If you’re overweight OR underweight OR have CFS, CIRS, autoimmunity or chronic inflammation, then leptin is relevant to your health. This post will tie several threads together that I’ve been discussing for a while and cause some brain sparks to fly.

What is Leptin?


Leptin is a satiety hormone that causes weight loss. It is produced by the body’s fat cells [1].

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 [2].


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 [3].

However, it is now considered a multifunctional hormone that is produced by various tissues and organs including the placenta [4], kidney [5], salivary glands [6], and stomach [7].

Leptin is one of the big 4 hormones that determine weight. It is synthesized in fat tissue and receptors are found in higher concentrations in the hypothalamus and hippocampus [8].

The more body fat we carry, the more leptin we produce [9]. Leptin gets released into the blood and goes into the brain, where it sends a satiety signal to the hypothalamus.

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 [10].

Chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including hypertension, metabolic syndrome, and heart disease [11]. Leptin resistance can contribute to hardening of the arteries [11].

It affects the growth of blood vessels and bone, the immune system, and the reproductive system.

Normal Levels

You can find out your leptin levels with a simple blood test. The results are usually given as ng/mL (nanogramsng/mL per mililiter).

Normal leptin levels are 4.7 – 23.7 ng/ML, though they may slightly vary between labs.

If your levels are normal, you should be able to eat until you are full and not crave any more food.

Circulating leptin levels are directly proportional to the amount of body fat and they change depending on food intake [12, 13, 14].

Factors that affect leptin levels include:

  • Time of day: Leptin levels are higher at night than during the day [15].
  • Sex: Women have higher leptin levels than men [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.

More About Leptin

The next section will dive deep into the science of leptin in the human body. If you want the bottom line, skip to the posts linked above instead.

What Does Leptin Do?

Controls Food Intake & Energy Use


I separated this section for science geeks. No need to read this part.

The image above shows that when you lose weight, your leptin levels fall, your rest-and-digest system activates, and your food intake normally goes up.

This is because weight loss mimic a state of mild starvation, and your body tries to fight it by making you want food. The same happens with fasting.

On the other hand, the more fat cells you have–and the more weight you gain–the more your leptin levels will rise.

Your body usually interprets this as a state of abundance, but one that can lead to obesity. In response, your body will want to increase your energy use to avoid falling too deep into this trap.

That’s probably why obesity can also increase your fight-or-flight response, as your body is trying to get you out of staying in the dangerous “overeat and rest” phase for too long. High leptin levels are meant to facilitate weight loss in such cases.

Causes Weight Loss

The primary actions of leptin have been thought to occur in the arcuate nucleus of the hypothalamus.

It suppresses food intake and increases energy expenditure at least partially by activating POMC and CART neurons and by suppressing NPY and AgRP [17].

The fact that leptin elevates BDNF in the hypothalamus suggests that BDNF might mediate the effects of leptin on food intake and energy homeostasis [8].

Leptin works synergistically with GLP-1, CCK, and Amylin in reducing food consumption and weight [18].

It also increases TRH (via STAT3 and MSH/MC4R) [19], MSH [20] and CRH [21] (contradictory), all of which inhibit appetite.

By increasing growth hormone release, it can also cause weight loss [22]. Leptin inhibits AMPK, an energy sensor which is activated by decreased ATP.

Leptin activates mTOR in the hypothalamus, which reduces appetite [23].

In the ventral tegmentum (an area important for cognition, motivation, orgasm, drug addiction, and intense emotions relating to love), leptin reduces dopamine neurotransmission and makes food less rewarding [24].

Chronic leptin infusion in rats increases blood pressure, by activating the nervous system [25].

MSH is considered to be an important mediator of some of the action of leptin to reduce food intake.

MSH (binding to MC3R/MC4R) is the mechanism by which leptin decreases food intake (MC4R), activates the nervous system in the kidneys (MC4R) and increases blood pressure (MC3R) [25].

It also inhibits NPY and AgRP, which increase appetite and weight, but it’s thought that these mechanisms only come into play when MC4R is compromised [25].

Stimulates the Immune System

Leptin levels are increased upon infectious and inflammatory stimuli such as LPS (from bacteria), turpentine, and cytokines [26].

The leptin receptor is found in B and T lymphocytes, in neutrophils and monocytes, which suggests that it directly regulates these immune responses [27].

Leptin potentiates the stimulatory effect of LPS on the proliferation and activation of human monocytes.

It increased oxidative stress in macrophages [28] but decreases oxidative burst in previously activated monocytes [29].

Leptin could act as a monocyte/macrophage chemoattractant, which means that it attracts immune cells to local areas [30].

How It Interacts With Other Hormones


  • Stimulates growth hormone release [22]
  • Increases CRH in the PVN [31], but decreases stress-induced ACTH and Cortisol in mice [32].
  • Stimulates thyroid hormone release (TRH, TSH, T4) [33, 34]. Leptin is able to prevent the decline in T3 from fasting [35].
  • Increases 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 [35].
  • Increases estrogen
  • Decreases Ghrelin [36, 37]
  • Increases Gonadotropin Releasing Hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH) and human chorionic gonadotrophin (hCG) [38, 39, 40].
  • Increases alpha-MSH [18, 41]

Leptin inhibits progesterone in placental cells [39]. Higher levels are associated with lower testosterone in men, even when controlling for BMI [42].

On the other hand, leptin supplementation prevents the decline in testosterone from fasting in men (by increasing LH) [35].

So it makes more sense that leptin resistance is what’s causing testosterone to decline in overweight men.

Irregular Leptin Levels?

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