Elevated Leptin, Autoimmune Disorders, and Chronic Inflammation

April 23, 2018 | Linda J. Dobberstein, Chiropractor, Board Certified in Clinical Nutrition

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Elevated Leptin, Autoimmune Disorders, and Chronic Inflammation
The hormone leptin was discovered more than 20 years ago. Since that time, a tremendous amount of information has been discovered about leptin and its many effects. Leptin is still at the forefront of metabolic health, but it is far more than that. As scientists unearth leptin’s role in other areas, we find that it is intimately involved with inflammation, especially autoimmune inflammation.

Too much leptin, leptin resistance, and even too little leptin greatly affects the immune system and more. In a modern world that often offers high calorie, nutrient poor diets with grazing and disrupted schedules that impact leptin, there is no doubt that this has contributed to the epidemic levels of obesity. Increasing evidence shows that high leptin levels impact autoimmune disorders and even the obesity-cancer connection. Mastering leptin is still at the forefront of daily health.

The Role of Leptin

Leptin is a hormone, or adipokine, produced by fat cells. Leptin is also found in smaller amounts in the brain (hypothalamus, pituitary), stomach and intestines, skeletal muscle, breast tissue, cartilage and bone cells, placenta, and immune cells. Leptin was initially considered an anti-obesity hormone, but it influences the formation of all types of blood cells (hematopoiesis), heat and energy production (thermogenesis), reproduction, new blood vessel formation (angiogenesis), and most importantly, immune homeostasis

In addition to being a hormone, leptin is also a cytokine, an immune compound capable of immune responses and inflammation. It is directly involved with the interplay between metabolism and inflammatory responses. This is seen as an almost circuitous loop as fat cells produce leptin which assists in the secretion of proinflammatory cytokines like TNF-a, IL-1, and IL-6 and others. In turn, these and other cytokines promote release of leptin from fat cells, which can create a cyclical response. With higher body mass index (BMI) as in obesity, increased leptin leads to increased inflammation.

In addition to the proinflammatory cytokines stimulating leptin, other factors influence leptin levels. Hormones like insulin and cortisol impact leptin levels. High calorie intake, low nutrient intake, and mistiming of meals affect leptin. Acute infections, LPS toxins which are toxic by-products from bacteria, and severe overwhelming infections also increase leptin levels. Women also have higher leptin levels than men.

Leptin Related Disorders

High leptin contributes to increased likelihood of developing cardiovascular disease, diabetes, cancer, degenerative joint disease, surgical complications, and autoimmune disorders. It is involved with allergic disorders and oral health

Elevated leptin levels are thought to contribute to systemic autoimmune disease like type 1 diabetes and inflammatory bowel disease. Leptin is elevated in inflammatory nephritis/kidney disease, endometriosis, nonalcoholic hepatitis, chronic pulmonary/lung inflammation, Behcet’s disease, and even Grave’s disease (thyroid). More recent research shows that elevated leptin may contribute to autoimmune disorders that affect connective tissues such as inflammatory arthritis, i.e. rheumatoid, osteoarthritis and vasculitis.

Additional research shows that elevated leptin stimulates the disease process with the connective tissue disorder, systemic lupus erythematosus (SLE) or lupus. Obese patients with elevated leptin are more likely to develop multiple sclerosisLiver cirrhosis may also occur with increased leptin levels because of its proinflammatory scarring that induces fibrotic tangles in the liver.

Elevated leptin levels are seen in the brain with Alzheimer’s disease. In this case, it is thought that leptin receptor sites are damaged from the brain tangles from the disease process. This is thought to interfere with the normal leptin signaling pathway and create a different type of leptin resistance.

Leptin and Immune System

Leptin is directly involved with immune balance and homeostasis as it talks directly to the thymus gland and is essential for the thymus gland to mature. Here are some basic things that leptin is known to influence in the immune system. Leptin promotes T cell activation and can shift the body towards a Th1 dominant response while suppressing Th2 immune balance. It also affects the production of natural killer cells. Several of the disorders listed above are considered Th1 dominant disorders.

Chronically elevated leptin changes natural killer cell function in the body. Natural killer cells are innate immune cells that are essential to immune defense. Their primary purpose is to kill tumor cells and virus-infected cells. When natural killer (NK) cell function is impaired from elevated leptin, the total number of NK cells decrease and tumor cell killing capacity becomes compromised. Researchers suspect that this may be one reason for increased cancer susceptibility in obese individuals.

There is a flip-side to leptin, as low leptin levels contribute to other dynamics with the immune system. Individuals who have low leptin and are malnourished have an increased risk of infection and other issues of impaired immune function. The focus of this article though is on elevated leptin and the immune system.

Leptin and Inflammation Modulation

Researchers are still trying to figure out how to manage leptin with drugs in order to block, modulate, or make more leptin hormone. There is, however, a natural way to help modulate leptin. Several resources exist. Here are some recent studies describing natural support for leptin modulation.


Plant-based compounds called saponins are one group of phytochemicals that have received significant attention for leptin, obesity, inflammation, diabetes, etc. Saponins exhibit a number of powerful biochemical pathways in the body ranging from antidiabetic, cholesterol lowering, anticancer, and blood sugar lowering effects. Saponins are involved in energy metabolism and the AMPK pathway. Saponins have been shown to modulate the same signaling pathways (JAK2/STAT3, MAPK, PI3K and AMPK) as leptin. Saponins are found in green tea extract and panax ginseng.


Other phytochemicals show promising results for leptin modulation and antioxidant support for immune inflammation. Berries like cranberries, raspberries, bilberry, were shown to decrease leptin expression by as much as 90 percent and improved adiponectin levels by four times in a recent cellular study. Adiponectin counterbalances leptin like a teeter-totter effect. Berries are well-known for their powerful antioxidant support which helps manage inflammation.


Ashwagandha (Withania somnifera) contains a compound called withaferin A. This medicinal herb has been used for centuries in traditional Indian medicine to treat numerous concerns including autoimmune disorders, inflammation, tumors, stress, aging and anxiety.

Recent research shows withaferin A helps leptin resistance and elevated leptin levels. Mice were fed a high fat, simple carbohydrate diet and developed high leptin levels. They were given withaferin A to evaluate its effect on leptin. Treated obese mice had a reduction in food intake, improved body weight, and blood sugar levels improved as it supported antidiabetic pathways. It was found to help cells become more sensitized to leptin rather than leptin resistant when given this ashwagandha compound. Scientists designated withaferin A as a potent anti-obesity agent.

Omega-3 DHA

Numerous studies continue to outline the benefits of the omega-3 fish oil DHA for chronic inflammation, leptin resistance, obesity, and blood sugar management. A randomized single-blind, placebo-controlled pilot study on 54 adults showed significant benefits when given 520 mg of DHA/EPA per day. After 24 weeks, waist size was reduced, blood sugar and hemoglobin A1C levels, leptin, adiponectin levels and cholesterol levels all improved. Omega-3 DHA intake has been shown to buffer against the damaging effects of a high fat diet and a high-fructose diet. These diets are used to induce obesity and diabetes in research as it models the Standard American Diet.

A recent study found that individuals who followed a very low calorie ketogenic diet fared much better with inflammation reduction when DHA supplementation occurred. Those who did not use DHA failed to remediate inflammation even with the ketogenic diet as high levels of arachidonic acid were still found in cell membranes.


Curcumin helps modulate several cytokines like NF kappa B and has been shown to improve adiponectin levels, the buffer to elevated leptin. Curcumin helps reverse insulin resistance, high blood sugars, and high cholesterol levels. It is often used to help inflammation related with osteoarthritis, which is often related with elevated leptin levels.


The sleep hormone melatonin is an interesting compound for leptin, brain/hypothalamus, autoimmune disorders, and anti-inflammatory activity. New research shows that melatonin and leptin interact together in the hypothalamus of the brain to regulate the energy balance in the brain and in brown adipose tissue. Low melatonin leads to a higher incidence of obesity and leptin resistance. This is often seen in night-shift workers or those who are exposed to artificial light at night. Steps to remedy sleep environments and artificial light at night should be addressed too.

I mentioned earlier that leptin is involved with T cells and several autoimmune inflammatory disorders like lupus/SLE, multiple sclerosis, and type 1 diabetes. Recent research shows that melatonin may just be a helpful key factor in managing these disorders. Melatonin has been shown to modulate T-cell immune responses and provide anti-inflammatory benefit to type 1 diabetes, lupus/SLE, and MS

Melatonin deficiency and dysfunction has been linked with Grave’s autoimmune thyroid disease and SLE/lupus. It seems plausible to connect the dots of high leptin levels, obesity, impaired immune function, increased autoimmune inflammation, and several autoimmune disorders (MS, Graves, type 1 diabetes, SLE/lupus) that develop within this context linked with low levels of melatonin.

Leptin and autoimmunity research is a fascinating topic and one that will be explored for years to come. This article only scratches the surface of the topic, but it gives important clues. Leptin’s effect on the immune system is profound. When it fails to be in balance, then the propensity is to develop significant dysregulation, chronic low-grade inflammation, degenerative disease and autoimmune disorders. Autoimmune disorders and obesity statistics has increased dramatically in the last few decades. There are many additional reasons for this, but clearly leptin is integral.

We must have a healthy dietary lifestyle with nutrient-dense foods, not calorie-rich foods and appropriate meal timing as per the Five Rules of The Leptin Diet. We must find ways to reduce inflammation to stop the vicious cycle of fat cells releasing leptin that directs release of more cytokines which increases inflammation. Nutrients like green tea extract, panax ginseng, ashwagandha, curcumin, DHA and berries (cranberries, bilberry, etc.) help interrupt this process. Melatonin coupled with these nutrients may add another layer of support for autoimmune dysregulation. Many other nutrients help support leptin and reduce inflammation as well.

Rebalancing leptin and turning off inflammation has many different layers of needs and necessary support. When it is out of balance, it is like turning a ship around. It takes time, effort, and work, but it can be done. If the ship is not turned around when in a storm, then it becomes a task of managing the storm damage and trying to prevent the ship from sinking. Are you the captain of your leptin-autoimmune ship?

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