Category Archives: Leptin
by Mike T Nelson – 6/12/2012
Every time you turn around, there’s a new diet plan based on a hormone. While there’s some merit to all this madness, most of the plans fail to completely understand their respective physiological underpinnings. The body isn’t a simple, linear, straightforward machine – it’s complex and redundant at almost every turn.
This article will reveal some new research on the hormone leptin to provide some simple actions for you to take to help you get leaner. Just because the physiology is messy doesn’t mean your actions need to be complicated!
First, here’s a short crash course on this important hormone.
Leptin was discovered by Ingalls and friends in the early 1950’s (Ingalls, AM, et al 1950). Fast forward to the early 90’s when it was “rediscovered”, and many were predicting it would be the biggest weight loss breakthrough ever.
It’s a hormone that is released primarily by fat cells (adipocytes) and works to regulate appetite, body fat mass, and basal metabolic rate.
Until just a few years ago, researchers thought that fat cells sat on their collective butts all day and were only a storage place for unsightly body fat.
We know now that those pesky fat cells are very metabolically active, releasing and receiving a myriad of messenger hormones, one of which is leptin.
How Does Leptin Work?
Leptin travels up to the brain where it acts on receptors in the hypothalamus to inhibit appetite.
More leptin in your brain = less food intake.
This is great news for anyone looking to get leaner, since more leptin means you’ll be less likely to prowl your kitchen at 3 AM in search of leftover birthday cake. Leptin is your body’s way of putting the brakes on fat gain by decreasing appetite.
The chronic level of leptin you have is also a rough measure of the amount of fat you have on your body. Many things can affect leptin as shown in the table below:
Factors promoting leptin secretion
Excess energy stored as fat (obesity)
Inflammatory cytokines, including tumor necrosis factor and Interleukin-6 (acute effect)
Factors inhibiting leptin secretion
Low energy states with decreased fat stores (leanness)
Catecholamines and adrenergic agonists
Peroxisome proliferator–activated receptor-agonists
Inflammatory cytokines, including tumor necrosis factor (prolonged effect)
Leptin Super Mouse to the Rescue!
Researchers lead by Zhang,Y in the mid-1990s did a series of mouse experiments to show that mice with messed up leptin (ob/ob mouse) became fat little fury bastards (Zhang, Y et al. 1994).
Their metabolic rate was lower, they didn’t move as much, and they ate tons of mouse chow.
The catch was that this mouse ob/ob (think double obese) didn’t make any leptin at all.
To make the mouse lean, they injected it with leptin, and voila – a thin mouse again!
The researchers all joined hands, sang Kumbaya, and went out for tasty adult beverages while taking turns patting each other on the back for single-handedly solving the obesity problems. We just need to inject humans with leptin and poof, thin humans, and more visually appealing shopping experiences at Walmart.
The problem was it didn’t work.
Researchers measured blood levels of leptin in obese humans and found that leptin levels were sky high!
That wasn’t supposed to happen. Leptin levels were expected to be low since the humans were fat. As leptin increases, it signals that the body has enough fat, so we would expect low leptin levels in obese populations.
As you recall, when injected with leptin (thus increasing the level), the mice in the studies got thinner.
But these obese humans already had high levels of leptin. Injecting more leptin was like pissing in the ocean to try to raise the water level.
Leptin 201: The Receptor
It appeared that the receptor for leptin is out of joint. The receptor isn’t telling the brain that leptin is high. Tons of leptin, but the silly brain can’t tell since the receptor is as broke as Terrell Owens.
Why it Matters
We already know that sprint training is a great way to burn fat, but it may have another benefit.
A study done by Guerra et al. in 2011 looked at sprints as a leptin signaling mimetic.
Unlike most research, this study used a group of T Nation style humans who were pretty lean (about 15% body fat) and young (23 years old). They split them into two groups: a fasting group, and a glucose group where they ingested 75 grams of glucose one hour before sprints.
Both groups did one Wingate bike sprint for only 30 seconds.
If you’re not familiar with this set up, in short, it’s hop on a bike set to a high workload (10% of body weight used here) and pedal like a rabid grizzly bear is chasing you.
What They Found
Subjects had a series of muscle biopsies done over the course of the study and researchers found that a single session of sprint training showed alterations in leptin signaling. The sprints were jacking up leptin that, in theory, should get the waddling Walmart shoppers to start dropping fat.
However, this was not seen in the group that ingested glucose before their sprint. Only the fasted group saw leptin alterations.
It appears insulin may interfere with the leptin signaling to some degree. To quote the researchers directly:
“Altogether, these results indicate that sprint exercise performed under fasting conditions elicits signaling events similar to those described in the rodent skeletal muscle after leptin injections, i.e. sprint exercise under fasting conditions acts as a leptin signaling mimetic in human muscle. However, glucose ingestion before the sprint training exercise blunts this effect.” (Guerra et al. 2011)
So it appears that fasted sprint training can pinch hit for leptin.
Do This! A Training Template
Hop on a bike and work up to one maximum, all out, pedal-as-hard-as-you-can sprint for 30 seconds.
The tension should be relatively high, but the goal is to keep your pedaling at a fast pace for the entire 30 seconds. If you slowed to a snail pace 20 seconds in, go to a lighter workload.
Make sure this is done in a fasted condition, such as first thing in the morning.
Don’t have a bike? While the study didn’t look at running, it may elicit the same response as the pathways are very similar.
It sounds ridiculously simple, but my purely anecdotal experience with my athletes shows that this does seem to help speed fat loss.
More leptin is associated with less food intake.
Some may have a leptin receptor issue where it’s not responding to the amount of leptin floating around. Unfortunately, science isn’t at the point yet where we can easily tell who has a receptor issue, but the more overweight you are, the more prone you are to having broken leptin receptors.
Doing just one sprint in a fasted state works to pinch hit for leptin, putting you on the road to leanness. However, non-fasted training does not have the same effect. So add some sprint training in, but it has to be done in a fasted state.
Fasted sprints can be done any time on a fasting day (where you’re not consuming any calories), or done before breakfast. This way it’s unlikely to interfere with your normal training session.
While we don’t have a long-term study to show how much this will help your body composition, it’s simple to add in and there’s some very strong data to show it will help.
Heck, it only takes literally 30 seconds to do the sprint. Try it out, and let me know what you find.
Questions or comments? Post them in the LiveSpill below.
Everard, A., Lazarevic, V., Derrien, M., Girard, M., Muccioli, G. G., Neyrinck, A. M., Cani, P. D. (2011). Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes, 60(11), 2775-2786. doi:10.2337/db11-0227
Finocchietto PV, Holod S, Barreyro F, Peralta JG, Alippe Y, Giovambattista A, Carreras MC, Poderoso JJ. Defective leptin-AMP-dependent kinase pathway induces nitric oxide release and contributes to mitochondrial dysfunction and obesity in ob/ob mice. Antioxid Redox Signal. 2011 Nov 1;15(9):2395-406. Epub 2011 Jun 28.
Galgani, J. E., Greenway, F. L., Caglayan, S., Wong, M. L., Licinio, J., & Ravussin, E. (2010). Leptin replacement prevents weight loss-induced metabolic adaptation in congenital leptin-deficient patients. The Journal of Clinical Endocrinology and Metabolism, 95(2), 851-855. doi:10.1210/jc.2009-1739
Guerra, B., Olmedillas, H., Guadalupe-Grau, A., Ponce-Gonzalez, J. G., Morales-Alamo, D., Fuentes, T., . . . Calbet, J. A. (2011). Is sprint exercise a leptin signaling mimetic in human skeletal muscle? Journal of Applied Physiology (Bethesda, Md.: 1985), 111(3), 715-725. doi:10.1152/japplphysiol.00805.2010
Ho, J. N., Jang, J. Y., Yoon, H. G., Kim, Y., Kim, S., Jun, W., & Lee, J. (2012). Anti-obesity effect of a standardised ethanol extract from curcuma longa L. fermented with aspergillus oryzae in ob/ob mice and primary mouse adipocytes. Journal of the Science of Food and Agriculture, doi:10.1002/jsfa.5592; 10.1002/jsfa.5592
INGALLS, A. M., DICKIE, M. M., & SNELL, G. D. (1950). Obese, a new mutation in the house mouse. The Journal of Heredity, 41(12), 317-318.
Kelesidis, T., Kelesidis, I., Chou, S., & Mantzoros, C. S. (2010). Narrative review: The role of leptin in human physiology: Emerging clinical applications. Annals of Internal Medicine, 152(2), 93-100. doi:10.1059/0003-4819-152-2-201001190-00008
Kowalik, S., & Kedzierski, W. (2011). The effect of interval versus continuous exercise on plasma leptin and ghrelin concentration in young trotters. Polish Journal of Veterinary Sciences, 14(3), 373-378.
Plinta, R., Olszanecka-Glinianowicz, M., Drosdzol-Cop, A., Chudek, J., & Skrzypulec-Plinta, V. (2011). The effect of three-month pre-season preparatory period and short-term exercise on plasma leptin, adiponectin, visfatin and ghrelin levels in young female handball and basketball players. Journal of Endocrinological Investigation, doi:10.3275/8014
Wolsk, E., Mygind, H., Grondahl, T. S., Pedersen, B. K., & van Hall, G. (2011). The role of leptin in human lipid and glucose metabolism: The effects of acute recombinant human leptin infusion in young healthy males. The American Journal of Clinical Nutrition, 94(6), 1533-1544. doi:10.3945/ajcn.111.012260
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J. M. (1994). Positional cloning of the mouse obese gene and its human homologue. Nature, 372(6505), 425-432. doi:10.1038/372425a0
Leptin – you’ve probably heard someone mention it at one time, but aren’t really sure what it is. I remember when I first heard a bodybuilding coach mention it, saying that managing leptin was crucial to keeping the metabolism humming. I had no clue what he was talking about, but it did intrigue me.
Leptin wasn’t even discovered until 1994, but research into the mysterious hormone has been increasing. Scientists certainly don’t know everything about leptin yet, but let’s discuss what we do know.
What is Leptin?
First, it’s important to understand that fat isn’t simply just a storage tank for excess calories or “potential energy.” Fat is actually an endocrine organ, like a thyroid or adrenal gland, for example. This means that fat – in this case white adipose tissue – secretes hormones, and leptin is one of them.
Leptin is a polypeptide hormone produced by adipocytes (fat cells). The more fat the adipocytes contain, the more leptin is released. Think of leptin as a metabolism controller and a hunger regulator. It links changes in body fat stores to CNS control of energy homeostasis (1-4).
Here’s a simple example:
You eat above maintenance calories over a period of days or weeks.
- As you eat more, fat cells fill with triglyceride, which increases the release of the hormone leptin into the bloodstream.
- The hypothalamus in your brain has an intricate system of communication with fat cells which include leptin receptors. When leptin levels increase, leptin binds to leptin receptors in the hypothalamus, sending the message that you’re “fueled up.”
- The hypothalamus then sends signals to the brain and the rest of the body, decreasing appetite and turning up your metabolic rate.
You eat below maintenance calories over a period of days or weeks.
- Your fat cells shrink as you diet, not eat, etc., and fat cells release less leptin.
- Your brain senses that leptin levels are low, and that you are no longer “fueled up.”
- The hypothalamus senses the decrease in leptin levels, lowering metabolic rate and decreasing energy expenditure. It also sends a “hungry” signal, increasing appetite and encouraging you to eat.
Leptin action isn’t confined to just the hypothalamus. There are leptin receptors all over the body. This allows leptin to precisely coordinate appetite, metabolism, and energy expenditure.
|Location||Leptin mode of action|
|Pancreatic islets||(-) Insulin production and secretion (5, 6)|
|Adipose tissue||(+) Fatty acid oxidation (7)
(+) Lipolysis (7)
(-) Lipogenesis (8)
|Liver||(+) Lipolysis (7)
(-) Lipogenesis (8)
|Skeletal muscle||(+) Fatty acid oxidation (9)|
This is nature at its finest. Your body is programmed to survive. On one hand, when food is available, leptin keeps you from adding too much fat mass, which would have been a liability back in the caveman days (or today, for that matter).
On the other hand, leptin responds to and defends against excessive body fat loss that might threaten survival or reproductive ability (10). Eat too much and metabolism speeds up to keep up. Don’t eat enough and it slows down to keep you alive.
What if the Hypothalamus Stops Receiving Messages?
Check out the picture below of the fat mouse. Let’s call him Jumbo. Jumbo is unique – he’s an ob/obmouse. This is a mouse that becomes a type II diabetic, can’t stop eating, and packs away body fat like crazy. No matter how much you feed him, he won’t stop.
Poor Jumbo has a mutation in the gene coding for leptin – he’s totally missing it! His fat cells can’t properly communicate with his hypothalamus because he has no leptin. If you inject Jumbo with leptin, he’ll stop eating and lose weight, but the solution isn’t so simple for us non-mutants.
Most obese people don’t have missing or mutated leptin genes – they can make plenty of it. The problem is that in spite of leptin still finding and binding its receptors all over the body, no downstream message is sent. The system that senses leptin is broken.
This is called leptin resistance, a condition in which the brain can’t determine when body fat is at an okay level. The fat cells are sending leptin out to the hypothalamus to signal that fat stores are full. Leptin binds the receptors, but no downstream messages are sent. It’s like knocking on the door when nobody is home. In spite of all the extra body fat mass, the brain perceives starvation and orders fat storage. The kicker is that you’re also very hungry, and continue to eat more and more.
If you know anyone who just can’t stop eating like Jumbo, as tempting as it may be to instantly judge them, it’s likely not entirely their fault. Many obese people have metabolic systems that are simply broken. You can’t outrun Mother Nature, and if the leptin signaling is messed up, you can only control yourself so much.
But it’s not just the clinically obese who must be concerned. You permabulkers, take note: as you continue to overeat, triglyceride stores increase, causing fat cells to produce more leptin. With so much leptin around, leptin receptors become desensitized. Eventually they just tune out, which has big consequences. You have plenty of fat but your brain doesn’t know it.
How Do We Become Leptin Resistant?
Reduced blood-brain barrier transport. The idea that leptin levels were higher in obese people was a surprise. When scientists tested the ability of various tissues from leptin resistant animals to respond to leptin in vitro, most of the time leptin receptors isolated from the hypothalamus were still somewhat sensitive.
This was a big puzzle until it was discovered that part of the body’s response to high leptin levels is to shut down leptin access to the brain. For leptin to travel from fat cells to the hypothalamus, it travels through the bloodstream but has to cross the blood-brain barrier to gain access.
The blood-brain barrier is extremely selective as far as what it lets through, and it was discovered that an early response to high leptin levels is to shut down transport across the blood-brain barrier. This allows the body to preserve leptin sensitivity in the hypothalamus as long as it can, holding out until leptin levels drop back to normal.
Reduced leptin receptor sensitivity. Like the insulin receptor, when leptin receptors are constantly bombarded with high amounts of leptin, they become resistant. The mechanism of reduced leptin receptor sensitivity was partly discovered by accident, when scientists were studying the role of a protein phosphatase calledprotein tyrosine phosphatase 1B (PTP1B) in the regulation of insulin receptor signaling.
It’s been known for some time that insulin receptor sensitivity is controlled by a number of kinases and phosphatases, and in this case, scientists hypothesized that PTP1B was limiting insulin sensitivity. This would be great news for diabetics.
To test this hypothesis, they created a group of knockout mice that lacked the PTP1B protein. As the researchers predicted, these mice became very sensitive to insulin when they were given a glucose test. The scientists also noticed something else. These mice got ripped, and lost considerable body fat.
The mice had incredibly fast and efficient metabolisms, the cause of which came as a big surprise – eliminating the PTP1B gene was also massively upregulating leptin sensitivity (11). It was later found that the PTP1B protein is a negative–feedback inhibitor to leptin receptor signaling. When the leptin receptor is stimulated with high amounts of leptin, PTP1B kicks in to reduce receptor sensitivity.
Another protein called suppressor of cytokine signaling 3 (SOCS3) is also a negative feedback inhibitor of leptin. When the leptin receptor is activated by large amounts of leptin, SOCS3 increases which reduces leptin receptor sensitivity (12, 13).
You might have noticed that insulin and leptin resistance appear to be inseparable. This isn’t a coincidence; like PTP1B, SOCS3 is also a negative regulator of insulin signaling, so insulin resistance and leptin resistance are linked at the molecular level.
Inflammation also activates PTP1B and SOCS3, which explains why it affects both insulin and leptin receptor sensitivity.
Dieting and Leptin Resistance
Let’s take a guy in perpetual bulk mode, we’ll call him “Beefcake.” First, Beefcake eats a ton of calories and puts on some body fat in his quest to get hyoooge. This causes an increase in leptin release. Leptin tells the hypothalamus that fuel stores are full, and the response is a reduction in appetite and increase in energy expenditure.
In this way, leptin restores the metabolism to homeostasis by matching appetite to food intake – but this came at a price! The continual pounding of food and garbage calories more than likely caused a degree of leptin resistance. This means he now has increased the amount of leptin needed to just maintain energy homeostasis.
The more leptin resistant you are, the more your metabolic set point will shift towards “fat” and away from “lean.” Have you ever dieted down and got lean, then after a Beefcake-inspired bulk up, had a really hard time leaning out again? Now you know why. This is one major reason why “bulk ups” aren’t recommended.
Let’s continue. In Beefcake’s leptin resistant state, when he decreases calories, his super-enlarged fat cells start to shrink, causing a reduction in leptin levels. The problem is, the leptin resistance caused a new “set point,” which prompts his screwed up metabolism to defend his increased fat stores, for survival purposes!
Think of it this way: under normal circumstances, the leaner you get, the harder it is to lose body fat without burning muscle. Your body eventually goes into “survival” mode – you become more tired, lethargic, and your appetite increases. When things are working correctly, this only happens when body fat levels are extremely low.
But when you start a diet in a leptin resistant state, you lose some weight at first but quickly get into the same survival mode, only now you’re nowhere close to being in shape as you were before.
This leads to no man’s land real quick. You’re eating less and less, feeling worse and worse, weak and stringy, but still can’t lose weight. Your leptin receptors are resistant – at a higher set point – so even small decreases in leptin are perceived as starvation. Start a diet in a leptin-resistant state and reduced calorie levels will simply put your body into perpetual starvation mode.
This is the ugly side of dieting for many, and the main reason why many popular diet books suggest that simple calorie restriction does not work long term. The reality is that calorie restriction isn’t the problem, it’s leptin resistance.
Leptin and Insulin
Leptin and insulin signaling have a very close relationship. When insulin increases, so does leptin. It makes sense – you eat a big meal, your insulin levels go up, and then leptin goes up, signaling to the brain that you’re full and to keep the metabolism chugging.
The insulin producing beta cells in the pancreas also have leptin receptors, where leptin is a negative regulator of insulin release. So there’s a tight intertwined relationship between these two hormones.
Here’s how it looks:
- You eat some wild salmon and a big sweet potato. The beta cells in your pancreas produce insulin in response to your blood glucose level.
- Insulin stimulates leptin production in your fat cells.
- Leptin levels go up, triggering the hypothalamus to decrease appetite.
- High levels of leptin also tell your pancreas to stop making insulin.
But here’s how it looks when you have leptin resistance:
- You eat some wild salmon and a big sweet potato with some pop tarts, as you’re in “permabulk” mode. The beta cells in your pancreas produce insulin in response to your blood glucose level.
- Insulin stimulates leptin production in your fat cells, overwhelming your body.
- Leptin levels go up but leptin resistance starts to set in.
- High levels of leptin try to tell your pancreas to stop making insulin, but you’re leptin resistant so the pancreas doesn’t get the message to stop!
- We now have chronically high levels of insulin, leading to insulin resistance.
Leptin and Inflammation
As mentioned in our inflammation article, the fatter you are, the more inflammation you probably have due to extra fat (30% of cells in white adipose tissue are immune cells) causing more immune signals to increase IL-6 and TNFa.
- Hyperleptinemia is associated with an increased pro-inflammatory response (14).
- Leptin is capable of increasing TNFalpha production and increasing macrophage activation (15).
It’s a good idea to try to calm inflammation as best as you can. You can greatly reduce inflammation and increase glucose utilization by replacing some of your fat and refined carb sources with essential fatty acids. Omega 3 and Omega 6 supplements are excellent in this regard.
Leptin and Your Thyroid
It’s common knowledge among meat heads that when you diet, your thyroid slows down the conversion of T-4 to T-3. What isn’t so commonly known is that leptin is a major player in keeping this conversion going.
When your brain senses correct levels of leptin, it tells your liver to convert the inactive T-4 to active T-3 (the active version of thyroid hormone). Your liver will stop this when your brain perceives starvation, which is exactly what happens when you have leptin resistance.
How Can We Fix Leptin Resistance and Perceived Starvation?
- Insulin resistance and leptin resistance are inseparable, and driven by “metabolic inflammation.” Fixing insulin resistance improves leptin resistance and vice versa.
- Reducing inflammation, improving liver health, adrenal health, etc., all help.
- Recent research has revealed that this is intertwined at the molecular level, but science hasn’t evenscratched the surface. The research on leptin is still in its infant stages.
Get and stay leaner. This is the obvious one. Don’t “bulk” up. Stay close to target weight, and minimize body fat gain during offseason. The harder you make your diet by “bulking up” excessively in the off-season, the more you’re going to make the leptin rebound a challenge down the road. You’ll likely have to resort to extremes that put your body into survival mode to get lean.
Add in periodic refeed/cheat meals. There have been some very good articles posted on T Nation about cheat meals. When you go sub-maintenance calorically and get into a depleted state, adding in a cheat meal or two can stop you from entering “perceived starvation.” This will help prevent leptin resistance. Some advocate a full day or weekend, but in our experience 1 to 2 large meals per week are sufficient for most.
Limit inflammation. Fat (white adipose tissue) doesn’t only produce leptin, it also houses extra immune cells that generate inflammatory cytokines such as IL-6 and TNFa. Reducing inflammation increases leptin and insulin receptor sensitivity by limiting the effects of PTP1B and SOCS3.
Don’t go carb-crazy. High insulin levels cause insulin resistance, which causes increased inflammation. Insulin and leptin resistance are so intertwined that fixing one helps the other. Since insulin increases leptin production (16), those in perpetual “bulk mode” are also generating metabolic inflammation.
Sleep. Chronic (17) and acute (18) sleep deprivation reduces serum leptin levels. In the acute sleep deprivation study, 11 males were subjected to sleep deprivation (4 hours of sleep) for six nights. Compared to the control group that slept for 8 hours, this reduced mean and maximum levels of leptin by 19% and 26% respectively.
In another study, those who habitually slept for 5 hours had 15.5% lower leptin levels than those who habitually slept for 8 hours (19). Sleep deprivation also increases inflammation, and has been linked to increased IL-6 secretion (20, 21). Even mild sleep loss (2 hours/night lost for 7 nights) results in a significant increase in TNFα levels in men (21). In some cases, dysfunctional sleep can also increase leptin levels, leading to leptin resistance.
Sleep apnea is associated with high leptin levels and leptin resistance (22). Leptin is a powerful stimulation of ventilation (23), so leptin levels can increase during sleep apnea. If you’re a hard-core snorer, talk to your doctor about getting a sleep study.
Diet/supplement intervention: Supplements to fight leptin resistance:
Dietary Ca2. Increased dietary calcium intake helps overcome leptin resistance. Although the mechanism is unknown, it was recently hypothesized that increased calcium intake may decrease the levels of calcitriol (1,25-dihyroxyvitamin D) in adipocytes. In a leptin-resistant state, fat cells seem to have more calcitriol, which has been linked to decreased fat burning and increased fat storage.
Increasing dietary calcium suppresses adipocyte calcitriol levels and puts leptin-resistant fat cells back into “fat-burning” mode. This reduces leptin resistance, resulting in increased weight and fat loss in leptin resistant people (24, 25).
Take Taurine. If you’re leptin resistant, supplementing with the amino acid taurine can help. Taurine reduces leptin resistance by reducing ER stress (26, 27). Possibly related to the effect of taurine on ER stress, it’s also been shown to be helpful for the prevention of several other metabolic disorders including obesity, insulin resistance, and atherosclerosis (28, 29).
ALCAR. While this hasn’t been established in human studies, animal studies suggest that supplementing with acetyl-L- carnitine (ALCAR) may also help overcome leptin resistance (30).
EFA’s. EFA’s hammer down inflammation! Enough said.
And We’re Out!
Whew! This article has been a workout! Post any questions or comments you may have in the LiveSpill.
Thanks everyone for reading!
Bill and John