When you eat to fill and satisfy your hunger, your body releases a hormone that sends signals to the brain and tells you to stop eating. This hormone is known as leptin. Its level in the blood depends on the amount of body fat we have.
The leptin hormone controls hunger and appetite. It is responsible for informing the brain when your body gains enough fat, thus, helping to prevent overeating and maintaining weight gain. Sometimes, your body can fail to respond to this hormone and your brain misses the signal. This results in a condition known as leptin resistance.
Leptin resistance has a great influence on weight gain and obesity. It is thought to be the main cause of weight because it reduces the rate of metabolism, leading to the storage of excess body fat.
What is leptin?
Leptin, otherwise known as the satiety hormone, is a peptide hormone synthesized and secreted from the adipose tissue (fat tissue), and encoded by the obese (ob) gene.1 It plays a huge role in the regulation of food intake (appetite), energy homeostasis, neuroendocrine function as well as other physiological processes. Some factors such as metabolic hormones, total body fat index and gender influence the concentration of this hormone in the plasma. For instance, people assigned female at birth (PAFAB) have higher levels of circulating leptin than people assigned male at birth (PAMAB). At the brain level, leptin reflects the tendency of one to become obese.
How does leptin work?
Leptin acts as an appetite suppressant. The primary function of leptin is to regulate the balance between food intake and energy expenditure. Its principal site of action is the brain, particularly the brainstem and hypothalamus. Leptin sends signals to the hypothalamus, where hunger and satiety centres are located.
When you fast, your fat stores decrease, causing your leptin levels to drop. This makes you feel hungry while your body conserves energy to prevent weight loss.
The reverse happens when you eat. Your fat stores increase with a corresponding increase in your leptin levels, followed by decreased appetite and increased energy expenditure, resulting in weight loss. Several studies have pointed out that the concentration of circulating leptin reduces during fasting or energy restriction but increases when you feed, overfeed or during surgical stress.2 A properly functioning leptin signalling system ensures that your hunger and energy expenditure levels are balanced with your energy needs.
What is leptin resistance?
Leptin resistance is characterized by increased circulating leptin. It occurs when your brain is stimulated constantly by leptin, yet fails to respond to the leptin signals. This makes you feel hungry more often than normal even when your body has enough fat stores. Your metabolism is also altered as you conserve fuel and burn fewer calories for energy. So in addition to not feeling full, your body doesn't burn the calories you have.
Leptin resistance has been noted to be a major cause of weight gain and obesity. And because fat cells produce leptin in proportion to the body size, an overweight and obese person usually has higher leptin levels that are ineffective.3 Hence, they feel persistent hunger, increased appetite and reduced energy expenditure, making it difficult for them to achieve weight loss.
Causes of leptin resistance
Several mechanisms have been proposed to explain why the body fails to respond to leptin. Although researchers are not entirely sure, the following could cause leptin resistance:
Consumption of a high fat diet
In obese people, their serum leptin levels increase as their fat cells increase, leading to the development of resistance in the brain. What this means is that a smaller amount of leptin will get to the brain. In turn, this affects the rate at which signal for body weight regulation is activated.4
Foods that are high in saturated fat are also high in fatty acids. Some of these fatty acids such as palmitate can stop leptin signals to the brain or block your brain’s response to leptin, thereby promoting leptin resistance. Examples of high-fat diets include beef, pork, cheese, full-fat dairy products, etc. They can cause inflammation and alter the normal functioning of leptin receptors, causing decreased sensitivity to leptin.
Impairment in leptin transportation and signalling
Studies suggest that reduced brain access is the origin of leptin resistance in obese subjects while others point out lower leptin receptor levels to be an issue.5 High levels of leptin in the blood can lead to decreased blood-brain barrier (BBB) permeability, thus, altering the leptin transport across the BBB.
Inflammation of the hypothalamus is another likely cause as the inflammatory molecules can disrupt the leptin signalling pathway, hindering the brain’s response to the hormone.
A negative feedback exists between insulin and leptin. While insulin helps to store fat, leptin helps to burn fat; hence, the insulin and leptin signaling pathways are interconnected. Conditions such as insulin resistance can make one less responsive to insulin, contributing to leptin resistance.6
Another metabolic hormone called ghrelin works in synergy with leptin to regulate hunger and satiety. Ghrelin is a stomach-derived peptide hormone that stimulates appetite and food intake consequently. Conversely, leptin suppresses appetite and promotes losing weight naturally.
Sleep plays a huge role in energy balance.7 When you sleep, your leptin levels rise, hence suppressing hunger by sending signals to the brain that you have enough energy reserves. But when you are deprived of sleep, your ghrelin levels rise while leptin levels reduce, thereby signalling your brain that there is a need to eat more food, potentially disrupting the leptin pathway and causing resistance. Recent studies suggest that poor quality sleep or chronic sleep deprivation negatively influences metabolic homeostasis. This contributes to increased hunger and appetite, and in turn, increased food intake.
The LEP gene, which is responsible for producing the leptin hormone, can develop mutations in rare cases and cause a recessive disorder known as Congenital leptin deficiency. This condition presents with low or absent leptin levels due to abnormal deposition of fat tissues in the body. It causes a child to get hungry constantly and become severely obese in the first few months after birth.
Below are other risk factors for leptin resistance:
- Extreme stress which leads to high cortisol levels
- Intense exercise or lack of physical activity
- Overfeeding, especially late-night snacking
- Alternate starvation with binge eating
It is important to note that aside from causing leptin resistance, these factors are worsened by obesity and could lead to a continuous cycle of weight gain and leptin resistance over time. Hence, the more you overfeed and become obese, the more you develop leptin resistance.
Signs and symptoms of leptin resistance
Common signs and symptoms are
- Weight Gain or obesity: A person with leptin resistance feels the need to keep eating since the brain fails to respond to the leptin signals. They feel insatiable hunger. This results in weight gain and oftentimes, obesity
- Increased appetite and junk food cravings: when your body is resistant to leptin, you are likely to crave junk food and constantly experience an increased appetite
- Belly fat: Leptin resistance can make people have fat deposited on their belly instead of being evenly distributed all over the body
- Fatigue: Because leptin resistance leads to a slower metabolism and reduced energy levels, you may feel tired and sluggish
- Low immune levels: Your body may find it difficult to fight infections when your leptin levels are high
- High pain susceptibility: Some people with high levels of leptin may be more sensitive to pain than normal or have more chances of developing chronic pain disorders such as fibromyalgia
- Metabolic disturbances: Insulin resistance, dyslipidemia, intensive hyperphagia and impaired glucose metabolism are disease conditions that could be associated with leptin resistance
Management and treatment for leptin resistance
Overeating causes obesity which can in turn, predispose one to other chronic health conditions such as high blood sugar levels, high cholesterol, inflammation, etc over time. Scientists suggest that overeating may contribute to increased leptin levels, causing leptin resistance and inducing endoplasmic reticulum stress.8 Being mindful of your portion sizes by eating smaller and more frequent meals throughout the day can help control your appetite.
Eat a balanced diet
Foods high in refined grains, added fats and sugar, other synthetic ingredients and processed foods stimulate your hunger and interfere with regular leptin and ghrelin levels. Maintaining a balanced diet that focuses on whole, nutrient-dense foods such as high-fibre foods (fresh and cooked vegetables, fruits) and whole grains can help regulate hunger and boost satiety after eating. Incorporating high-protein foods like yoghurt, wild fish, legumes, beans and egg into every meal also helps to retain lean muscle mass, makes you eat less and maintain metabolism.
Fasting intermittently helps to reduce inflammation in the hypothalamus that causes leptin resistance. It includes various forms such as alternate-day cycling and time-restricted eating, and has been found to improve leptin sensitivity and regulate weight loss. Fasting also helps to sustain energy balance and protect against severe obesity.
Avoid night time feeding
Eating at the wrong time, particularly at night, has been found to significantly contribute to disrupting your circadian cycle and cause weight gain. Some studies hypothesise that eating after 8 pm is associated with weight gain and this could be due to the delay of the calories from being burned.
Reduce sugar intake
Consumption of excess sugar, including refined sugar, high-carb foods and foods with high-saturated fats contributes greatly to your chances of getting obese. This is because these foods have been found to cause inflammation in the brain, promoting leptin resistance and obesity. Therefore, you must limit the amount of sugary beverages, candies and other highly processed foods you consume. You could substitute it with natural sweeteners like honey or maple syrup.
When you are stressed over a long time, it is termed chronic stress and this is usually associated with weight gain. Researchers have found that long-term stress often makes one prone to overeating.9 Chronic stress increases the amount of cortisol circulating in your bloodstream, thereby contributing to some hormonal imbalances such as boosting leptin resistance. Engaging in activities that aid relaxation is a good way to manage stress. Some such activities include meditation, yoga, walking in the park and participating in hobbies.
Exercising regularly helps to build lean muscle mass and boosts your metabolism. The more you exercise, the higher your metabolic rate and your ability to regulate leptin. Studies indicate that exercise is very beneficial for weight loss.10 Furthermore, it is suggested to improve hypothalamic sensitivity partly by inhibiting inflammation in the hypothalamus.
Since poor quality sleep is associated with leptin resistance, ensure that you sleep for at least 7 hours each night in order to maintain a healthy circadian rhythm and improve your metabolic health.
What foods are high in leptin?
Because leptin is a hormone, not a nutrient, most food sources don’t directly deliver leptin to your brain. However, eating certain foods high in some nutrients may help increase your brain’s response to leptin. They include; eggs, nuts, berries, vegetables, legumes and other foods rich in vitamin D and folate.
How can I raise my leptin levels?
Since leptin resistance stops your brain from responding to leptin, the focus should be on improving the body’s sensitivity to leptin. You can do the following to increase your body’s sensitivity to leptin, thereby raising its levels:
- Eating protein-rich foods
- Reducing stress and getting enough sleep
- Regular exercise
- Consume omega-3-fatty acids
What are normal leptin levels?
Although the regular leptin value range may show slight variation, the general normal range is 0.5 - 12.5 ng/ml for males and 0.5 - 15.2 ng/ml.
How are leptin levels controlled?
Leptin levels are controlled by a feedback mechanism between the adipose tissue (fat tissue) and the hypothalamus in the brain. Although very little is known about this cellular pathway, it is established that leptin serves as a signal that informs the brain about the size of energy reserves in order to regulate food intake and energy balance. Based on a study carried out in rodents, it was indicated that insulin directly influences leptin secretion.
People who have leptin resistance don’t respond to leptin as they should because their brain is continuously stimulated by leptin. This prompts your brain to lower your energy levels, make you feel less satisfied after eating and cause you to eat more. Weight gain and obesity are symptoms as well as a cause of leptin resistance because it forms a cycle of feeding more to get full, and in turn, increases the amount of circulating leptin which causes leptin resistance.
Consult your doctor if you notice the symptoms of leptin resistance to work out a weight loss plan for you or suggest other strategies to manage your symptoms. Although there are leptin supplements available, it is important to note that they don't contain leptin itself. Rather, they focus on helping you feel full or burn calories faster.
- Wasim M, Awan FR, Najam SS, Khan AR, Khan HN. Role of leptin deficiency, inefficiency, and leptin receptors in obesity. Biochem Genet [Internet]. 2016 Oct [cited 2023 Oct 17];54(5):565–72. Available from: http://link.springer.com/10.1007/s10528-016-9751-z
- Hernández C, Simó R, Chacón P, Sabin P, Baena JA, Castellanos JM, et al. Influence of surgical stress and parenteral nutrition on serum leptin concentration. Clinical Nutrition [Internet]. 2000 Feb [cited 2023 Oct 17];19(1):61–4. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0261561499900754
- Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med [Internet]. 1996 Feb [cited 2023 Oct 17];334(5):292–5. Available from: http://www.nejm.org/doi/abs/10.1056/NEJM199602013340503
- Rodríguez EM, Blázquez JL, Guerra M. The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: The former opens to the portal blood and the latter to the cerebrospinal fluid. Peptides [Internet]. 2010 Apr [cited 2023 Oct 17];31(4):757–76. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0196978110000239
- Izquierdo AG, Crujeiras AB, Casanueva FF, Carreira MC. Leptin, obesity, and leptin resistance: where are we 25 years later? Nutrients [Internet]. 2019 Nov 8 [cited 2023 Oct 17];11(11):2704. Available from: https://www.mdpi.com/2072-6643/11/11/2704
- Amitani M, Asakawa A, Amitani H, Inui A. The role of leptin in the control of insulin-glucose axis. Front Neurosci [Internet]. 2013 [cited 2023 Oct 17];7. Available from: http://journal.frontiersin.org/article/10.3389/fnins.2013.00051/abstract
- St-Onge MP. The role of sleep duration in the regulation of energy balance: effects on energy intakes and expenditure. Journal of Clinical Sleep Medicine [Internet]. 2013 Jan 15 [cited 2023 Oct 17];09(01):73–80. Available from: http://jcsm.aasm.org/doi/10.5664/jcsm.2348
- Hosoi T, Sasaki M, Miyahara T, Hashimoto C, Matsuo S, Yoshii M, et al. Endoplasmic reticulum stress induces leptin resistance. Mol Pharmacol [Internet]. 2008 Dec [cited 2023 Oct 17];74(6):1610–9. Available from: http://molpharm.aspetjournals.org/lookup/doi/10.1124/mol.108.050070
- Peters A, Kubera B, Hubold C, Langemann D. The selfish brain: stress and eating behavior. Front Neurosci [Internet]. 2011 [cited 2023 Oct 17];5. Available from: http://journal.frontiersin.org/article/10.3389/fnins.2011.00074/abstract
- Reseland JE, Anderssen SA, Solvoll K, Hjermann I, Urdal P, Holme I, et al. Effect of long-term changes in diet and exercise on plasma leptin concentrations. The American Journal of Clinical Nutrition [Internet]. 2001 Feb [cited 2023 Oct 17];73(2):240–5. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0002916523064821