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. A future post will be about how to combat the harmful effects of leptin and how to reverse leptin resistance.

What is Leptin?

Leptin causes weight loss. It is a satiety hormone that 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.

Leptin’s Role in Weight

Leptin acts as a signal to the brain to inhibit food intake and enable the storage of surplus calories (in fat cells).

It simultaneously protects non-fat tissue from toxic effects of fat overload. Increased leptin is associated with higher body fat mass, a larger size of individual fat cells, and the act of overeating/hunger.

In rodents, it increases energy expenditure by using brown fat for energy [12].

The more fat you have, the more leptin you produce, which is supposed to make you thinner, keeping your weight in homeostasis [13].

This is what’s supposed to happen in healthy people:

Eating->Increased body fat->Increased leptin->Decreased appetite, increased energy expenditure.

Leptin: The Bad

Leptin has some bad and good properties. We need to understand what the pros and cons are to make smart decisions.

1) Increases Inflammation

Leptin is an inflammatory marker, as it responds to inflammatory cytokines from fat tissues.

Autoimmune diseases are associated with increased secretion of leptin [14]. In terms of both structure and function, it resembles IL-6.

Leptin increases the release of the proinflammatory cytokines TNF-alpha, IL-2, IL-6, and IL-12 [15].

It also increases C-Reactive Protein (CRP) [16].

Leptin provokes the release of proinflammatory cytokines from many cell types, including microglia in the brain [17], and is a mediator of cytokine-induced sickness behavior (CFS) [18].

Multiple studies have demonstrated elevated levels of leptin in chronic inflammatory conditions [19].

It also increases red and white blood cells [14].

Elevated leptin is associated with higher white blood cell (WBC) counts in both men and women [20]. WBC‘s increase inflammation in the body.

This may be one reason why the thin people that I deal with seem to have lower WBC counts (lower leptin, lower WBCs).

2) Causes Fatigue and CFS

Leptin causes inflammatory fatigue [21]. Interestingly, it is higher in women even when controlled for weight [22] and women are more likely to get CFS.

This is, in part, because testosterone suppresses leptin in men (clinical trials) [23].

The fatigue would make sense, given that leptin inhibits orexin [24, 25], which can cause fatigue and lower motivation.

Leptin increases were associated with greater fatigue scores in people with CFS, and it’s assumed that it plays a causal role in CFS [26].

Leptin levels in the blood are also associated with fatigue severity in patients with chronic hepatitis C and irritable bowel syndrome (IBS) [21].

In people with CFS, leptin increases more in response to cortisol [27].

Why Are People With CFS More Susceptible to Leptin?

Note that leptin isn’t necessarily higher in people with CFS. Some studies show it is and some studies show it isn’t.

Rather, it triggers inflammation in people with CFS more so than it does in healthy people.

According to Dr. Younger, people with CFS have microglia that is more primed to activate, and leptin is the trigger, which causes a spike in fatigue.

Interestingly, leptin receptors are increased by pro-inflammatory signals [14]. This means that if you have inflammation, you will get an increased response from leptin – at least in some ways.

3) Causes Th1 Dominance

Leptin activates the JAK2 STAT3 pathway [28] and promotes Th1 responses [14].

By stimulating STAT3, it might also stimulate Th17 responses [29]. Leptin also changes human dendritic cells (DCs), directing them towards Th1 dominance [30].

It was also found to be necessary for Th1 dependent inflammatory processes, acting as a critical regulator of CD4 T cells [31].

The effect of leptin polarizing T cells towards a Th1 response seems to be mediated by stimulating the synthesis of IL-2, IL-12, and IFN-gamma (all Th1 cytokines) and inhibiting the production of IL-10 and IL-4 [32, 33].

Th1 dominance correlates with excess leptin in this study of dialysis patients [34]. If you’re Th2 dominant, it doesn’t mean leptin isn’t causing you problems. It simply means that it’s causing you different problems.

Real world example:

People often have more inflammation upon awakening. It’s known that people with arthritis have worse joint pain in the morning [35].

Well, leptin rises as the day goes on and peaks at midnight and continues to be elevated while you’re sleeping (to prevent you from getting hungry in the middle of the night) [35] – and that may spike inflammation, which you will feel the next morning.

4) Mast Cells and Histamine Intolerance

Leptin may have to do with histamine intolerance. Mast cells in human skin, lungs, gut, and the urogenital tract contains leptin and leptin receptors [36], suggesting that it has some effect on mast cells.

It seems like leptin causes mast cells to be more inflammatory [37].

In metabolic syndrome patients, there was a positive correlation between leptin levels and the number of fat tissue mast cells, suggesting that leptin may stimulate mast cells [38].

Leptin correlates with (probably increases) mast cell activation in children with asthma who exercised [39].

It suppresses appetite, in part, by increasing histamine release and activating histamine H1 receptors in the hypothalamus [40, 41].

5) Chronic Inflammatory Response Syndrome (CIRS)

Many people with CIRS gain weight, and it’s thought that this is from leptin resistance.

My theory is that people get inflammation and mount an anti-inflammatory SOCS3 response, which causes leptin resistance. I believe this is somewhat unique in CIRS patients, who are mainly Th2 dominant, compared to other people with CFS.

SOCS3 is increased by a variety of cytokines. It blocks leptin function [42].

While excess SOCS3 decreases leptin function, SOCS3 deficiency enhances leptin sensitivity and decreases diet-induced weight gain in animals [43].

What’s interesting is that CIRS is thought to have problematic HLA-DR genes. Human leptin was found to stimulate monocytes surface markers, such as HLA-DR [44].

It may also increase surface molecules that stimulate the immune system, such as CD80, CD83, or CD86 [14].

Therefore, leptin probably contributes to the inflammatory state of CIRS. With that said, leptin is not all that bad for CIRS.

Leptin directly activates the POMC/CART neurons causing a release of alpha-MSH [45], which is often lower in people with CIRS.

Real world scenario:

I have a client with CIRS who tells me that they feel better when they fast and, oddly, when they sleep less. In both cases, leptin declines, which would cause less inflammation in some ways. This might explain why they feel better when they sleep less (not recommended, because in the long term it’s bad for you).

6) Lowers T Regulatory (TREG) Cells

Leptin lowers Treg cells [14]. Tregs are a critical part of the immune system that creates a tolerance to agents that set our immune system off.

So when you ingest or breathe something and it causes you an inflammatory reaction, it’s in part because of lower Tregs.

7) Activates the HPA Axis

Leptin increases the stress response and the activity of the sympathetic nervous system (fight or flight) [46].

It activates the HPA axis and lowers heart rate variability (HRV) [47].

8) Promotes the Growth of Cancer

Leptin promotes the growth and spread of cancer. This is one reason why obesity is a risk factor for cancer [48].

It increases angiogenesis by increasing vascular endothelial growth factor (VEGF) levels.

9) May Cause Heart Disease

Leptin receptors are found in the heart [49]. Studies have linked high leptin levels to an increased risk of cardiovascular disease [49].

In obese subjects, leptin levels are the most significant predictor of higher levels of fibrinogen, a clotting factor considered to be one of the most important risk factors for heart disease [50].

Even so, high leptin levels also are associated with high blood pressure [51], although this might be because of leptin resistance because leptin infusion in rats lowers blood pressure [52].

Leptin’s increases endothelin-1 production, which is a potent vasoconstrictor [51]. By constricting blood vessels, leptin/endothelin-1 could play a role in the development of heart disease [51].

10) Increases Pain Sensitivity

Higher leptin levels in the body can cause the body’s pain sensitivity to increase. This is because it can cause inflammation, which plays a role in pain [53].

In a study of 3 fibromyalgia patients, they reported higher pain levels on days when they had increased leptin in their blood. A cohort study of 5,600 postmenopausal women showed similar results [53].

Leptin may increase pain by activating inflammatory markers (IL-1B, IL-6, IL-18) or preventing pain modulating signaling [53].

Leptin: The Good

Leptin is obviously good and necessary in many ways. The problem is leptin resistance in certain parts of the body (hypothalamus), which leaves excess leptin in the blood.

1) Reduces Anxiety and Depression

Recent studies suggest that leptin may have antidepressant and anti-anxiety properties.

In rat models of depression and anxiety, leptin levels are low. When given leptin, symptoms improve [54].

On the other hand, Ghrelin, the hunger hormone, causes anxiety and depression [54], which leads to the ‘hangry’ feeling – hungry and angry.

Depression and anxiety are common in women with anorexia nervosa (AN), an illness associated with low leptin and increased ghrelin [54].

Similarly, there is an increased prevalence of depression and anxiety in normal-weight women with functional hypothalamic amenorrhea (HA), a disorder also characterized by low leptin and high ghrelin [54].

Recently, obesity has been linked to an increased risk of depression and anxiety [54], which can result from leptin resistance. High leptin levels were associated with lower depression scores [54].

Leptin’s anti-anxiety effects are mediated in part by its actions in the Prefrontal cortex (PFC), the ventral tegmental area (VTA) and substantia nigra (SN) [54]. Leptin also reduces anxiety by inhibiting orexin A in the Suprachiasmatic Nucleus (SCN) [55].

Real world example:

A client asked me why sometimes he feels his depression and anxiety decline after meals. There are a few reasons for that, but one reason, I told him, might be leptin.

He said it happens in the evening, which makes sense because leptin increases as the day goes on.

2) May Improve Cognitive Function

Leptin has some positive effects on cognitive function.

Like BDNF, leptin facilitates synaptic plasticity in the hippocampus [8] and long-term potentiation (LTP) [8], processes that are critical for memory.

Leptin also helps spatial learning [8]. It increases BDNF in the hypothalamus (VMH) [56].

Animal models of Alzheimer’s disease have shown that chronic administration of leptin can be beneficial for the condition and improve cognitive performance, by reducing b-amyloid and Tau proteins, two hallmarks of Alzheimer’s pathology [57, 58].

3) Improves Fertility and Bone Health

Leptin is proven to restore fertility and may improve bone health in lean women [59].

Women with extremely low body fat, including runners and dancers, as well as women with eating disorders, are prone to develop hypothalamic amenorrhea (HA), a condition in which their menstrual periods cease, triggering serious problems such as infertility and osteoporosis [59].

Without leptin, menstrual periods cease, the body becomes chronically energy-deprived and women experience bone loss and an increased risk of bone fractures [59].

Treatment with a synthetic form of leptin can restore fertility and reduce the risk of bone fractures in this group of patients [59]. This is one reason why during fasting or starvation, fertility declines [59].

Leptin helps fertility by increasing luteinizing hormone (LH), follicle stimulating hormone (FSH) and human chorionic gonadotrophin (hCG) [60, 61].

Real world example:

People who are very thin and anxious often have fertility problems.

This is because thin and anxious people have low leptin and high ghrelin, both of which increase anxiety.

Ghrelin reduces fertility by inhibiting GnRH [62].

4) Strengthens the Immune System

It has been shown that conditions of reduced leptin production are associated with increased infection susceptibility [14].

The decline of leptin during fasting is one of the main mechanisms by which fasting suppresses the immune system [14]. (Lower T3 is another.)

Leptin Stimulates Natural Killer Cells

People who get chronic infections often have lower immune function and blood tests for Natural Killer Cells and Natural Killer Cell Activity often come back low.

Leptin stimulates the maturation, production, activation, and function of human Natural Killer cells [63].

It increases the production of IL-2, IL-12 and perforin in natural killer (NK) cells [64, 65].

It also activates NK cells indirectly by increasing IL-1, IL-6, and TNF – by monocytes and macrophages [66].

5) Improves Insulin Sensitivity

Leptin improves insulin sensitivity (by way of MC4R) [45].

6) May Lower Cholesterol

Humans born with a genetic leptin deficiency are profoundly obese, have high insulin and high cholesterol [67].

Leptin replacement in these people can improve insulin, cholesterol, triglyceride, and LDL cholesterol levels [67].

7) Might Combat Allergic Reactions By Inhibiting IgE Immune Responses

True to its Th1 dominant role, leptin suppresses IgE-mediated cytokine production.

Additionally, studies showed that Leptin receptor deficiency magnifies IgE-mediated anaphylaxis.

It may only inhibit IgE responses in mice that are Th1 dominant.

How Leptin Interacts With Other Hormones


  • Stimulates growth hormone release [68]
  • Increases CRH in the PVN [69], but decreases stress-induced ACTH and Cortisol in mice [70].
  • Stimulates thyroid hormone release (TRH, TSH, T4) [71, 72]. Leptin is able to prevent the decline in T3 from fasting [73].
  • 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 [73].
  • Increases estrogen
  • Decreases Ghrelin [74, 75]
  • Increases Gonadotropin Releasing Hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH) and human chorionic gonadotrophin (hCG) [60, 61, 56].
  • Increases alpha-MSH [67, 76]

Leptin inhibits progesterone in placental cells [61]. Higher levels are associated with lower testosterone in men, even when controlling for BMI [22].

On the other hand, leptin supplementation prevents the decline in testosterone from fasting in men (by increasing LH) [73].

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


Leptin may help get people into ketosis.

Leptin-deficient mice do not get into ketosis well and have a defective response to the ketogenic diet (no increase in liver FGF21) [77].

It might improve mitochondrial function (by increasing hsp60), which decreases insulin resistance [78].

Leptin Inhibits The Absorption of Amino Acids and Sugar

It is secreted by the stomach and enters the small intestine. Several studies have shown that leptin interferes with the absorption of some nutrients.

It enhances butyrate uptake [79], intestinal transport of fructose [80] and oligopeptides [81].

Leptin decreases glucose [82] and galactose uptake [83]. It also inhibited the absorption of Proline, Beta-Alanine, and Glutamine [84].

On the one hand, I could see this being both bad and good. If it blocks absorption of glucose and amino acids, it can help weight loss.

However, blocking glucose uptake gives a better chance for SIBO to arise or for malnutrition from not absorbing amino acids.

Leptin Increases VIP

Leptin leads to the production of VIP, the anti-inflammatory hormone (synergistically with TGF-beta) [85].

What Increases Leptin

Leptin is increased after meals – more by carbohydrates then by fat in both obese and healthy people [86, 87].

When stressed, you release leptin and the more you release, the more you eat comfort foods after [88].

Lectins are proteins that bind to sugar molecules. Leptin receptors have these sugar molecules that lectins like to bind to such as ConA (in legumes) and WGA (in wheat). If the sugar molecules on leptin receptors are bound (or removed), then the receptors don’t function nearly as well [89].

Some factors that increase leptin:

  • Endotoxin in both rodents and humans leads to increased leptin levels [9091].
  • Cytokines such as TNF/IL-1 [9293]
  • Estrogen [94]
  • Emotional stress [95]
  • Cortisol [93], Dexamethasone [96]
  • Insulin [97] – Leptin increases 4 – 6 hours after meals in response to insulin secretion [98].
  • Obesity [99]
  • Restful sleep – in non-obese individuals (i.e., 8 – 12 hours of unbroken sleep) – can increase leptin to normal levels [100].
  • Sleep apnea – in obese people, but it decreased after CPAP treatment [101].
  • Glucosamine (and hexosamines) (in pancreatic beta-cells) [102].
  • Circadian clock proteins (BMAL1/CLOCK) increase leptin production [103].

What Decreases Leptin

Since I’m Th1 dominant, decreasing leptin would be beneficial for me, with regards to inflammation.

Mechanisms of Leptin


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

Other Ways That Leptin Stimulates The Immune System

Leptin levels are increased upon infectious and inflammatory stimuli such as LPS (from bacteria), turpentine, and cytokines [111].

The leptin receptor is found in B and T lymphocytes, in neutrophils and monocytes, which suggests that it directly regulates these immune responses [14].

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

It increased oxidative stress in macrophages [112] but decreases oxidative burst in previously activated monocytes [113].

Leptin could act as a monocyte/macrophage chemoattractant, which means that it attracts immune cells to local areas [114].

The Mechanisms by Which Leptin 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 [115].

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 [67].

It also increases TRH (via STAT3 and MSH/MC4R) [116], MSH [117] and CRH [118] (contradictory), all of which inhibit appetite.

By increasing growth hormone release, it can also cause weight loss [68]. Leptin inhibits AMPK, an energy sensor which is activated by decreased ATP.

Leptin activates mTOR in the hypothalamus, which reduces appetite [119].

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 [120].

Chronic leptin infusion in rats increases blood pressure, by activating the nervous system [121].

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) [121].

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 [121].

Irregular Leptin Levels?

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