Everyone – from people who are overweight or underweight to those with autoimmunity or chronic inflammation – is starting to talk about leptin. What exactly is leptin and how is it relevant to health? This post dives into the science of leptin.
What is Leptin?
Leptin is produced by the body’s fat cells. It has been called the “satiety hormone that causes weight loss.” It has also been called the “obesity hormone” or “fat hormone.” And lastly, it’s been nicknamed the “starvation hormone.”
Initial research hyped leptin’s alleged weight loss effects, but further studies revealed that leptin is not the weight loss pill everyone has been searching for. No proper clinical trials speak to its anti-obesity effects .
In fact, leptin levels increase exponentially, not linearly, with fat mass. This means that increased body weight can cause leptin to go much higher. Fat cells release more than 50 hormones and signaling molecules .
Initially, leptin was known to be secreted by fat tissue, and circulate at levels directly proportional to the total amount of fat in the body .
However, it is now considered a multifunctional hormone that is produced by various tissues and organs including the placenta , kidney , salivary glands , and stomach .
Some people think that leptin is one of the big 4 hormones that determine weight. However, no proper research supports such a simplified approach, since many hormones and factors are involved in weight control.
Leptin is synthesized in fat tissue and receptors are found in higher concentrations in the hypothalamus and hippocampus .
Recent theories suggest that the more body fat we carry, the more leptin we produce. Some scientists say that leptin gets released into the blood and goes into the brain, where it sends a satiety signal to the hypothalamus. There, it tells the brain that we have enough fat stored, that we don’t need to eat, and that we can burn calories at a normal rate. This is still a hypothesis, though [9, 10].
In some studies, chronically-elevated leptin levels have been associated with obesity, overeating, and inflammation-related diseases, including hypertension, metabolic syndrome, and heart disease . However, no cause-and-effect has been established.
According to other theories, leptin resistance may contribute to hardening of the arteries. These theories are still somewhat controversial .
Lab results are commonly shown as a set of values known as a “reference range”, which is sometimes referred to as a “normal range”. A reference range includes the upper and lower limits of a lab test based on a group of otherwise healthy people.
Your healthcare provider will compare your lab test results with reference values to see if any of your results fall outside the range of expected values. By doing so, you and your healthcare provider can gain clues to help identify possible conditions or diseases.
Leptin levels can be measured with a blood test. The results are usually given as ng/mL (nanograms per milliliter).
Normal leptin levels may be 4.7 – 23.7 ng/ML, though they may slightly vary between labs. They may also depend on a person’s age, gender, and the time of the day they gave blood:
- Time of day: Leptin levels may be higher at night than during the day .
- Sex: Women have higher leptin levels than men .
Studies suggest that circulating leptin levels are directly proportional to the amount of body fat and that they may change depending on food intake [14, 15, 16].
A leptin test is usually ordered for overweight/obese individuals, especially if there is a family history of obesity. It can also be ordered for an obese person who has symptoms of frequent, persistent hunger to detect a leptin deficiency or excess.
Sometimes, it is used with other tests, such as a thyroid panel, glucose, cholesterol, and insulin, to determine the health status of an overweight/obese person and detect underlying conditions that may be contributing to or worsening their condition.
Some lab-to-lab variability occurs due to differences in equipment, techniques, and chemicals used. Don’t panic if your result is slightly out of range – as long as it’s in the normal range based on the laboratory that did the testing, your value is normal.
However, it’s important to remember that a normal test doesn’t mean a particular medical condition is absent. Your doctor will interpret your results in conjunction with your medical history and other test results.
Remember that a single test isn’t enough to make a diagnosis. Your doctor will interpret this test, taking into account your medical history and other tests. A result that is slightly low/high may not be of medical significance, as this test often varies from day to day and from person to person.
More About Leptin
- Factors that may increase leptin levels
- Factors that may lower leptin levels
- Factors that may counteract the effects of leptin resistance
What Does Leptin Do?
This section will dive deep into the science of leptin. Leptin research is still in the early stages and none of the findings listed below deal with leptin supplements. The scientific findings below focus on the potential roles of naturally-produced leptin in the human body.
If you are concerned about your leptin levels or weight, speak to your healthcare provider. He or she will ensure an accurate diagnosis and treatment.
Food Intake & Energy Use
The image above shows that when people lose weight, leptin levels tend to fall, the rest-and-digest system activates, and food intake normally goes up .
According to one hypothesis, this might be because weight loss mimics a state of mild starvation, and the body tries to fight it by triggering food cravings. The same happens with fasting .
On the other hand, the more fat cells people have – and the more weight they gain – the more their leptin levels are likely to rise. Some scientists say that the body usually interprets this as a state of abundance, but one that can lead to obesity. In response, the body will want to increase energy use to avoid falling too deep into this trap .
To back up this theory, some people say that this might be why obesity can also increase the fight-or-flight response, as the body may be trying to get out of staying in the dangerous “overeat and rest” phase for too long. They say high leptin levels are meant to facilitate weight loss in such cases. Nonetheless, these theories remain clinically unproven.
The primary actions of leptin have been thought to occur in the arcuate nucleus of the hypothalamus. Scientists studied the way it suppresses food intake and increases energy expenditure in animals at least partially by activating POMC and CART neurons and by suppressing NPY and AgRP .
In animals, leptin increases BDNF in the hypothalamus. Some researchers believe that BDNF might mediate the effects of leptin on food intake and energy homeostasis. The potential synergy of leptin with GLP-1, CCK, and Amylin in reducing food consumption is an area of research [8, 20].
Other research groups are investigating the effects of leptin on:
- TRH (via STAT3 and MSH/MC4R) , MSH  and CRH 
- growth hormone release .
- Inhibition of AMPK, an energy sensor that is activated by decreased ATP.
- mTOR in the hypothalamus, which may affect appetite .
- Dopamine in the ventral tegmentum (an area potentially involved in everything from cognition, motivation, orgasm, drug addiction, to intense emotions relating to love), which may affect how rewarding food is .
- Blood pressure .
- MSH (binding to MC3R/MC4R), which may activate the nervous system in the kidneys (MC4R) and affect blood pressure (MC3R) .
- Inhibiting NPY and AgRP, potentially when MC4R is compromised .
None of these mechanisms have been explored in humans.
Scientists are studying leptin in cells to see if it increases upon infectious and inflammatory stimuli such as LPS (from bacteria), turpentine, and cytokines. They also want to know how it affects oxidative stress in macrophages and monocytes and if it can attract immune cells to local areas [28, 29, 30, 31].
The leptin receptor is found in B and T lymphocytes, in neutrophils and monocytes, which suggests that it plays a role in the immune response .
How It May Interact With Other Hormones
Research is aiming to determine whether leptin has the following effects:
- Increasing Growth hormone release 
- Increasing CRH in the PVN , but decreases stress-induced ACTH and Cortisol in mice .
- Stimulating thyroid hormone release (TRH, TSH, T4) [35, 36]. Leptin is able to prevent the decline in T3 from fasting .
- Increasing IGF-1, but not free IGF-1, because it also increases its binding protein. Leptin is able to prevent the decline in IGF-1 from fasting .
- Increasing estrogen
- Decreasing Ghrelin [38, 39]
- Increasing Gonadotropin Releasing Hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH) and human chorionic gonadotrophin (hCG) [40, 41, 42].
- Increasing alpha-MSH [20, 43]
- Inhibiting progesterone in placental cells .
These effects have not been properly researched or determined in humans.
Limited studies have shown that higher leptin levels are associated with lower testosterone in men, even when controlling for BMI. On the other hand, leptin supplementation was suggested to prevent the decline in testosterone from fasting in men (by increasing LH). Therefore, the interaction between leptin and testosterone has yet to be clarified [44, 37].