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The Causes of Leptin Resistance & 12 Ways to Reverse It

Written by Joe Cohen, BS | Last updated:

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I’ve written a comprehensive post about Leptin before. This post is about leptin resistance. Sensitivity to leptin may result in significant weight loss and lower inflammation.

Leptin resistance is common in cases of obesity, because it doesn’t decrease appetite. Learn about the causes & how you can increase sensitivity.

What is Leptin Resistance?

Obese humans have high levels of leptin, even though leptin is supposed to cause satiety, which suggests that leptin resistance causes human obesity [1].

Leptin resistance is when leptin doesn’t work as well to decrease appetite or increase energy expenditure.

Leptin resistance is now believed to be the leading driver of fat gain in humans [2].

Because fat cells produce leptin in proportion to our size, obese people also have very high levels of leptin [3], but it doesn’t perform its job the way it’s supposed to [4].

Leptin resistance leads to increased appetite and decreased energy expenditure.

What Are The Mechanisms of Leptin Resistance?

Many mechanisms have been proposed to explain leptin resistance, including impairment in leptin transportation and leptin “signaling” issues [5, 6].

In obese subjects with very high leptin, leptin levels in the cerebrospinal fluid only increase slightly [7]. This shows that leptin is not getting into the brain much, and this is part of the problem.

If you have high blood Triglycerides, it will impair leptin from entering the brain [8, 9].

A second issue might be from fewer leptin receptors [10].

A third issue can arise from a problem in the leptin signaling cascade, which can cause leptin resistance (high SOCS3, low JAK2, low STAT3) [10].

BDNF is also needed for leptin to cause weight loss, and lower BDNF can result in leptin resistance and weight gain [10].

Tips to Increase Leptin Sensitivity

1) Keep to a Circadian Rhythm

One significant underlying cause of leptin resistance is Circadian Rhythm Disruptions.

Indeed, circadian disruption is associated with obesity (11).

Night-shift workers, who must be awake, active, and eating during the night are at a higher risk for obesity and metabolic diseases [12].

Chronic jet lag is sufficient to disrupt the clock in fat cells and also induce Leptin resistance in the brain in mice (11).

While you may not travel across time zones much, most people don’t get enough light in the day and get too much light at night, which disrupts our natural biological rhythm.

It is hypothesized that eating during the ‘wrong’ circadian time contributes to circadian desynchronization and increased weight gain.

Eating at the wrong time can also cause changes in leptin that result in weight gain (rodents). In humans, eating at the wrong time (after 8 PM) is also associated with weight gain [9, 13].

Mice eating a high-fat diet only during the ‘wrong’ circadian phase gain 2.5x more weight than mice fed the same diet during the mouse’s natural feeding period [14].

One mechanism by which obesity can result from eating at the wrong time (night) is by not burning off the calories as much.

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

Similarly, studies in free-living healthy adults have shown that meal satiety also varies with time of day and that food intake during the night is less satiating and leads to greater daily caloric intake compared to food consumed in the morning hours [16, 17].

For the natural course of mammalian history, we’ve eaten for about 12 hours in the day and fasted for 12 hours at night.

So for weight loss, when you eat might be more important than what you eat – and maybe even how much you eat to a degree.

2) Eat Less – especially at night

Chronically high levels of leptin cause leptin resistance, as a means to stay in homeostasis [18].

The act of overeating leads to chronically high levels of leptin, causing leptin resistance. At that point, it’s harder to lose weight because you’ve moved yourself to a new homeostasis.

Many people don’t care about their weight until they are already overweight, and so they diet to lose the weight, but at that point, it’s harder than if they always ate a normal amount.

This might not be a problem if people stop eating for 12 hours and give their system time for leptin to become more sensitive again.

Also, eating too many calories can also increase inflammation and fatty acids, which can cause leptin resistance as well.

3) Cut Out Sugar

The consumption of Western diets, high in sugar AND saturated fat (usually the combination is needed), is a crucial contributor to the alarming incidence of obesity [19].

These diets have been reported to induce an inflammatory response in the hypothalamus, which promotes the development of brain leptin resistance and obesity [19].

Eating too much fat and carbs can also increase fatty acids in the blood.

Reducing carbs decreases triglycerides [20], which was one mechanism that inhibited leptin transport to the brain.

4) Reduce Inflammation

Low-grade, chronic hypothalamic inflammation is closely associated with various metabolic disorders including obesity [21].

If you’re Th2 dominant, you might increase SOCS3, which will cause leptin resistance.

5) Exercise

Exercise can be beneficial in multiple ways for weight loss [22].

Besides burning calories, exercise improves hypothalamic leptin sensitivity at least in part through suppressing hypothalamic inflammation and inhibiting Endoplasmic Reticulum stress in rodents [23].

Exercise also increases BDNF and can likely help in lowering triglycerides.

6) Eat More Protein and Fewer Carbs

An increase in dietary protein from 15% to 30% of caloric intake (at a constant carbohydrate intake) produces a sustained decrease in caloric intake that may be mediated by increased leptin sensitivity in the brain and results in significant weight loss. This appetite-reducing effect of protein may contribute to the weight loss produced by low-carbohydrate diets [24].

A low carb diet with exercise lowered leptin levels and increased adiponectin and results in weight loss [25].

Also reducing carbs can lower triglycerides [20].

7) Take a Cold Shower and Lower the Thermostat

The Leptin Receptor seems to increase with colder temperatures and is associated with defense against cold temperatures [26].

Therefore, cold can make you more leptin sensitive.

Cold is a good way to burn fat and lose weight [27, 28].

8) Chill Out

Chronic stress is often associated with weight gain. Chronically high levels of Cortisol causes leptin resistance [29].

There are many other mechanisms by which stress can cause weight gain, so it’s a good idea in many ways if you’re interested in weight loss [29].

9) Sleep More/Increase Autophagy

Autophagy is a process by which cells remove and recycle junk proteins.

Autophagy is important for leptin sensitivity [10].

Saunas and sleeping are two simple ways to increase autophagy.

Poor sleep has been implicated in problems with leptin [30].

10) Try to Avoid Lectins

For some, lectins cause leptin resistance, especially wheat lectins [31].

Lectins bind to sugar structures on the receptors of cells and can mimic or block the effects of that receptor [32].

The leptin receptor has these sugar molecules that lectins bind [32].

Thus, lectin avoidance could possibly bind to the leptin receptor and affect its function.

11) Make Sure Estrogen Levels Are Adequate

Estrogen deficiency causes leptin insensitivity in the brain [33], so make sure your levels are normal for your gender.

12) Increase BDNF

Leptin works, in large part, through BDNF [10].

My post on BDNF delves into all of the ways to increase BDNF, but suffice it to say that a generally healthy lifestyle will increase BDNF.

Others

Overview of the Causes of Leptin Resistance:

  1. Inflammation in the hypothalamus [19]
  2. Triglycerides and Free Fatty Acids in the blood [8, 9] – this can be from eating too many carbs or fat, or from mitochondria that are not able to burn it for fuel well enough. Triglycerides block leptin from entering the brain and are an important cause of leptin resistance and this may have evolved to increase hunger during starvation [8].
  3. Lectins [31]
  4. Emotional Stress and cortisol [29]
  5. Insulin resistance
  6. Inadequate autophagy [10]
  7. Lower SIRT1 [35]
  8. Lower STAT3 and JAK2: Ketogenic diets inhibit STAT3 and cause leptin resistance [36].
  9. Low BDNF [10]
  10. Higher SOCS3, caused by inflammation [37, 38].
  11. Higher PTP1B [39] – Deletion of this protein increased leptin and insulin sensitivity, preventing body weight gain in a diet-induced obesity animal model [40, 41]
  12. Endoplasmic reticulum stress [21]
  13. Estrogen deficiency causes leptin insensitivity in the brain and increased hypothalamic neuropeptide Y [33].

About the Author

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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