying. Some of the adipose secretagogues, like leptin and ASP, increase as adiposity increases. Other secretagogues, like adiponectin, have an inverse relationship with body fat, so that as your fat mass increases, you will produce less and less of adiponectin and its ilk.
Why is Leptin the Poster Child for Adipose Hormones?
When the existence of leptin was first discovered ( 1949 ) and long before it was first isolated ( 1994 ) it was quickly determined that there was a circulating factor the lack of which caused a certain strain of mouse (Ob/Ob) to eat voraciously and thereby become obese. When the blood of a normal mouse was transfused with that of an Ob/Ob mouse, normal eating behaviour and weightloss ensued in the Ob/Ob mouse. Understandably, the possibility of developing a therapy that could cure obesity via the administration of this mystery factor raised a great deal of interest. Coincidentally, and somewhat more subtly, leptin also played very nicely with the dogma that obesity is caused by sloth and overeating, with the slight twist that now it was no longer a character flaw causing it, but rather a hormonal deficiency. Leptin was also one of the first adipose hormones to be identified, so it stimulated the most interest, due to first mover advantage.
What does it mean to be leptin resistant?
If you’ve ever waited for an elevator and observed an alpha dog type A personality come up and repeatedly mash the already lit elevator call button, although you may not have been aware of it, you were watching a saturable system in action. That is to say, once the elevator call button has been pressed ( the stimulus ) the response rate of the elevator will not change with any further stimulus ( furiously pressing the call button again and again ) If you happened to be a metabolic researcher, you may even be tempted to say that the elevator had become call button resistant.
In much the same way, the early promise of leptin failed to materialize. While it was true that administering leptin to an Ob/Ob mouse decreased its appetite, increased its metabolic rate, and caused it to lose weight, this did not prove to be the case with obese, yet genetically normal ( i.e. non Ob/Ob ) mice. The version of leptin that Ob/Ob mice produce is truncated by a substitution in one of the base pairs, and this reneders it incapable of binding to and activating the leptin receptor in the hypothalamus. This is why administering any normal leptin at all to these mice results in an improvement. Obese, but otherwise normal, mice don’t have this problem. They produce plenty of leptin, in fact they seem to produce too much.
It was this over production of leptin that led to the formulation of the idea that what was happening was that despite the stimulus ( leptin ) the response, decreased appetite and increased metabolic rate, failed to materialize. Further research also showed that injecting leptin directly into the brain of obese, but otherwise normal, mice did show some results, while infusing leptin into the blood stream did not, suggesting that some transport mechanism from the blood across the blood brain barrier was being saturated. Despite repeatedly mashing the elevator call button, the elevator fails to arrive any sooner.
More support was provided for the leptin resistance hypothesis with the discovery of the Db/Db mouse. Like the Ob/Ob mouse, the Db/Db mouse exhibits a ravenous appetite and is morbidly obese. In direct contrast, however, transfusing the blood of a normal mouse with that of a Db/Db mouse does not improve the ravenous appetite or weight gain of the latter. Moreover, the reverse transfusion of Db/Db blood in a normal mouse causes it to stop eating and eventually starve to death. Apparently, the Db/Db mouse secretes an over abundant circulating factor to which its body is incapable of responding.
It turns out that the Db/Db mouse has a genetic defect in the hypothalamic leptin receptor. As a result, despite producing bucketloads of leptin, the hormone is incapable of binding to the damaged receptor and activating it. Unfortunately, in this case, there is no therapeutic approach that is possible, as we are essentially dealing with irreversible brain damage.
But you are not a mouse, although, if you are a mouse and are reading this, well done you!! For those of us who are not mice, the principal effect of being leptin resistant would result in a higher appetite than is warranted by the degree of body fat that we are carrying – hyperphagia:
The concept of leptin resistance was originally proposed to explain the observation that elevated leptin did not reduce food intake or prevent body weight gain in obese humans. However, it is now recognized that resistance to leptin action may be primarily centered within the neuronal pathways regulating food intake and that other leptin responsive processes remain intact in the obese state. - Adipose Tissue In Health and Disease, Todd Leff, p. 190
Which is to say that, according to leptin researchers, given the amount of excess fat that an obese individual is carrying, they ought to be eating a whole lot less than they actually do. We’ve heard this before : overweight is caused by over eating, apparently, but in this case the over eating is due to assumed leptin insensitivity.
How do normal people become leptin resistant?
The $65,000 question is how does one go from having a normal response to leptin to being leptin resistant? Well, something had to happen to elevate leptin levels and repeatedly press the already lit leptin elevator call button ( the saturation model ). And how do we get increased leptin levels? By increasing adipose tissue mass. Which means that because we got fatter, we became leptin resistant, not the other way around. You may want to pause here and go over that again.
But wait, it actually gets a little more complicated:
Leptin resistance is commonly associated with hyperleptinemia … suggesting that leptin causes its own resistance. This concept was further supported in rats receiving prolonged central leptin infusion: Even though these animals initially lose weight, their body weights normalize over time despite ongoing leptin treatment. In this state, even additional acute leptin injections failed to induce any anorexigenic effect. – Frontiers in Eating and Weight Regulation, Wolfgang Langhans, p. 129
So, effectively, these researchers artificially elevated the leptin of rats by directly injecting it into their brains, bypassing any potential saturation effects at the blood brain barrier transport level. After an initial weightloss period, the weight of the rats stabilized. At that point, they increased the leptin dose, but this basically had no effect, no additional weightloss occured, or, in science speak, this “failed to induce any anorexigenic effect.”
Hang on to your hats, folks, because we’re not done yet:
In contrast, low leptin levels (e.g. in mice after prolonged fasting) as well as lack of leptin ( Ob/Ob mice ) increases leptin sensitivity … The evolutionary adaptiveness of a leptin-driven feedback mechanism in which low body weight ( low leptin levels ) produces the most potent anorexigenic effect seems questionable. A potential explanation for this is that leptin action may be less important in times of plenty, but be critical to coordinate reproductive behaviour with information about body fat stores in states of scarcity.
Translation: it seems that we have a paradox where the ability of leptin to affect feeding behaviour, that is, to curb appetite and increase metabolic rate, works best at low body weights?! But this doesn’t make sense. Or does it?
From an evolutionary and energy balance perspective does it matter to you that you have 60 vs. 70 days worth of stored body fat? Would your driving behaviour change if you had 7/8th of a tank of gas instead of it being full? Personally, I wouldn’t give it a second thought. How about if the needle was on empty and the gas light was illuminated? Well, that’s an altogether different beast, now, you’d think about every time you touched the accelerator, you’d start obsessing over traffic lights, coasting as much as possible to conserve momentum, and frantically looking for the nearest gas station. Or, to bring the analogy home, from a survival of the organism and species perspective, it is far more important to take action when you have low stores of body fat and low levels of leptin than it is to address states where leptin levels are high. If you are an organism living in a temperate climate, low leptin levels indicate that you may not survive the winter, whereas high leptin levels suggest that you may be on your way to all of the metabolic syndrome problems in a couple of decades, but at least you are pretty likely to live to see next Spring. Faced with the choice, I’d rather be fat and alive than skinny and dead.
Is leptin an obesity or starvation signal?
You can never be too rich or too thin.
- Wallis Simpson
It is extremely important, although virtually impossible, to try to escape the cultural biases that one brings to the research table. An egregious example where this did not happen comes from a 2004 review of the state of leptin research from the journal Cellular and Molecular Life Sciences:
Circulating leptin serves to communicate the state of body energy repletion to the central nervous system (CNS) in order to suppress food intake and permit energy expenditure.
These authors, because they are preoccupied with obesity and adiposity, have framed the role of leptin as preventing obesity, or in their words, suppressing food intake. In so doing, however, they are led directly into the paradox of leptin resistance, where high leptin levels fail to achieve the presupposed function of suppressing food intake. This closely parallels the saturated fat theory of coronary heart disease which had researchers run headfirst into the French paradox, where high saturated fat intake did _not_ result in a higher incidence of CHD! In that case, rather than abandon their untenable assumptions about the role of fat in CHD, researchers grasped at straws and came up with resveratrol and red wine. You would think that we would have learned from that experience and be far more willing to question our base assumptions in the face of contradictory evidence. Unfortunately, it seems that in the case of leptin, we are repeating the pattern.
The remarkable thing about all of this is how easy it is to dispense with the leptin resistence paradox while maintaining almost the exact structure of the original statement:
Circulating leptin serves to communicate the state of body energy reserves to the central nervous system (CNS) in order to promote food intake and enhance energy conservation.
With this framing, all the observed data is easily explained. The body is fanatically worried about the possibility of starvation, so when leptin levels fall dangerously low, thereby indicating a starvation state, the brain makes you ravenous, and dials down energy expenditure. Conversely, when there are “adequate” levels of circulating leptin, the body has a nice energy reserve, and there is nothing to do. Dialing back appetite is not necessary, because the body does not care what it looks like in the mirror, it is only concerned with survival. As far as your metabolism is concerned, Wallis Simpson was a collossal idiot.
How do we deal with leptin resistence?
If we are dealing with a saturable system, there are only two general approaches we can take to bring the system into the responsive state: we can either attempt to manipulate the level of the stimulus, or the response. Of the two, manipulating the response requires us to have a very good understanding of all of the aspects governing the behaviour of the system. Essentially, we have to crack open the black box and figure out what makes it tick. In contrast, manipulating the stimulus, assuming that we can correctly identify it, is relatively straight forward, we can effect change completely oblivious as to why the system is resonding. As soon as we lower or raise the stimulus to the responsive range of the system, we’re good to go.
Lessons learned from hyperinsulinemia
Keep in mind that we’ve seen this play out before, but under the guise of insulin resistence. In that case, the primary causal factor, as outlined by Gary Taubes in Good Calories, Bad Calories, was excessive carbohydrate consumption and its impact on insulin:
“Carbohydrate is driving insulin is driving fat,” is how George Cahill, a former professor of medicine at Harvard Medical School, recently described this …
This should not be very controversial: carbohydrate consumption leads to increased blood glucose levels which cause insulin levels to rise, and the corresponding increase in insulin directs all tissues capable of doing so to absorb the glucose. Eventually, if this persists, tissues will reach a limit to their capacity to absorb blood glucose and the glucose absorption system will be saturated, becoming incapable of responding to the insulin signal.
Armed with this information, we then know how to modulate the insulin stimulus: we reduce carbohydrate and other insulinogenic nutrients ( whey, for instance ) in our diet. In so doing, we reduce the insulin stimulus and move the whole system back into the sensitive part of the curve.
But, in the case of hyperleptinemia and leptin resistence, the fundamental stimulus for increased leptin production is … increased adipose tissue. This in turn suggests that we need to reduce fat mass in order to reduce leptin and thereby move the whole system into the responsive part of the curve! And how should we accomplish this? To paraphrase George Cahill :
Carbohydrate is driving insulin is driving fat is driving leptin is driving leptin resistence.
It turns out that the solution for leptin resistence is exactly the same as for insulin resistence!
The Leptin Marketing Machine
More generally, any diet that reduces fat mass, whatever its details may be, will make you leptin sensitive. This is fantastic news if you want to set yourself up as a diet guru, especially if your diet pitch hinges on leptin sensitivity. Leptin is novel, and novelty sells. So, in the finest tradition of magicians, you misdirect the audience with all your talk about leptin so that they do not notice the standard calorie restricted, or paleo, or ketogenic, or, God help you, vegan diet up your sleeve. Were you to try to market the “Slight tweak on the paleo diet, diet”, nobody would bite. Instead, talk about leptin, the hypothalamus and the neuroendocrinology of leptin, plasma membrane fatty acid binding proteins, AMPK, and so much more. You can easily fill a few hundred pages with the details.
Further, you can also differentiate and brand your approach with irrelevant details, which really do not have any material impact on the diet. You can have your clients wave a dead chicken over every meal while facing the temple of the oracle at Delphi ( once they figure out in which direction Delphi lies ), or have them eat 70 grams of protein within 30 mins of waking. The dirty little secret is that if we are speaking of calorie restricted diets, which is what the word diet has come to mean, they all work. Even those monumentally stupid diets like the Twinkie Diet or the All Potato Diet will work as long as they restrict calories. This buys you a lot of latitude to fiddle with the details.
So leptin becomes part of the smoke and mirrors being used to sell a particular collection of dietary principles, supplements, or other weight loss talismans. You may think that I’m overstating my case, but you can already find “The Leptin Boost Diet” in your local bookstores. When you consider that obesity is supposedly the result of leptin insensitivity to the already over boosted leptin levels, it would seem that boosting leptin levels yet higher still might not be the optimal approach. So, whoever came up with the title for this book probably hadn’t read it. This has the whiff of smoke and mirrors about it, and that’s being charitable.
Alternatively, if you are not keen on reading, you can now address your leptin issues with a pill, “clinically proven” to work. Of course, the clinic in question was in Cameroon, because, apparently, researchers were unable to find 92 obese subjects in North America on which to perform their study. Or, perhaps the researchers were motivated to go to Cameroon by other reasons? We can only speculate, but we can at least take a look at the miracle ingredients: pomegranate extracts, beta carotene, carob, blue green algae, guar gum and konjac. Those last two are quite interesting, because they both are indigestible fibre. If you read the patent application, the formulation is basically 30% guar gum and 50% konjac. It is fairly well known that soluble fibre increases satiety, increases gastric emptying time, and basically interferes with absorption of nutrients from the digestive tract by creating an indigestible gel. This idea of filling your digestive system with zero calorie bulk is not new, but, whether or not this is a worthwhile thing to do in order to involuntarily reduce caloric intake and lose weight is debatable. What is certain, however, is that the mechanism of operation has very little to do with leptin.
Once the novelty of leptin wears off, and in this internet driven micro-attention span age, it surely will, then it will be up to resistin, or adipsin, or ASP, or any one the myriad adipose secretagogues to step into the diet marketing spotlight. It will not be long before “The Resistin Advantage Diet (RAD)” hits the shelves. I’m seriously thinking of getting copyright or a trademark on that just to prevent some marketing wonk from actually producing such a monstrosity. I will confess to having a morbid curiosity with respect to what the marketing wonks will do with interleukin-6. It does have an ominous Death Star sound to it …I like to imagine James Earl Jones intoning “I’m your father Interleukin-6!”
Well, then, what diet should I follow?
This is a question that deserves much more time and space than I have to devote to it here and now. Suffice it to say, though, that you should try to eat a sane diet! Sanity, here, would require that the diet that you ultimately pick helps you to attain your goals, and, most importantly, that you could conceivably sustain indefinitely. However, what that practically means for a given individual is very difficult for me to predict from behind my keyboard, especially as the diet will vary according to ones goals. Although it should not need to be said … one size cannot possibly fit all. And, as much as it pains me to say it, please note that this does not rule out in any way selecting a “leptin reset” diet as the preferred approach. Apart from the marketing malarkey, if the underlying diet is sound, then I cannot object overmuch. I will object, however, to wrapping a sound diet in irrelevant detail in an attempt to brand and differentiate yourself.