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/ob mouse. 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 called protein 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.
Key Point: Leptin resistance causes a new "set-point," which leads to the defense of a higher level of body fat storage and slower metabolic rate than would otherwise happen if Beefcake were still leptin sensitive! In other words, your body is smart, and if it thinks a "diet" is coming, it immediately holds on to fat as much as it can.
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 even scratched 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. Ideally, use a nutrient partitioning agent like Indigo-3G® to selectively increase insulin sensitivity in muscle and decrease it in fat.
- 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
- Myers MG, Jr., Munzberg H, Leinninger GM, Leshan RL. The geometry of leptin action in the brain more complicated than a simple ARC. Cell Metab 2009;9:117-23.
- Schwartz MW, Woods SC, Porte D, Jr., Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000;404:661-71.
- Rosenbaum M, Leibel RL. The role of leptin in human physiology. N Engl J Med 1999;341:913-5.
- Ahima RS, Saper CB, Flier JS, Elmquist JK. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol 2000;21:263-307.
- Emilsson V, Liu YL, Cawthorne MA, Morton NM, Davenport M. Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes 1997;46:313-6.
- Morioka T, Asilmaz E, Hu J, Dishinger JF, Kurpad AJ, Elias CF, et al. Disruption of leptin receptor expression in the pancreas directly affects beta cell growth and function in mice. J Clin Invest 2007;117:2860-8.
- Wang MY, Lee Y, Unger RH. Novel form of lipolysis induced by leptin. J Biol Chem 1999;274:17541-4.
- Jiang L, Wang Q, Yu Y, Zhao F, Huang P, Zeng R, et al. Leptin contributes to the adaptive responses of mice to high-fat diet intake through suppressing the lipogenic pathway. PLoS One 2009;4:e6884.
- Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002;415:339-43.
- Myers MG, Jr., Leibel RL, Seeley RJ, Schwartz MW. Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab 2010;21:643-51.
- Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, et al. PTP1B regulates leptin signal transduction in vivo. Dev Cell 2002;2:489-95.
- Bjorbak C, Lavery HJ, Bates SH, Olson RK, Davis SM, Flier JS, et al. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J Biol Chem 2000;275:40649-57.
- Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell 1998;1:619-25.
- Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, et al. Leptin regulates proinflammatory immune responses. FASEB J 1998;12:57-65.
- Bjorbaek C, Kahn BB. Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res 2004;59:305-31.
- Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends Endocrinol Metab 2000;11:327-32.
- Mullington JM, Chan JL, Van Dongen HP, Szuba MP, Samaras J, Price NJ, et al. Sleep loss reduces diurnal rhythm amplitude of leptin in healthy men. J Neuroendocrinol 2003;15:851-4.
- Spiegel K, Leproult R, L'hermite-Baleriaux M, Copinschi G, Penev PD, Van CE. Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab 2004;89:5762-71.
- Taheri S, Lin L, Austin D, Young T, Mignot E. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med 2004;1:e62.
- Vgontzas AN, Papanicolaou DA, Bixler EO, Lotsikas A, Zachman K, Kales A, et al. Circadian interleukin-6 secretion and quantity and depth of sleep. J Clin Endocrinol Metab 1999;84:2603-7.
- Vgontzas AN, Zoumakis E, Bixler EO, Lin HM, Follett H, Kales A, et al. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab 2004;89:2119-26.
- Campo A, Fruhbeck G, Zulueta JJ, Iriarte J, Seijo LM, Alcaide AB, et al. Hyperleptinaemia, respiratory drive and hypercapnic response in obese patients. Eur Respir J 2007;30:223-31.
- O'donnell CP, Schaub CD, Haines AS, Berkowitz DE, Tankersley CG, Schwartz AR, et al. Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med 1999;159:1477-84.
- Nobre JL, Lisboa PC, Santos-Silva AP, Lima NS, Manhaes AC, Nogueira-Neto JF, et al. Calcium supplementation reverts central adiposity, leptin, and insulin resistance in adult offspring programed by neonatal nicotine exposure. J Endocrinol 2011;210:349-59.
- Zemel MB. The role of dairy foods in weight management. J Am Coll Nutr 2005;24:537S-46S.
- Nonaka H, Tsujino T, Watari Y, Emoto N, Yokoyama M. Taurine prevents the decrease in expression and secretion of extracellular superoxide dismutase induced by homocysteine: amelioration of homocysteine-induced endoplasmic reticulum stress by taurine. Circulation 2001;104:1165-70.
- Gentile CL, Nivala AM, Gonzales JC, Pfaffenbach KT, Wang D, Wei Y, et al. Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease. Am J Physiol Regul Integr Comp Physiol 2011;301:R1710-R1722.
- Haber CA, Lam TK, Yu Z, Gupta N, Goh T, Bogdanovic E, et al. N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress. Am J Physiol Endocrinol Metab 2003;285:E744-E753.
- Petty MA, Kintz J, DiFrancesco GF. The effects of taurine on atherosclerosis development in cholesterol-fed rabbits. Eur J Pharmacol 1990;180:119-27.
- Iossa S, Mollica MP, Lionetti L, Crescenzo R, Botta M, Barletta A, et al. Acetyl-L-carnitine supplementation differently influences nutrient partitioning, serum leptin concentration and skeletal muscle mitochondrial respiration in young and old rats. J Nutr 2002;132:636-42.