How To Treat Leptin Resistance: A Functional Medicine Approach

Leptin is a hunger hormone that is made by your fat cells to help keep your food intake and weight balanced over the long term. When leptin is released from fat cells, it signals the brain to regulate hunger by providing the sensation of satiety (feeling full).

Leptin resistance occurs when the brain is constantly stimulated by leptin. This can cause dysregulation in this feedback system so that you constantly feel hungry and eat more even though your body has enough fat stores. Leptin resistance also alters metabolism so that you conserve fuel and burn fewer calories for energy. In this way, leptin resistance is a major metabolic contributor to weight gain and obesity and over time can contribute to further cardiometabolic consequences like metabolic syndrome, type 2 diabetes(T2D), and non-alcoholic fatty liver disease (NAFLD).

While there are not yet clearly established diagnostic criteria to allow for the quantification of this issue, obesity and metabolic dysfunction are increasingly concerning problems. Over 1.9 billion adults are overweight, and over 650 million overweight adults are obese. Studies show that elevated leptin and the accompanying resistance to a reduction in body mass are two common characteristics of obesity.

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What is Leptin?

There are several hormones that contribute to hunger and satiety. Three main ones are ghrelin, cholecystokinin (CCK), and leptin. Leptin and CCK are satiety signals which are produced in response to food and stored energy/fat, while the hunger hormone ghrelin is gradually suppressed when food is consumed. Together these hormones fluctuate to signal to the brain your level of nutrition.

Leptin is a hormone that is primarily produced by fat cells to help keep food intake and weight balanced over the long term. Hormones like leptin are chemical messengers that help to coordinate different functions by carrying signals throughout the body via the blood to organs, muscles, and other tissues.

Leptin secretion from fat cells increases during refeeding after fasting or when consuming more energy than is needed. Leptin travels through the bloodstream and binds to receptors mainly in the hippocampus and the hypothalamus, parts of the brain that help to regulate hunger and other bodily functions.

Leptin is referred to as the satiety hormone because of the way it influences feelings of fullness and satisfaction from eating. When leptin binds to its receptors in the brain, it sends signals to inhibit food intake and increase energy expenditure.

What is the Function of Leptin?

Leptin’s main role is to help regulate the body’s energy balance over the long term. Since leptin is mainly produced by white adipose or fat tissue, the amount of leptin in your blood is directly proportional to the amount of fat tissue your body has.

• Malnutrition or low energy/fat stores results in low levels of leptin which signal to the brain to have you eat more food
• Abundant energy/fat stores in obesity lead to high levels of leptin which signal to the brain that you have enough energy and do not need to eat more

More body fat leads to higher leptin levels which trigger a negative feedback loop to help control energy levels in the body. Leptin helps diminish hunger and regulate energy balance so that your body feels satisfied and does not seek food when it does not need additional energy.

When functioning properly, the leptin signaling system contributes to helping your brain know how much energy you have stored as fat so that your hunger and food consumption remains balanced with your energy needs. When leptin levels are sufficient, the brain receives the signal that the body has enough fat stored and enough energy available so you do not need to eat more at that time and can burn calories at a normal rate. As your body fat decreases, levels of leptin decrease, which signals the body that it is starving or needs additional energy. This stimulates intense hunger and increased appetite to help trigger increased food consumption.

Leptin also influences functions related to bone health, immunity, reproduction, and brain function. Leptin modulates both innate and adaptive immune functions and inflammation helping to explain some of the connections between obesity and other chronic diseases. For example, leptin produced from fat cells seems to cause osteoblast dysregulation in bone tissue which can promote joint destruction and contribute to both osteoarthritis and rheumatoid arthritis.

What is Leptin Resistance?

When the brain is chronically stimulated by high levels of leptin, it can stop responding normally to the feedback. When leptin resistance occurs, you don’t get the sensation of feeling full or satiated and are driven to eat more even though your body has enough fat stores and energy.

In leptin resistance, the leptin receptors in the brain get tired and stop responding normally to high levels of leptin in the blood. This makes the brain mistakenly think that you don’t have enough leptin and therefore don’t have enough energy stores. Higher levels of leptin are required to overcome this resistance and get the same level of response from the receptors. The body then enters into starvation mode in an effort to save energy, decreasing your metabolism so you use fewer calories at rest and triggering you to eat more food and build fat stores to produce more leptin.

Leptin resistance decreases the ability of leptin to send feedback signals that suppress the appetite or increase the body’s energy use. This lack of satiety and decreased metabolism that occurs in leptin resistance further contributes to obesity and causes additional weight gain in the form of fat storage.

What Causes Leptin Resistance?

Leptin resistance occurs when the brain fails to recognize leptin’s signaling. While still being studied, the brain’s ability to recognize leptin can be damaged due to chronic inflammation, chronically high levels of leptin, or elevated levels of fat metabolites in the blood over time. All of these factors may be involved in how obesity can trigger leptin resistance, a condition that further worsens obesity.

Fat cells produce leptin in proportion to the amount of lipids stored inside of them. In addition, there may be changes in gene expression in fat cells that lead to increased secretion of leptin with obesity. Having elevated levels of leptin and/or free fatty acids in the bloodstream seems to contribute to the development of leptin resistance over time. There may also be abnormalities in transporting leptin across the blood-brain barrier that contribute to leptin resistance. For example, overeating and overconsumption of processed fats and sugars can trigger elevated plasma triglycerides which impair leptin transport across the blood-brain barrier and contribute to leptin resistance.

Inflammation is a useful process when triggered in response to things like acute injury or infection, but when it remains elevated over time due to stressors like a lack of consistent sleep, a diet high in processed sugars and fats, or unmanaged psychological stress, it can result in imbalances. Chronic inflammation dulls the leptin receptors so that they do not recognize the leptin that is already present.

Chronic stress can lead to increased glucocorticoids like cortisol in the body. Glucocorticoids enhance the activity of the enzyme lipoprotein lipase in fat tissue leading to an increase in fat storage that can worsen leptin resistance. Excess glucocorticoids directly reduce the brain’s sensitivity to leptin and can also result in increased circulating free fatty acids and metabolic dysfunction that may induce leptin resistance. In addition, unmanaged stress can contribute to cravings for high-energy foods like sugars and trigger leaky gut syndrome, which causes systemic inflammation and worsening leptin resistance.

Microbes in the gut play a key role in regulating inflammation as well as influencing energy absorption and obesity. Certain types of imbalances in these microbes (dysbiosis) can contribute to a leaky gut barrier that allows food particles and microbes to get into the bloodstream and contribute to inflammation and dysregulated immune responses throughout the body. Certain types of bacteria can also extract more energy from the diet, contributing to obesity and the metabolic consequences.

What Are The Symptoms Of Leptin Resistance

Leptin resistance alters the body’s appetite and satiety system. This results in a diminished ability of leptin to signal satiety or fullness, suppress appetite, and increase the body’s energy usage.

Since the brain doesn’t perceive that enough food has come in when there is leptin resistance, it interprets that as starvation. Therefore, it turns on hunger signals and decreases metabolism in an attempt to make up for the falsely perceived food deficit.

This leads to the symptoms of leptin resistance including

• Increased appetite or constantly feeling hungry
• Increased food intake despite having adequate energy stores or excess amounts of body fat
• Storing calories taken in as fat instead of burning them as energy
• Overall, these adaptations result in weight-loss resistance and difficulty keeping weight off.

Elevated leptin levels in leptin resistance are also associated with fatigue and increased reactivity of mast cells which can contribute to allergic reactions and histamine intolerance.

How to Measure Leptin Levels

There are currently no accepted diagnostic criteria for leptin resistance, but fasting leptin levels and other metabolic markers can be measured in the blood to assess overall metabolic health. “Normal” leptin levels vary between laboratories and depend on a person’s weight, age, and gender as well as getting higher throughout the day with a peak towards nighttime.

Metabolic Profiles

The Metabolomic Profile measures several markers of adiposity including leptin and adiponectin as well as metabolic markers of glucose balance and insulin function to help assess the risk of leptin resistance and metabolic syndrome.

Lipids

To evaluate the balance of fats in the blood that can contribute to the risk of leptin resistance, a lipid profile including total cholesterol, HDL (“good” cholesterol), LDL (“bad” cholesterol), and triglycerides can be measured. In addition, lipoprotein(a) and ApoB-containing lipoproteins (ApoB) can provide a more specific risk assessment.

Inflammatory Profiles

In addition, inflammatory markers like high-sensitivity CRP can be used over time to track trends in inflammation within the body that contribute to and result from the metabolic imbalances involved in leptin resistance.

Comprehensive Stool Test

A comprehensive stool test like the GI Effects also helps to assess underlying causes of inflammation and hormone imbalances that can contribute to leptin resistance. This test reflects the overall health and balance of the digestive tract by measuring a variety of microbes and intestinal health markers. It can help assess the balance of the microbiome as well as how well you are breaking down and digesting fats, proteins, and carbohydrates, which can guide an individualized approach to metabolic health and nutrition based on your unique needs.

Body Composition

During a physical examination, your provider can screen for several of the components of metabolic health involved in leptin resistance including measuring waist circumference and/or waist-to-hip ratio and weight. Body composition can be more specifically assessed with foot-to-foot impedance meter (FFI) measurements using a smart scale or DXA (Dual-Energy X-ray Absorptiometry).

How to Treat Leptin Resistance

Leptin Resistance Diet

Since inflammation and overnutrition play key roles in the development of leptin resistance, an anti-inflammatory diet is important. A balanced nutrient-dense diet providing a metabolically-appropriate amount of calories can reduce elevated leptin and inflammation. Diets rich in fiber, vegetables, legumes, and other high-quality proteins like wild fish and grass-fed meats and that limit inflammatory foods like fried and processed foods, refined sugars, factory-raised meats, and sugary drinks are associated with more balanced weight and fat distribution, less insulin resistance, and improved markers of inflammation and fat and sugar metabolism.

Diets high in refined sugars and processed fats alter neurotrophins (“brain cell fertilizers'') such as brain-derived neurotrophic factor (BDNF) that may impact signaling pathways involved in hunger and satiety.

Keeping your levels of omega-6/omega-3 fatty acids balanced helps regulate inflammation and reduce the risk of obesity and leptin resistance. This can be done by eating omega-3-rich fish such as salmon or sardines, flax seeds, and walnuts or by taking a good quality omega-3 fish oil supplement while reducing your intake of factory-raised meats and dairy products.  

A gluten-free diet may also improve many aspects of leptin resistance, such as reducing waist circumference, balancing blood sugar and inflammation, and reducing triglyceride levels. Research suggests that ingested gluten may get into the bloodstream and inhibit leptin binding to its receptors in the brain, contributing to leptin resistance.

Time-Restricted Eating and Fasting

For some individuals, time-restricted eating, calorie restriction, or fasting may improve leptin sensitivity. Eating late in the day, especially after 8 pm, has been associated with higher leptin resistance levels, increased hunger, and more weight gain. Some studies suggest that fasting may help reduce inflammation and reset leptin receptors, encouraging weight loss. The length and frequency of this type of approach must be individualized with a knowledgeable provider.

Balance the Microbiome

The microbiome is very responsive to changes in diet and highly influential over weight balance. A diverse plant-focused diet rich in dietary fiber supports balanced gut bacteria that promote a healthy gut lining and proper digestion, weight, and metabolic balance.

Prebiotic foods like garlic, bananas, and asparagus feed healthy gut bacteria while probiotics in naturally fermented foods like sauerkraut and miso promote microbial diversity to help regulate weight, triglycerides, and inflammation.

Supplements and Herbs for Leptin Resistance

The herbs Cinnamomum cassia (Chinese cinnamon) and Gymnema sylvestre may regulate appetite by influencing leptin, glucose, and insulin levels.

Lifestyle Changes to Help with Leptin Resistance

Maintain a balanced weight

Maintaining a weight that is balanced for your body can improve the metabolic factors involved in leptin resistance.

Move regularly

Exercising consistently can help to decrease body fat, maintain a healthy weight, and decrease leptin levels. Incorporate regular consistent exercise to improve the body’s ability to regulate appetite, reduce abdominal obesity, and optimize metabolic health.

Get enough sleep and practice good sleep hygiene

Since a lack of adequate sleep, poor sleep habits, and altered circadian rhythms can increase the risk for leptin resistance, getting enough sleep can help to improve leptin sensitivity. For most people, it can help to go to bed at a consistent time before 10 pm and get at least 7-9 hours of good-quality sleep.

Manage stress

Unmanaged chronic stress is associated with metabolic dysfunction and leptin resistance, particularly through the impacts on inflammation and blood lipids. Finding a practice that is meaningful for you to manage stress is key for a balanced metabolism in the long term.

Summary

Leptin is a hormone that is produced by fat cells and circulates in the blood in proportion to body energy/fat stores and food availability. When fat and energy reserves or food availability are low, leptin levels decrease and signal the brain to increase food intake to ensure a steady supply of metabolic fuel.

Leptin resistance is a complex metabolic process that can contribute to weight-loss resistance. Although leptin suppresses the appetite when slightly raised in response to eating or adequate body fat levels, it seems to have the opposite effect when it gets too high for too long. When leptin is persistently elevated and/or leptin receptors cannot appropriately respond to leptin signals, it sends signals of increased hunger and makes your fat cells hang onto fat.

Leptin can be measured in the blood along with other markers of inflammation, gut function, and metabolic health. Fortunately, a functional medicine approach can be used to help balance weight and inflammation and reduce the risk of leptin resistance.

Consuming an individualized anti-inflammatory diet that focuses on whole foods like vegetables and removes processed grains, sugars, and fats helps to balance inflammation, keep the gut healthy, and regulate weight. In addition, consistent physical activity, managing stress, and getting enough sleep can improve leptin resistance and encourage weight loss.