Leptin resistance: what is it, symptoms, causes, treatment

Trying to maintain a healthy weight can be frustrating if you don’t feel full after meals. While it may feel like you lack “willpower,” there’s actually a scientific explanation for this, and it has to do with how your brain responds to leptin—a hormone some call the “fullness” hormone. 

When your brain doesn’t respond to leptin properly, leptin resistance can occur. This is why, despite eating a full meal, you may still feel hungry. 

We’ll cover more about leptin resistance, what causes it, and how to reverse it.

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Leptin is a hormone (or chemical messenger) made in fat tissue that plays an important role in regulating our appetite and metabolism by sending signals to a receptor in our brains. Our brains then interpret the signals as feelings of fullness (also known as satiety). This makes you stop eating and signals your body to burn more calories. 

For people with leptin resistance, the body makes plenty of leptin, but the brain doesn’t respond to those leptin signals, so they don’t feel full or burn the calories they have. Instead, they continue to feel hungry despite having eaten. The body can’t sense signals that tell it to increase metabolism and burn off calories, so they eat more without burning more. 

The balance of calories going in and out (energy balance) is uneven, and the excess calories make fat cells (adipocytes) grow. Those fat cells make more leptin, so you usually wind up with a high leptin level (hyperleptinemia) but no way for your body to use it. 

Leptin resistance causes many different signs and symptoms, including: 

• Obesity: Since people with leptin resistance don’t feel full after eating and don’t burn the calories they take in, they usually experience weight gain and obesity. This may begin as early as childhood (Lustig, 2006). 

• Belly fat: People who are resistant to leptin may specifically have more belly fat (also called abdominal or visceral fat) instead of fat stores distributed evenly around the body (Ma, 2002). That’s significant because visceral fat is linked to an increased risk of additional diseases like diabetes, heart disease, and more.

• Fatigue: People with high leptin levels and leptin resistance often feel excessively tired and fatigued (Stringer, 2013). People with leptin resistance may be less physically active because the brain doesn’t respond to the signals telling it to burn calories (Lustig, 2006). 

• Pain disorders: The high levels of leptin in people with leptin resistance may make a person more sensitive to pain or more prone to developing chronic pain disorders like fibromyalgia (Younger, 2016). 

• “Junk food” cravings: Leptin resistance and elevated leptin levels can make you more likely to crave high-fat “junk foods” and sweets (Reichelt, 2015; Macedo, 2014). 

While researchers aren’t entirely sure what the source of leptin resistance is for everyone, a couple of things likely contribute. 

Leptin resistance may be caused by a disruption to a part of the brain called the hypothalamus. Leptin works by sending signals to the hypothalamus, and studies suggest that people with obesity have increased inflammation in this area, which may disrupt the hormone’s communication with the brain (Thaler, 2012).  

Fatty acids can also cause leptin resistance. Fatty acids are a component of fats found in many foods. Some of them are essential for nutrition, but some of the fatty acids found in saturated fats (like palmitate) can block the brain’s response to leptin (Kleinridders, 2009).  

It may be difficult to diagnose leptin resistance since there are no standard criteria for a diagnosis. Healthcare providers usually make the diagnosis based on signs and symptoms. They may also get a blood test to check your leptin level, but they usually don’t make the diagnosis based just on the test (Gruzdeva, 2019).Unlike conditions like diabetes or heart disease, leptin resistance is more of an underlying condition that contributes to obesity rather than a distinct diagnosis on its own. That means that while some people with obesity may have leptin resistance, they may never be tested or treated specifically for the condition. 

Instead, lifestyle changes and treatments used to help with obesity and associated medical conditions will be the most likely treatments provided to people who may have underlying leptin resistance, even if it’s never explicitly diagnosed.

People with leptin resistance usually have obesity and may be at risk for conditions like high cholesterol, heart disease (cardiovascular disease), and type 2 diabetes. Since leptin decreases your appetite and helps burn calories, would a leptin supplement be a good treatment for these individuals? 

It turns out that it’s not. Studies have shown that giving people leptin doesn’t help treat obesity caused by leptin resistance (Paz-Filho, 2011). People with leptin resistance and obesity have more body fat, so they usually have very high leptin levels (since body fat produces leptin), and adding more isn’t helpful (Maffei, 1995). That’s because the problem is with the receptors for leptin.

The only people with obesity who benefit from leptin treatment are those who have a condition called congenital leptin deficiency (CLD), in which they produce almost no leptin at all (Sáinz, 2015). They have no leptin, but they are sensitive to its effects. After they’re treated with leptin, they often have lower cholesterol and blood sugar (glucose) and are able to lose weight (Paz-Filho, 2011). 

There’s currently no specific medication for treating leptin resistance, but there are dietary changes and lifestyle modifications that may help manage it. 

Leptin resistance may improve with some dietary modifications, such as: 

• A low-fat diet: Eating a high-fat diet leads to more inflammation, which interferes with the brain’s response to leptin. A low-fat diet may improve leptin sensitivity (De Souza, 2005). 

• Fewer processed carbs: A diet high in processed carbohydrates can lead to inflammation and interfere with leptin signals (Ghanim, 2009).

• Low sugar consumption: Some studies suggest that a high intake of sugars like fructose can interfere with leptin levels and prevent you from feeling full (Lowette, 2015).

• High protein intake: A diet that’s high in protein may increase leptin sensitivity, increase feelings of fullness, and lower body weight (Weigle, 2005). 

• Avoiding triglycerides: A type of fat called triglycerides, found in foods like butter and oil, can block leptin signals and lead to leptin resistance (Banks, 2004). 

Managing leptin resistance doesn’t just depend on eating the right foods. You can help reverse leptin resistance by modifying other lifestyle factors, including:  

• Sleep: Let’s face it—many of us don’t get as much sleep as we should. But getting enough sleep is more important than you may think. Sleep deprivation affects leptin levels and metabolism, interferes with appetite control, and increases the risk of obesity (Spiegel, 2004).

• Stress: Avoiding excess stress and taking care of your mental health can help keep your leptin levels balanced since leptin levels are closely tied to your emotional state (Licinio, 2015).

• Exercise: There’s a long list of benefits of regular exercise, but an important one is that it can significantly lower excess leptin. Exercise reduces fat mass, reducing leptin and improving leptin sensitivity (Reseland, 2001). 

Leptin resistance is an important contributor to obesity. There’s no medication to cure it, but there are ways to manage it and help reverse it naturally. If you have symptoms of leptin resistance, it’s a good idea to speak to a healthcare provider who can evaluate you and determine the best options for treatment. 

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Current version

April 27, 2022

Written by

Gina Allegretti, MD

Fact checked by

Yael Cooperman, MD

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About the medical reviewer

Yael Cooperman, MD, Ro

Yael Cooperman is a physician and works as a Senior Manager, Medical Content & Education at Ro.