Evidence Based

Dangers of High Leptin & How to Lower Levels

Written by Joe Cohen, BS | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:
Jonathan Ritter
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology) | Written by Joe Cohen, BS | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:

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High Leptin is linked with obesity
High leptin is dangerous: it’s tightly tied with obesity, overeating, and inflammation. If your leptin levels stay too high for too long, there’s a high chance you’ll get leptin resistance. Keep reading to learn about the dangers of high leptin and how to lower your levels naturally.

What is Leptin?

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

When you eat enough food, leptin is released into the bloodstream, where it travels to the brain, signaling that you’re full and that you can burn calories at a normal rate [2, 3, 4].

To learn more about normal leptin levels and what this hormone does in the body, read the first part of this series.

This post will focus on the dangers of high leptin. Elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases – including high blood pressure, metabolic syndrome, and heart disease [5].

Leptin’s Role in Weight

To recap, leptin is one of the big 4 hormones that determine your weight. It is made in fat tissue, while receptors for it are dense in two important brain regions (the hypothalamus and hippocampus) [6].

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

At the same time, it protects non-fat tissue from 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 [7].

The more fat you have, the more leptin you produce, which is supposed to make you thinner, keeping your weight in homeostasis [8].

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

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

High Leptin


High leptin levels can be caused by:

  • Overeating [9, 10]
  • Emotional stress [11]
  • Inflammation [9, 12]
  • Obesity [10]
  • Pregnancy [13]
  • Pre-eclampsia [13]
  • Gestational diabetes [13]
  • Sleep apnea [14]

Negative Health Effects

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 [15]. 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 [16].

It also increases C-Reactive Protein (CRP) [17].

Leptin provokes the release of proinflammatory cytokines from many cell types, including microglia in the brain [18], and is a mediator of cytokine-induced sickness behavior (CFS) [19].

Multiple studies have demonstrated elevated levels of leptin in chronic inflammatory conditions [20].

It also increases red and white blood cells [15].

Elevated leptin is associated with higher white blood cell (WBC) counts in both men and women [21]. 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 [22]. Interestingly, it is higher in women even when controlled for weight [23] and women are more likely to get CFS.

This is, in part, because testosterone suppresses leptin in men (clinical trials) [24].

The fatigue would make sense, given that leptin inhibits orexin [25, 26], 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 [27].

Leptin levels in the blood are also associated with fatigue severity in patients with chronic hepatitis C and irritable bowel syndrome (IBS) [22].

In people with CFS, leptin increases more in response to cortisol [28].

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 [15]. 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 [29] and promotes Th1 responses [15].

By stimulating STAT3, it might also stimulate Th17 responses [30]. Leptin also changes human dendritic cells (DCs), directing them towards Th1 dominance [31].

It was also found to be necessary for Th1 dependent inflammatory processes, acting as a critical regulator of CD4 T cells [32].

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 [33, 34].

Th1 dominance correlates with excess leptin in this study of dialysis patients [35]. 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 [36].

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) [36] – 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 [37], suggesting that it has some effect on mast cells.

It seems like leptin causes mast cells to be more inflammatory [38].

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 [39].

Leptin correlates with (probably increases) mast cell activation in children with asthma who exercised [40].

It suppresses appetite, in part, by increasing histamine release and activating histamine H1 receptors in the hypothalamus [41, 42].

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 [43].

While excess SOCS3 decreases leptin function, SOCS3 deficiency enhances leptin sensitivity and decreases diet-induced weight gain in animals [44].

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 [45].

It may also increase surface molecules that stimulate the immune system, such as CD80, CD83, or CD86 [15].

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 [46], 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 [15]. 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) [47].

It activates the HPA axis and lowers heart rate variability (HRV) [48].

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 [49].

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

9) May Cause Heart Disease

Leptin receptors are found in the heart [50]. Studies have linked high leptin levels to an increased risk of cardiovascular disease [50].

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 [51].

Even so, high leptin levels also are associated with high blood pressure [52], although this might be because of leptin resistance because leptin infusion in rats lowers blood pressure [53].

Leptin’s increases endothelin-1 production, which is a potent vasoconstrictor [52]. By constricting blood vessels, leptin/endothelin-1 could play a role in the development of heart disease [52].

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 [54].

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 [54].

Leptin may increase pain by activating inflammatory markers (IL-1B, IL-6, IL-18) or preventing pain modulating signaling [54].

11) Reduces 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 [55], intestinal transport of fructose [56] and oligopeptides [57].

Leptin decreases glucose [58] and galactose uptake [59]. It also inhibited the absorption of Proline, Beta-Alanine, and Glutamine [60].

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.

10) Increases the Risk of Leptin Resistance

Chronically high leptin levels can lead to leptin resistance. Symptoms of leptin resistance include [61]:

  • Weight gain and difficulty losing weight
  • Urge to snack soon after meals

I go into detail about how to combat and reverse the harmful effects of leptin resistance in this post.

How to Lower Leptin

Leptin is increased after meals – more by carbohydrates then by fat in both obese and healthy people [62, 63].

When stressed, you release leptin and the more you release, the more you eat comfort foods after [64].

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

1) Refrain from Over Eating & Change Your Diet

Refrain from overeating during meals. Eat more protein to feel more full [12, 65].

Consume a diet low in carbohydrates and fat [66].

Incorporate more anti-inflammatory foods in your diet, such as fatty fish, olive oil, nuts, fruits, and vegetables [67].

2) Reduce Stress

Emotional stress, the stress hormone cortisol, and anti-inflammatory steroid drugs all increase leptin [11, 68].

De-stress on a regular basis to lower your leptin levels.

3) Reduce Toxin Exposure & Inflammation

  • Endotoxin in both rodents and humans leads to increased leptin levels [6970].
  • Inflammatory cytokines such as TNF/IL-1 increase leptin [7172]
  • Interferon-gamma and LPS mixture in fat cell cultures raises leptin [73]

Try to uncover the underlying cause of your inflammation.

4) Check Your Estrogen Levels

Estrogen increases leptin. This is usually bad, especially in men and since excess estrogens have been linked to leptin resistance. Check your levels to make sure you are in the normal range [74]

5) Rule Out Sleep Apnea

Sleep apnea increases leptin in obese people. Their levels go back to normal after CPAP treatment [14].

6) Try Fasting

Short-term fasting decreases leptin (24-72 hours) [75].

You can start with intermittent fasting, unless you have a medical condition or are on any medications (in those cases consult with your doctor first) [75].

6) Get More Exercise

Exercise lowers leptin [76, 77].

7) Take Cold Showers

Take more cold showers. Cold temperatures can decrease leptin [12, 78].

8) Other Strategies to Look Into

All the following lower leptin:

For example, your leptin might be high because your thyroid hormones or testosterone are low. Check your levels to see if they are in the normal range.

Supplements that can help include:

  • African mango (Irvingia gabonensis) [80]
  • Fish oil. Fish oil helps decrease inflammation [67]

Irregular Leptin Levels?

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About the Author

Joe Cohen, BS

Joe Cohen, BS

Joe Cohen won the genetic lottery of bad genes. As a kid, he suffered from inflammation, brain fog, fatigue, digestive problems, anxiety, depression, and other issues that were poorly understood in both conventional and alternative medicine.Frustrated by the lack of good information and tools, Joe decided to embark on a journey of self-experimentation and self-learning to improve his health--something that has since become known as “biohacking”. With thousands of experiments and pubmed articles under his belt, Joe founded SelfHacked, the resource that was missing when he needed it. SelfHacked now gets millions of monthly readers.Joe is a thriving entrepreneur, author and speaker. He is the CEO of SelfHacked, SelfDecode and LabTestAnalyzer.His mission is to help people gain access to the most up-to-date, unbiased, and science-based ways to optimize their health.
Joe has been studying health sciences for 17 years and has read over 30,000 PubMed articles. He's given consultations to over 1000 people who have sought his health advice. After completing the pre-med requirements at university, he founded SelfHacked because he wanted to make a big impact in improving global health. He's written hundreds of science posts, multiple books on improving health, and speaks at various health conferences. He's keen on building a brain-trust of top scientists who will improve the level of accuracy of health content on the web. He's also founded SelfDecode and LabTestAnalyzer, popular genetic and lab software tools to improve health.

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