Leptin is an adipocyte hormone with pleiotropic effects to modulate energy expenditure, appetite, and neuroendocrine function leptin to increase CRP, P-selectin, and platelet aggregation in humans and may reflect heightened sensitivity to leptin in this model. In contrast, increased leptin levels may contribute to increased inflammation and thrombosis via effects on platelet activation and aggregation in obesity, contributing to cardiovascular disease, but such effects may be attenuated by leptin resistance. fat will reduce Leptin levels. You want low levels of Leptin. It works to decrease appetite not by increasing Leptin levels, but by decreasing leptin levels eat low carb (carbs raise insulin and leptin) eat less protein, (excess amino acids raise Leptin and insulin) eat MORE fat. Fat lowers Leptin and will lower Insulin. Leptin is a nutritionally regulated adipocyte-derived cytokine. Previous studies in obese patients have demonstrated increased inflammatory markers and increased platelet aggregation in association with leptin. physiological leptin administration stimulates inflammatory and platelet responses in humans during caloric deprivation. Intermittent Fasting, Set-Point and Leptin 8:15 AM | Posted by Martin Berkhan | Edit Post Share I ranted a little about diet approach, leptin and the set-point theory on bodybuilding.com. Figured it could make for a decent post here. I added some extras in the form of a short review on the effects of intermittent fasting on leptin. --- Short background on leptin and set-point Leptin is a master-hormone with downstream effects on other hormones related to metabolism (T3/T4, neuropeptide-Y, epinephrine, among many others). In the long-term, leptin is regulated by total amount of fat mass. A drop in leptin affects the other hormones negatively and vice versa. Low leptin leads to an increase in hunger and a decrease in metabolic rate, much like high leptin leads to a decrease in hunger and an increase in metabolic rate. Generally speaking, lean people have low levels of leptin while obese have high levels of leptin. However, in the latter case, leptin resistance develops. This is likely an effect of chronically elevated leptin, much like insulin resistance is an effect of chronically elevated insulin. The set-point theory of body weight-regulation is intimately connected to leptin and has a strong genetic component to it. Naturally lean people maintain a low body fat set-point by being leptin-sensitive; they can maintain a low body fat percentage and function optimally even with low leptin. But most of us aren't so lucky, which is why getting really lean is typically a difficult task. Dieting in the single digit body fat-range Lyle McDonald paints a dark picture of life in the low body fat percentage-range. Yet I and my clients maintain a low body fat % without any of the often cited symptoms, such as anhedonia, low libido and a general sense of weakness. It's hard to argue against the literature on the topic, since it's substantial and shows that these side-effects indeed occur. However, it bears mentioning that the studies looking at leptin levels after dieting are limited in the sense that they often use conventional dieting strategies that entail a pronounced weekly calorie deficit for both men and women. I too experienced the aforementioned side-effects in the past, That is, before I finally "got it right." What does that mean exactly? Me at a skinny 165 lbs. Editorial work in Milan. My approach to dieting back then wasn't exactly ideal. During my last cutting diet, that is the one that took me to 5.5% where I have hovered ever since, I did the following things right: 1. I lost the final pounds of fat very slowly and the weekly calorie deficit was subtle. The scale moved down as slow as one pound every other week. On the other hand, I barely felt like I was dieting and I maintained strength and muscle surprisingly well. 2. I was able to make a smooth transition into maintenance. I did not count the days until the diet ended, and I did not sit and plan a big refeed to celebrate when I was done. I didn't feel deprived, daydreaming about food. 3. I would do a extremely controlled and modest refeed 3x/week or 3x/8 day (on training days). Now contrast this to what I did in the past, which caused me to feel miserable during the whole process and experience rebound weight gain: 1. I wanted to lose as fast as possible so I could work on muscle gaining. The weekly calorie deficit was fairly substantial given my already low body fat percentage - I was losing in the range of 1-1.5 lbs/week. I felt deprived and just wanted to get it over with. Strength and muscle loss was substantial. Another one. From a shoot in Münich. Weight around 165 lbs or so. 2. I would sit and plan my big refeed meal at the end of the diet. I would count every day like an inmate counting the days to his release from prison. And once I reached my goal, I would go bonkers, eat a bunch of crap, take several steps back and then go back to dieting in a feeble attempt to make up for my screwed up "refeed" (aka binge in my case). 3. I did no refeeds during the diet. So what's the lesson here and how does it relate to the topic at hand? Leptin: science versus real world Leptin is controlled primarily by two things, which are a) Short term: acute energy balance. A high calorie deficit causes leptin to drop lower than what can be explained by fat loss, and a caloric surplus raises leptin higher than what can be explained by fat gain. b) Long term: total amount of fat mass. Fat cells are factories for leptin production. Not having many factories obviously impairs production and the aboslute amount of leptin in circulation. If A can be manipulated via a subtle energy deficit and regular refeeds of the right macrocomposition (carb refeeds acutely increase leptin, while fat has no effect), this should prove beneficial to circulating leptin levels during the diet. It might prove fruitful to "trick" the last few pounds of fat off while venturing into the single digits. Another cyclical diet that has much in common with this strategy is The Ultimate Diet 2.0 though I'm in favor of more frequent, more modest, refeeds and no glycogen depletion outside what occurs with a low-moderate training volume. If anecdotal reports mean something, this is my standard approach for clients and it's working well. I'm not an isolated case. For example, have a look at Andreaz in this post on maintaining low body fat. And we're no ectomorphs by any means. I grew up fat. Science dictates I wouldn't be able to stay this way (low body fat) without feeling completely miserable, but that's just not the case. The avatar pic was taken at the end of 2007, and I've stayed that way ever since. But I failed many times in the past. Only when I learned patience did I attain my goal. Now, this little theory of mine, that fat needs to be lost very slowly in the single digit range, still leaves questions as it pertains to B, which is that leptin is ultimately controlled by total amount of fat mass. Several years and 30 lbs later, I finally "got it right". Low fat mass equals low leptin. Can leptin sensitivity increase if weight is maintained on a low body fat % for a prolonged period of time? Sadly, there are no studies to suggest that for the time being. Can it increase through other means? Well, exercise and fish oil seem to improve leptin transport, so there's that. But what I think people really want to know is how intermittent fasting affects leptin levels and there's some interesting research on that topic. Intermittent fasting and leptin Generally speaking, studies show a neutral effect on average leptin levels during intermittent fasting. While the fasting period decreases circulating leptin, this is compensated by a big boost when refeeding. In comparison to conventional meal frequencies, intermittent fasting induces a "peak and valley"-pattern in leptin synthesis. Leptin secretion is thus entrained to the meal pattern and shifting meal timing causes a comparable shift in plasma leptin rhythm. However, there are some interesting discrepancies here in that women actually show a big increase in mean leptin levels during intermittent fasting. This occurs even in the absence of weight gain which is all the more fascinating. In the quoted study, despite calorie intake being elevated in comparison to baseline intake, the women actually lost weight and lowered waist circumference and body fat percentage. Intermittent fasting was also shown to decrease neuropeptide-Y, a hormone that stimulates hunger. This could probably be explained by elevated leptin levels, but there was no linear correlation between the two in this case. Similar effects have also been shown to occur in men. That is, fat loss occurred without any reduction in leptin - and these were fairly lean athletes to begin with. Intermittent fasting may also be of benefit when dieting in the single digit range due to the effect of fasting on the fat mobilizing hormones epinephrine and norepinephrine. When you’re in the single digit body fat range, you’re likely to have low circulating levels of leptin. One of leptin’s downstream effects is on epinephrine and norepinephrine output. Low leptin equals impaired output of the aforementioned hormones. This is part of how leptin regulates metabolic rate. However, it seems that these hormones increase regardless during fasting. That is, leptin is not able to exert it’s usual power over these hormones. In this case, their increase cannot be mediated by leptin which allows fat mobilization to go on unabated during fasting. That's it for now. There's plenty more on this topic, but I'll save that for some other time. Summary * Fat loss in the single digit body fat-range needs to be slow and tempered. In my experience, this allows for a smooth transition into maintenance and minimizes muscle loss. I also believe it might lessen the negative effect of dieting on leptin, which ultimately makes maintenance of low body fat achievable. I think most people diet too hard, which has a profoundly negative effect on leptin - and this is part of the reason why the weight gain rebound is so common in folks who finally manage to reach their goal (and then screw up everything by binging). * Planned and regular refeeds should be in place. This affects leptin positively and allows for maintenance of muscle and strength. Even if your goal ultimately is fat loss, entering an anabolic phase with post-workout overfeeding will serve you well. * Intermittent fasting seems to have interesting effects on leptin synthesis. Whether this has benefits for low body fat maintenance or circulating mean leptin levels is up for speculation for the time being. Print Email Bodyweight Regulation: Leptin Part 1 As I noted Set Points, Settling Points and Bodyweight Regulation Part 2, although I’ve been using bodyweight/body fat during this discussion, it’s probably more likely that it is body fat levels per se that are being regulated. Today you’ll see why and from here on out I’ll only talk about bodyfat regulation. With early research (I’m talking the 1950’s) having established the existence of some type of setpoint (again, primarily in animal models), early researchers had to sort of guess what might be going on in terms of regulating body fat levels. Essentially they postulated that the brain of the animal must be responding in some form or fashion to a hormone that scaled with body fat levels. They could only postulate what it was and it would take another 40 years before a major candidate would make itself known. In 1994, the gene for a hormone that would eventually be called leptin (from the Greek “leptos” for thin) was discovered in the OB (OB stands for obesity) mouse. The OB mouse had been studied for decades and was spontaneously overweight with a low resting metabolic rate, low levels of activity, etc. It ate a lot, put on fat easily, etc. Here’s what it looks like compared to a normal lean mouse. Superficially, the OB mouse appeared to be similar to obese humans (except furrier). It turns out that the OB/OB mouse doesn’t produce leptin at all, it has a gene defect and makes zero leptin. Inject it with synthetic leptin and it loses weight rapidly. After the discovery of leptin, the news was abuzz with thoughts that the cure for obesity was finally here. Companies spent a lot of money getting the rights to leptin, thinking it would fix the global obesity problem and they’d make zillions of dollars. So researchers went about measuring blood levels of leptin in humans of varying weight expecting obese humans to produce no leptin. To their dismay, it turned out that obese individuals invariably had very high levels of leptin and it was suggested that, in a similar vein to insulin resistance (where the body no longer responds appropriately to the hormone insulin), the body or brain had become leptin resistant. There was plenty of leptin floating around but it wasn’t sending the right signal to the brain to turn off appetite and reduce body fat. I’d note in this regards that two other rat strains, the DB (for diabetic) and DIO (dietary induced obesity) rat show varying degrees of leptin resistance (the existence of resistance to the supposed regulating hormone was also postulated back in the 50’s). In the case of the DB rat, it’s complete and genetic; in the DIO rat it develops with increasing obesity. A variety of things induce leptin resistance including high blood triglyceride levels and even leptin itself; when elevated chronically, leptin induces resistance to itself. I’d note that it is currently being debated if leptin resistance is truly the cause for what’s going on and other models, such as the leptin insufficiency theory are being discussed as well; in this concept, a lack of leptin in the brain (but not in the body) is the problem. In either case, the signal from leptin isn’t being sent properly. I’ll talk about what that signal is in the next post. And while a handful of individuals have been found who produce no leptin (and who respond to injectable leptin with massive weight loss and a normalization of metabolic rate), studies which injected leptin levels in the obese showed disappointing or no weight loss. Which doesn’t make leptin useless, mind you; it was simply being used incorrectly because researchers didn’t quite understand what it was actually doing or supposed to be doing. Many people still don’t. Before wrapping this up, I want to note that leptin isn’t the only candidate hormone for body weight regulation; as it turns out insulin is also a key player here (insulin also scales with bodyfat). Direct injection of insulin into the brains of animals reliably reduces food intake and bodyweight. There is also evidence, which I’ll discuss later, that there is a gender difference in how the brain responds to either leptin or insulin. Given that leptin scales mostly with subcutaneous fat (generally higher in women) and insulin scales mostly with visceral fat (generally higher in men), this will turn out to make some logical sense. Of course, there are other factors here as well. Hormones such as cholecystokinin, peptide YY, ghrelin as well as blood glucose, blood fatty acids, amino acids, and others being discovered damn near daily are all sending an integrated signal to the brain about what’s going on in the body. As well, varying hormones work on relatively longer or shorter time frames. For example, insulin can change in a matter of minutes, leptin may take hours, ghrelin operates on a meal to meal basis, etc. This makes for a very complicated system. But I’m getting ahead of myself.