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What Causes Leptin Resistance & Can You Reverse It?

Written by Puya Yazdi, MD | Last updated:
Nattha Wannissorn
Medically reviewed by
Nattha Wannissorn, PhD | Written by Puya Yazdi, MD | Last updated:

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We’ve written a comprehensive post about Leptin before. This post is about leptin resistance. Leptin resistance is common in obesity and it doesn’t suppress appetite. Scientists are investigating how leptin sensitivity affects weight loss and inflammation–but can you actually reverse leptin resistance? Read on to learn what the latest research suggests.

What is Leptin Resistance?

Obese humans have high levels of leptin, which suggests a strong link between leptin and obesity [1]. But is it really all that simple?
To rewind, leptin is produced by the body’s fat cells. It has been called the “satiety hormone that causes weight loss,” the “obesity hormone” or “fat hormone,” And lastly, 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 [2].

On the contrary, leptin levels increase exponentially (more drastically), not linearly, with fat mass. This means that increased body weight may cause leptin to go much higher [3].

Leptin resistance is when leptin doesn’t work as well to decrease appetite or increase energy expenditure. Tissues and cells seem to become resistant to even high amounts of it–a similar mechanism to insulin resistance, but different hormonal pathways are involved [4].

Leptin resistance is now believed to be the leading driver of fat gain in humans [5].

Because fat cells produce leptin in proportion to their size, obese people tend have very high levels of leptin [6] that doesn’t perform its job properly [7].

Although leptin is thought to suppress appetite when it’s slightly raised,it seems to have the opposite effects when it gets too high. That’s why scientists think leptin resistance leads to increased appetite and decreased energy expenditure [4].

What Are The Mechanisms of Leptin Resistance?

Scientific Theories

Many mechanisms have been proposed to explain leptin resistance, including impairment in leptin transportation and leptin “signaling” issues [8, 9].

Limited studies suggest that in obese people with very high leptin, levels in the cerebrospinal fluid only increase slightly [10].

Thus, scientists believe that leptin might not be getting into the brain and this could be a part of the problem. This theory hasn’t been verified yet, though [10].

Animal and cell-based experiments suggest that high blood Triglycerides may impair leptin from entering the brain. Human studies are needed to determine if this is true [11, 12].

Other researchers say that the second issue be fewer leptin receptors [13].

Lastly, the third issue is thought to arise from a problem in the leptin signaling cascade, which has been linked with leptin resistance (high SOCS3, low JAK2, low STAT3). However, human studies have yet to look into these pathways [13].

In animals, BDNF seems to be needed for leptin to cause weight loss. Lower BDNF has been associated with leptin resistance and weight gain. Although intriguing, this doesn’t tell us anything about leptin resistance in humans. Plus, we can’t measure BDNF commercially and scientists are still trying to understand its roles in the human body [13].

All in all, there is no single cause of leptin resistance. Many pathways have been proposed, and it’s likely that each one contributes to a certain extent. Large human studies are needed to better understand what might lead to leptin resistance in humans.

Factors that May Increase Leptin Sensitivity

When to See a Doctor

If you’re struggling with obesity or leptin resistance, it’s important to schedule a visit with your doctor.

He or she should diagnose, treat, and monitor any underlying conditions causing your symptoms.

Your doctor may also order some blood tests. 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 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 identify underlying conditions that may be contributing to or worsening their condition.

It’s uncertain whether leptin resistance can be reversed. The complementary approaches listed below may help support metabolic and overall health.

That said, you may try them if you and your doctor determine that they could be appropriate.

Remember that none of them should ever be done in place of what your doctor recommends or prescribes.

1) Sleep & Circadian Cues

Circadian Rhythm Disruptions have been linked with leptin resistance and obesity in animals (14).

Most of the existing human studies deal with associations, so it’s impossible to determine whether circadian issues can cause leptin resistance. However, keeping a healthy circadian rhythm is known to support mental and metabolic health.

For example, one study suggested that night-shift workers, who must be awake, active, and eating during the night seem to be at a higher risk of obesity and metabolic diseases [15].

In another study, chronic jet lag disrupted the clock in fat cells and induced Leptin resistance in the brains in mice (14).

Many people that don’t travel across time zones much might not get enough light in the day and too much light at night, which could disrupt the natural biological rhythm.

Thus, it would be a good idea to stick to a certain sleep hygiene. If possible, aim to keep a healthy circadian rhythm. Get some sunlight during the day and enough restful sleep and darkness during the night.

2) Avoiding Nighttime Snacks

Some studies propose that we’ve eaten for about 12 hours in the day and fasted for 12 hours at night over the natural course of mammalian history [16].

In line with the circadian cues theory, it has also been hypothesized that eating during the “wrong” time may contribute to circadian desynchronization and weight gain.

In small human studies, eating after 8 PM was associated with weight gain. Larger studies are needed to understand exactly which foods, in what amounts, and at what time are “wrong” in most humans, though [12, 17].

In lab animals, eating at the wrong time seems to cause changes in leptin that result in weight gain [12, 17].

Mice eating a high-fat diet only during the “wrong’”circadian phase appear to gain 2.5x more weight than mice fed the same diet during the mice’s natural feeding period [18].

One mechanism by which obesity is hypothesized to result from eating at the wrong time–namely, at night–is by preventing the calories from being burned.

In humans, eating identical meals (~544 kcals; 15% protein, 35% fat, 50% carbohydrate) in the nighttime vs daytime results in less generation of heat [19].

Similarly, studies in healthy adults have suggested that meal satiety also varies with time of day and that food intake during the night may be less satiating and leads to greater daily caloric intake compared to food consumed in the morning hours [20, 21].

Thus, some scientists have proposed that when people eat might be more important than what they eat and maybe even than how much people eat. However, all of these factors are important.

Aside from not overeating and following a nutritious diet, avoiding nighttime meals seems like a good idea.

3) Avoiding Overeating

Chronically high levels of leptin may eventually cause leptin resistance as a means to stay in homeostasis, animal studies suggest [22].

Researchers consider that the act of overeating may lead to chronically high levels of leptin in the long run, potentially causing leptin resistance. At that point, people usually find it harder to lose weight because several metabolic pathways are out of balance [23].

Also, eating too many calories–or overeating–eventually leads to obesity and other detrimental health consequences, especially in people who eat unhealthy foods. It can increase inflammation, blood lipids, blood sugar, and increase the risk of many chronic diseases [24].

If you’re not sure where to start, talk to your healthcare provider. They should help you set an initial plan to limit your daily calories while upping your intake of nutritious foods.

4) Reducing Refined Sugars

The consumption of too much sugar AND saturated fat in the typical Western diet is thought to be a crucial contributor to the alarming incidence of obesity [25].

Unhealthy, fast-food-type diets have been reported to induce an inflammatory response in the hypothalamus in animals, which seems to promote the development of brain leptin resistance and obesity [25].

Studies suggest that eating too much fat and carbs can also increase fatty acids in the blood. On the other hand, reducing refined carbs likely decrease triglycerides [26], which theoretically might support leptin transport to the brain.

These mechanisms haven’t been proven in humans, but we know that diets high in refined sugars and fat are unhealthy. Aim to reduce your intake of sugar, refined carbs like white bread, and saturated fats. Opt in for high-fiber foods and complex (low glycemic index) carbs instead.

5) Increasing Healthy Proteins

In a small study of 19 people, an increase in dietary protein from 15% to 30% of caloric intake (at a constant carbohydrate intake) produced a sustained decrease in caloric intake. The participants also lost weight [27].

The authors proposed that this may have been mediated by increased leptin sensitivity in the brain. They believe the appetite-reducing effect of protein may contribute to the weight loss produced by low-carbohydrate diets [27].

In a trial of postmenopausal women, a low-carb diet with exercise lowered leptin levels and increased adiponectin, which resulted in weight loss [28].

Studies found that reducing carbs may also lower triglycerides. However, people should have in mind that these studies used very specific diets and typically had strict food lists [26].

Therefore, it’s usually not just about reducing your carb intake by any means. You should make sure to get healthy protein sources and be mindful of the carbs that you take in. For example, even if carbs make up only a minority of your calories, you don’t want to be consuming sugar and pasta for carbs only.

If you’d like to lower your carb intake but aren’t sure how, speak to your healthcare provider and a licensed nutritionist to get some recommendations.

6) Exercise

Research suggests that exercise can be beneficial in multiple ways for weight loss [29].

Besides burning calories, scientists think that exercise improves hypothalamic leptin sensitivity at least in part through suppressing hypothalamic inflammation and inhibiting Endoplasmic Reticulum stress in rodents. These pathways haven’t been explored in humans [30].

Moderate, regular exercise also likely increases BDNF and supports healthy blood lipid levels and general well-being [31].

7) Reducing Stress

Chronic stress is often associated with weight gain. Chronically high levels of Cortisol have been proposed as another contributing factor to leptin resistance [32].

There are many other mechanisms by which too much stress might cause weight gain. Finding ways to de-stress and relax on a regular basis is also key to a healthy lifestyle [32].

8) Resolving Inflammation

Low-grade, chronic hypothalamic inflammation has been associated with various metabolic disorders including obesity [33].

Work with your doctor to treat any underlying conditions causing your low-grade inflammation.

Experimental

The following factors are theoretical or anecdotal. They aren’t backed up by solid science. We bring them up for informational purposes.

Cold Showers

Scientists are investigating whether Leptin Receptor activity increases with colder temperatures. Animal studies suggest it is associated with defense against cold temperatures [34].

Cold showers are popular among people who want to burn fat, lose weight, or get rid of cellulite. Some people think that cold can make them more leptin sensitive, but this hasn’t been proven [35, 36].

Be cautious with any form of sudden temperature change in your environment, especially if you have heart disease or other chronic conditions.

Pathways

Scientists are investigating whether the following pathways reduce leptin resistance in animals and cells:

Autophagy

Autophagy is a process by which cells remove and recycle junk proteins.Some researchers think it is important for leptin sensitivity [13].

Estrogen Levels

Estrogen deficiency is hypothesized to cause leptin insensitivity in the brain based on animal data [37].

BDNF

Leptin is thought to work, in part, through BDNF [13].

Our post on BDNF delves into factors that may increase BDNF, but suffice it to say that a generally healthy lifestyle will be beneficial.

PEA

PEA supplements have not been approved by the FDA for medical use. Supplements generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective. Speak with your doctor before supplementing.

Lectins

Researchers are investigating whether lectins can cause leptin resistance, especially wheat lectins [39].

Some theories suggest that lectins may bind to sugar structures on the receptors of cells–including leptin receptors–and mimic or block the effects of that receptor. This theory still remains unproven and it hasn’t been tested in proper clinical trials (R, R).

The lectin avoidance diet with certain modifications may support weight loss, but this is anecdotal .

Hypothetical Pathways of Leptin Resistance:

Animal and cellular studies are exploring whether the following pathways can trigger leptin resistance:

  1. Inflammation in the hypothalamus [25]
  2. Triglycerides and Free Fatty Acids in the blood [11, 12]. Triglycerides are hypothesized to block leptin from entering the brain, which may have been an evolutionary advantage in the past (increased hunger during starvation to seek food) [11].
  3. Lectins [39]
  4. Emotional Stress and cortisol [32]
  5. Insulin resistance
  6. Inadequate autophagy [13]
  7. Lower SIRT1 [40]
  8. Lower STAT3 and JAK2: Ketogenic diets inhibit STAT3 and cause leptin resistance [41].
  9. Low BDNF [13]
  10. Higher SOCS3, caused by inflammation [42, 43].
  11. Higher PTP1B [44] – Deletion of this protein increased leptin and insulin sensitivity, preventing body weight gain in a diet-induced obesity animal model [45, 46]
  12. Endoplasmic reticulum stress [33]
  13. Estrogen deficiency causes leptin insensitivity in the brain and increased hypothalamic neuropeptide Y [37].

Human data are lacking.

About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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