Low levels of the satiety hormone leptin have been linked with poor memory, anorexia, depression, and frequent infections. Read on to learn about the causes and symptoms of leptin deficiency and how to increase your levels naturally.

What is Leptin?

Leptin is a satiety hormone that causes weight loss. It is produced by the body’s fat cells [1].

To learn more about normal leptin levels and what this hormone does in the body, read the first part of this series.

In this post, we’ll focus on what can go wrong when leptin levels fall too low and why this can happen in the first place. Leptin deficiency has been associated with cognitive changes, anorexia, depression, and Alzheimer’s disease [2, 3].

Leptin’s Role in Weight

To recap, leptin is one of the big 4 hormones that determine your weight. It is made in fat tissue, while receptors for it are dense in two important brain regions (the hypothalamus and hippocampus) [4].

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-fat tissue from fat overload. Increased leptin is associated with higher body fat mass, a larger size of individual fat cells, and the act of overeating/hunger. In rodents, it increases energy expenditure by using brown fat for energy [5].

The less fat you have, the less leptin you produce [6].

Leptin Deficiency (Low Leptin)

Leptin is obviously good and necessary in many ways. The problem is leptin resistance in certain parts of the body (hypothalamus), which leaves excess leptin in the blood. Another problem are low leptin levels, or, in the extreme cases, leptin deficiciency.

Causes

Low leptin levels can be caused by:

  • Low body mass index (BMI) [7, 8]
  • Cold exposure [9]
  • Alcohol [10]
  • Exercise [11, 12]
  • Short-term fasting [13]
  • Sleep deprivation [14]
  • Anorexia [15]

Leptin deficiency can also be caused by disorders such as:

  • Congenital leptin deficiency [15]
  • Congenital and acquired lipoatrophy (localized loss of fat tissue) [15]

Symptoms

Symptoms of low leptin levels vary depending on the underlying cause. You may experience [15, 16, 17, 18]:

  • Feeling hungry more often
  • Difficulty losing weight (slower metabolism)
  • High or low percentage of body fat
  • Absent period (in women)
  • Weak and brittle bones (osteoporosis)
  • Frequent infection

If your leptin levels are too low, you are missing out on all its beneficial health effects.

Leptin’s Beneficial Health Effects

1) Reduces Anxiety and Depression

Recent studies suggest that leptin may have antidepressant and anti-anxiety properties.

In rat models of depression and anxiety, leptin levels are low. When given leptin, symptoms improve [19].

On the other hand, Ghrelin, the hunger hormone, causes anxiety and depression [19], which leads to the ‘hangry’ feeling – hungry and angry.

Depression and anxiety are common in women with anorexia nervosa (AN), an illness associated with low leptin and increased ghrelin [19].

Similarly, there is an increased prevalence of depression and anxiety in normal-weight women with functional hypothalamic amenorrhea (HA), a disorder also characterized by low leptin and high ghrelin [19].

Recently, obesity has been linked to an increased risk of depression and anxiety [19], which can result from leptin resistance. High leptin levels were associated with lower depression scores [19].

Leptin’s anti-anxiety effects are mediated in part by its actions in the Prefrontal cortex (PFC), the ventral tegmental area (VTA) and substantia nigra (SN) [19]. Leptin also reduces anxiety by inhibiting orexin A in the Suprachiasmatic Nucleus (SCN) [20].

Real world example:

A client asked me why sometimes he feels his depression and anxiety decline after meals. There are a few reasons for that, but one reason, I told him, might be leptin.

He said it happens in the evening, which makes sense because leptin increases as the day goes on.

2) May Help You Get Into Ketosis

Leptin may help get people into ketosis.

Leptin-deficient mice do not get into ketosis well and have a defective response to the ketogenic diet (no increase in liver FGF21) [21].

It might improve mitochondrial function (by increasing hsp60), which decreases insulin resistance [22].

3) May Improve Cognitive Function

Leptin has some positive effects on cognitive function.

Like BDNF, leptin facilitates synaptic plasticity in the hippocampus [4] and long-term potentiation (LTP) [4], processes that are critical for memory.

Leptin also helps spatial learning [4]. It increases BDNF in the hypothalamus (VMH) [23].

Animal models of Alzheimer’s disease have shown that chronic administration of leptin can be beneficial for the condition and improve cognitive performance, by reducing b-amyloid and Tau proteins, two hallmarks of Alzheimer’s pathology [24, 25].

4) Improves Fertility and Bone Health

Leptin is proven to restore fertility and may improve bone health in lean women [26].

Women with extremely low body fat, including runners and dancers, as well as women with eating disorders, are prone to develop hypothalamic amenorrhea (HA), a condition in which their menstrual periods cease, triggering serious problems such as infertility and osteoporosis [26].

Without leptin, menstrual periods cease, the body becomes chronically energy-deprived and women experience bone loss and an increased risk of bone fractures [26].

Treatment with a synthetic form of leptin can restore fertility and reduce the risk of bone fractures in this group of patients [26]. This is one reason why during fasting or starvation, fertility declines [26].

Leptin helps fertility by increasing luteinizing hormone (LH), follicle stimulating hormone (FSH) and human chorionic gonadotrophin (hCG) [27, 28].

Real world example:

People who are very thin and anxious often have fertility problems.

This is because thin and anxious people have low leptin and high ghrelin, both of which increase anxiety.

Ghrelin reduces fertility by inhibiting GnRH [29].

5) Strengthens the Immune System

It has been shown that conditions of reduced leptin production are associated with increased infection susceptibility [30].

The decline of leptin during fasting is one of the main mechanisms by which fasting suppresses the immune system [30]. (Lower T3 is another.)

Leptin Stimulates Natural Killer Cells

People who get chronic infections often have lower immune function and blood tests for Natural Killer Cells and Natural Killer Cell Activity often come back low.

Leptin stimulates the maturation, production, activation, and function of human Natural Killer cells [31].

It increases the production of IL-2, IL-12 and perforin in natural killer (NK) cells [32, 33].

It also activates NK cells indirectly by increasing IL-1, IL-6, and TNF – by monocytes and macrophages [34].

6) Improves Insulin Sensitivity

Leptin improves insulin sensitivity (by way of MC4R) [35].

7) May Lower Cholesterol

Humans born with a genetic leptin deficiency are profoundly obese, have high insulin and high cholesterol [36].

Leptin replacement in these people can improve insulin, cholesterol, triglyceride, and LDL cholesterol levels [36].

8) Might Combat Allergic Reactions By Inhibiting IgE Immune Responses

True to its Th1 dominant role, leptin suppresses IgE-mediated cytokine production.

Additionally, studies showed that Leptin receptor deficiency magnifies IgE-mediated anaphylaxis.

It may only inhibit IgE responses in mice that are Th1 dominant.

9) Reduces the Absorption of Amino Acids and Sugar

Leptin is secreted by the stomach and enters the small intestine. Once it reaches the intestines, leptin can interfere with the absorption of some nutrients.

For example, it enhances butyrate [37], fructose [38] and oligopeptides uptake [39].

On the other hand, it decreases glucose [40] and galactose uptake [41]. It also inhibited the absorption of several amino acids, including Proline, Beta-Alanine, and Glutamine [42].

I could see this being both bad and good. By blocking 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.

10) May Lower Inflammation

Leptin leads to the production of VIP, the anti-inflammatory hormone (synergistically with TGF-beta). VIP has mixed effects on weight, however. Although it blocks appetite, its net effect may be to promote obesity [43].

How to Increase Leptin

Various factors increase leptin, but many of them are unhealthy. An example of an unhealthy factor that raises leptin is stress. Obesity and sleep apnea also increase leptin [44, 45, 46]

When stressed, you release leptin and the more you release, the more you eat comfort foods after [47].

Leptin is mainly increased after meals – more by carbohydrates then by fat in both obese and healthy people [48, 49].

1) Try Avoiding Lectins

Lectins are proteins that bind to sugar molecules. Leptin receptors have these sugar molecules that lectins like to bind to such as ConA (in legumes) and WGA (in wheat). If the sugar molecules on leptin receptors are bound (or removed), then the receptors don’t function nearly as well [50].

Therefore, avoiding lectins might be a good idea if you want to increase the activity of leptin in your body.

2) Eat More Carbs and Fats

Meals with carbohydrates and fats increase leptin [48, 51].

2) Check Your Estrogen Levels

Estrogen increases leptin. This is usually bad, since excess estrogens have been linked to leptin resistance. However, if you are in menopause, maintaining estrogen activity might help balance your leptin levels. Work with a physician to make sure your hormones are balanced [52]

3) Check Your Insulin

Leptin increases 4 – 6 hours after meals in response to insulin secretion. Check your insulin and glucose levels to make sure they are in the normal range [53].

4) Get Enough  Sleep

Restful sleep in non-obese individuals (i.e., 8 – 12 hours of unbroken sleep) can increase leptin to normal levels [54].

On the other hand, sleep deprivation lowers leptin levels [14]

Similarly, circadian clock proteins (BMAL1/CLOCK) increase leptin production [55].

Make sure you are getting enough quality sleep.

5) Reduce Alcohol

Alcohol decreases leptin more compared to other calories [56].

5) Maybe Glucosamine

Glucosamine (and hexosamines) increased leptin in pancreatic beta-cells [57]. There is not enough evidence to recommend glucosamine for increasing leptin in humans, though.

Irregular Leptin Levels?

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