High leptin is tied to obesity, overeating, and inflammation, and if leptin remains high for a long time, leptin resistance may result. Learn about the causes, symptoms & natural factors that lower leptin levels here.
What is Leptin?
Leptin is a satiety hormone that promotes weight loss. It is produced by the body’s fat cells [1].
When a person eats enough food, leptin is released into the bloodstream, where it travels to the brain, signaling that they are full and that can burn calories at a normal rate [2, 3, 4].
To learn more about normal leptin levels and what this hormone does in the body, read the first part of this series.
This post will focus on the dangers of high leptin. Elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including high blood pressure, metabolic syndrome, and heart disease [5].
Leptin’s Role in Weight
To recap, leptin is one of the big 4 hormones that determine weight. It is made in fat tissue, while receptors for it are dense in two important brain regions (the hypothalamus and hippocampus) [6].
Leptin acts as a signal to the brain to inhibit food intake and enable the storage of surplus calories (in fat cells).
At the same time, it protects non-fatty tissue from fat overload. Increased leptin is associated with higher body fat mass, a larger size of individual fat cells, overeating, and excessive hunger. In rodents, it increases energy expenditure by using brown fat for energy [7].
The more fat is present, the more leptin is produced. This feedback loop, when functioning normally, keeps body weight in homeostasis: eating more food increases body fat, which increases leptin secretion, which decreases appetite and increases energy expenditure [8].
High Leptin
Underlying Conditions
High leptin levels are believed to be caused by, among other factors:
- Overeating [9, 10]
- Emotional stress [11]
- Inflammation [9, 12]
- Obesity [10]
- Pregnancy [13]
- Pre-eclampsia [13]
- Gestational diabetes [13]
- Sleep apnea [14]
If you believe that your leptin system is unbalanced, talk to your doctor about any underlying conditions which may require attention.
Negative Health Effects
1) Inflammation
Leptin is an inflammatory marker, as it responds to inflammatory cytokines from fat tissues. Autoimmune diseases are associated with increased secretion of leptin [15]. In terms of both structure and function, leptin resembles IL-6.
Leptin increases the release of proinflammatory cytokines TNF-alpha, IL-2, IL-6, and IL-12 [16].
It also increases C-Reactive Protein (CRP) [17].
Leptin provokes the release of proinflammatory cytokines from many cell types, including microglia in the brain [18], and is a mediator of cytokine-induced sickness behavior (CFS) [19].
Multiple studies have demonstrated elevated levels of leptin in chronic inflammatory conditions [20].
It also increases both red and white blood cells [15].
Elevated leptin is associated with higher white blood cell (WBC) counts in both men and women [21].
2) Fatigue
Leptin is believed to cause inflammatory fatigue [22]. Leptin is higher in women even when controlling for weight, and women are more likely to be diagnosed with chronic fatigue syndrome (CFS) [23].
This is believed to be, in part, because testosterone suppresses leptin in men (clinical trials) [24].
Leptin increases were associated with greater fatigue scores in people with CFS. Some researchers believe that it plays a causal role in CFS; however, chronic fatigue is a controversial and poorly understood condition, and this conclusion is by no means unanimous [25].
Leptin levels in the blood are also associated with fatigue severity in patients with chronic hepatitis C and irritable bowel syndrome (IBS) [22].
In people diagnosed with CFS, leptin increases more in response to cortisol [26].
3) Th1 Immunity
Leptin activates the JAK2– STAT3 pathway [27] and promotes Th1 responses [15].
By stimulating STAT3, it might also stimulate Th17 responses [28]. Leptin also changed human dendritic cells (DCs), directing them towards Th1 dominance [29].
It was also found to be necessary for Th1 dependent inflammatory processes, acting as a critical regulator of CD4 T cells [30].
The effect of leptin polarizing T cells towards a Th1 response seems to be mediated by stimulating the synthesis of IL-2, IL-12, and IFN-gamma (all Th1 cytokines) and inhibiting the production of IL-10 and IL-4 [31, 32].
Th1 dominance correlates with excess leptin in this study of dialysis patients [33]. If you’re Th2 dominant, it doesn’t mean leptin isn’t causing problems. It simply means that it’s causing different problems.
4) Mast Cells
Mast cells in the human skin, lungs, gut, and the urogenital tract contain leptin and leptin receptors [34], suggesting that leptin communicates with mast cells.
It seems like leptin causes mast cells to be more inflammatory [35].
In metabolic syndrome patients, there was a positive correlation between leptin levels and the number of fat tissue mast cells, suggesting that leptin may stimulate mast cells [36].
Leptin correlates with (probably increases) mast cell activation in children with asthma who exercised [37].
It suppresses appetite, in part, by increasing histamine release and activating histamine H1 receptors in the hypothalamus [38, 39].
5) Regulatory T cells
Leptin impedes the production of Treg cells. Tregs are a critical part of the immune system that creates a tolerance to agents that would otherwise trigger an immune response [15].
6) HPA Axis
Leptin increases the stress response and the activity of the sympathetic nervous system (fight or flight) [40].
It activates the HPA axis and lowers heart rate variability (HRV) [41].
7) Cancer
Leptin promotes the growth and spread of cancer. This is one reason why obesity is considered a risk factor for cancer [42].
It increases angiogenesis by increasing vascular endothelial growth factor (VEGF) levels.
8) Heart Disease
Leptin receptors are found in the heart [43]. Studies have linked high leptin levels to an increased risk of cardiovascular disease [43].
In obese subjects, leptin levels are the most significant predictor of higher levels of fibrinogen, a clotting factor considered to be one of the most important risk factors for heart disease [44].
Even so, high leptin levels also are associated with high blood pressure [45], although this might be because of leptin resistance because leptin infusion in rats lowers blood pressure [46].
Leptin increases endothelin-1 production, which is a potent vasoconstrictor [45]. By constricting blood vessels, leptin/endothelin-1 could play a role in the development of heart disease [45].
9) Pain Sensitivity
Higher leptin levels in the body can cause the body’s pain sensitivity to increase. This is because it can cause inflammation, which plays a role in pain [47].
In a study of 3 fibromyalgia patients, they reported higher pain levels on days when they had increased leptin in their blood. A cohort study of 5,600 postmenopausal women showed similar results [47].
Leptin may increase pain by activating inflammatory markers (IL-1B, IL-6, IL-18) or preventing pain modulating signaling [47].
10) Nutrient Absorption
It is secreted by the stomach and enters the small intestine. Several studies have shown that leptin interferes with the absorption of some nutrients.
It enhances butyrate uptake [48], intestinal transport of fructose [49] and oligopeptides [50].
Leptin decreases glucose [51] and galactose uptake [52]. It also inhibited the absorption of Proline, Beta-Alanine, and Glutamine [53].
On the one hand, I could see this being both bad and good. If it blocks the absorption of glucose and amino acids, it can help weight loss.
However, blocking glucose uptake gives a better chance for SIBO to arise or for malnutrition from not absorbing amino acids.
11) Leptin Resistance
Many researchers have argued that chronically high leptin levels can lead to leptin resistance, much like chronically high insulin levels can lead to insulin resistance. Symptoms of leptin resistance include [54]:
- Weight gain and difficulty losing weight
- Urge to snack soon after meals
This post goes into more detail about leptin resistance.
Factors that Affect Leptin Levels
Leptin is increased after meals, more by carbohydrates than by fat in both obese and healthy people [55, 56].
When stressed, the body releases leptin, and increased leptin is associated with increased consumption of comfort foods [57].
1) Diet
Overeating during meals promotes increased leptin production. By contrast, eating smaller meals and a higher proportion of protein may decrease leptin [12, 58].
A diet low in carbohydrates and fat may reduce leptin release [59].
Anti-inflammatory foods, such as fatty fish, olive oil, nuts, fruits, and vegetables may likewise reduce leptin production [60].
Fasting
Short-term fasting decreases leptin (24-72 hours) [61].
Intermittent fasting is considered the safest and most accessible form of fasting. Talk to your doctor before making significant changes to your diet [61].
2) Stress
Emotional stress, the stress hormone cortisol, and anti-inflammatory steroid drugs all increase leptin. Reducing stress may reduce leptin [11, 62].
3) Exercise
Exercise lowers leptin production [63, 64].
4) Toxin Exposure & Inflammation
- Endotoxin in both rodents and humans leads to increased leptin levels [65, 66].
- Inflammatory cytokines such as TNF/IL-1 increase leptin [67, 68].
- Interferon-gamma and LPS mixture in fat cell cultures raises leptin [69].
If you are suffering from inflammatory symptoms, especially if they persist for more than two weeks, talk to your doctor about possible underlying causes of this inflammation.
5) Estrogen
Estrogen increases leptin. This is usually bad, especially in men and because excess estrogens have been linked to leptin resistance [70]
6) Sleep Apnea
Sleep apnea is linked to increased leptin in obese people. In one study, leptin levels returned to normal after CPAP treatment [14].
7) Cold Showers
Exposure to cold temperatures can decrease leptin [12, 71].
Other Factors
All the following have decreased leptin in various studies. However, these do not present appropriate strategies for decreasing leptin and improving health.
- Adrenaline, Norepinephrine, and Dopamine (catecholamines) [68]
- Thyroid hormones (T3/T4) [68]
- Testosterone [70] and androgens [68]
- cyclic AMP [68] – you can increase cAMP by taking forskolin.
- Nitric Oxide in fat cell cultures. This would translate to making sure you have good circulation [69]
- PPAR alpha and PPARgamma [72]
