Leptin – The Hormone that Controls Appetite

Leptin is a hormone that regulates appetite. It was discovered in 1994 by researchers studying an obese mouse model.

Its role in the body is to tell your brain when you are full to stop eating. Sometimes called the “Obesity” or “Starvation” hormone, leptin tells your brain when you need and do not need any more food.

There are many ways that leptin helps regulate appetite, making it essential for weight loss or gain because it plays a significant role in how much we eat each day.

This blog post will discuss how leptin can help you lose weight and what foods to eat to increase your leptin levels!

What is leptin, and how does it work?

Leptin’s job is to control hunger and appetite for food. Its levels are usually low when you haven’t eaten in a while, which triggers the brain to tell your body it’s time to eat.

Leptin flows out into the bloodstream from fat cells and by reporting the adipose tissue mass around to the central hypothalamus to indicate that you need more (or no more) food.^[2]

Leptin can be produced by fat cells or made in the body from proteins including prolactin, adiponectin, and others.

Its production fluctuates with leptin itself, and it has many effects on metabolism and weight control. It helps signal basal metabolic rate and lipolysis (fat breakdown).

Leptin also works with other hormones like ghrelin, which stimulates hunger to regulate how much we eat throughout the day.

Structure

Leptin is primarily a product of intestinal absorptive cells (enterocytes) and adipose/fat cells (adipocytes) based in the small intestine. When it inhibits hunger to regulate balance, adipocytes shed their fat storage.

We can easily determine four helical cytokines (peptides, apart from hormones and growth factors, important in cell signaling) here, and each comprises between 20 to 25 smaller proteins.

Interactions

Leptin acts on and affects many targets around the body for different functions, as follows:

• hypothalamus
• leptin receptors in human/vertebrate cell membranes
• hormones and energy regulators
• immune cells
• beta islet cells
• growth factor
• other peripheral (non-hypothalamic) targets

With these peripheral targets, leptin can regulate energy consumption, body processes between a mother and her fetus, and its permissive factor in puberty.

• insulin
• glucagon
• insulin-like growth factor
• growth hormone
• glucocorticoids
• cytokines
• metabolites

Leptin Levels Vary By Condition

The blood levels need to be within specific ranges for a good shape and healthy lifestyle for men and women alike.

But, generally, women tend to outmatch men in leptin levels, not to mention pregnant women with their gestation.

Which People are Poor in Leptin?

Leptin levels decrease with age, which means older people may have less ability to control their appetites than younger people due to lower leptin levels.

The levels are often low among obese people because they have leptin-producing cells that do not work correctly or too much body fat to produce enough leptin.

Known Levels in Specific Conditions

Between the human body and brain, leptin exclusively communicates nutritional status. However, there exist many cases where it varies no more with body fat levels.^[5]

Appetite Regulation

Leptin comes out from the adipose tissue and signals the hypothalamus of storage of this particular amount of fat, as it usually does. Leptin then sends “stop eating” signals to the brain.

Leptin also inhibits ghrelin, making one feel fuller after they eat. As the appetite starts to decrease, satiety gradually proceeds.

When leptin levels are high enough, it can also help suppress hunger. Abounding in the blood, it tells your brain you are not hungry anymore.

When leptin levels drop, it signals our brains to eat more food because we need energy for metabolism and much more.

Leptin and its Effects on the Body

Metabolism

The levels rise when we eat and fall when we don’t have food in our stomachs.

Leptin also plays a role in how quickly food is digested and used by the body for energy.

Besides appetite and thirst, it even regulates the body temperature, which is an essential factor in weight loss or gain because it affects how many calories you burn.

It changes how your body processes food and boosts energy while suppressing appetite to help with weight loss or gain.

The hormone, along with insulin in glucose homeostasis, acts as the hormones that feed you when you start feeling hungry.

It reduces insulin and glucose levels in your blood. It also helps to control how much food you eat during the day.

When there are higher levels of calories coming into the body than needed, leptin tells our brain we’re full, making us stop eating at a fast rate before slowing down digestion with a spike of insulin level.

Leptin also controls how our bodies use insulin and glucose to make energy from our food during the day.

The amount of leptin fluctuates throughout the day and night as a result of our eating habits. Despite no correlation, leptin exhibited slight decreases against spikes of insulin and blood glucose in their profiles.

Leptin shows both inhibitory and stimulatory effects.

Leptin- and insulin-deficient states display many similarities between leptin’s primary (in vivo) glucoregulatory effects, despite reduced lipolysis in white adipose tissue with low insulin levels.

In leptin therapy, T1-diabetic mice showed improved metabolism, with mostly constant blood sugar, less cholesterol, and body fat. Insulin alone did not give results as good as leptin or both together.

Circulatory System

By increasing the vascular permeability factor, externally derived leptin can contribute to angiogenesis (formation of new blood vessels from existing vessels).

An infusion, or a transfer of adenoviral genes^[6], produces hyperleptinemia (abnormally high leptin levels in the blood), consequently decreasing blood pressure in rats.

We have observed excitatory responses in the sympathetic nervous system after leptin microinjections into the lower brain solitary nucleus (SN) tract, with induced responses to activate arterial receptors responsive to chemical stimuli.^[7]

Central Nervous System (CNS)

For its primary function of maintaining fat storage, leptin acts on its (hypothalamic) receptors in the central nervous system, while for secondary functions, it acts on (peripheral) receptors in the peripheral nervous system.

Science has revealed many ways of how leptin was influential in the CNS:

• Leptin shots reinstated modified proteins and functions of the brain caused by leptin shortage.^[8]
• Animal subjects treated with leptin found their memory and brainpower improved by activating leptin receptors (LepR) in the hippocampus.^[9]

• Psychological changes linked to depression, anorexia, and even Alzheimer’s Disease corresponded to scarcely flowing plasma leptin.^[10]

• Alzheimer’s-affected mice, genetically modified before birth, recovered their brain from pathology and cognitive function when provided with leptin for long.^[11] The studies concluded with leptin suppression on two attributes of the disease.^[12]

We got to locate leptin receptors in the brain as leptin bound intensely to those present in the choroid plexus (part of the brain ventricles), while those receptors could serve as a transport mechanism.^[13]

Sleep too can vary leptin production since the CNS detects circulating leptin levels and its rhythm during the day, which regulates the satiety signal.

Leptin correlates negatively with melatonin,^[14] but it is the opposite in the presence of insulin. As a result, the latter contributes to a lower appetite during sleep,^[15] while equating shorter sleep with low leptin levels.^[16]

In a study comparing bedtimes of 4, 8, and 12 hours, leptin levels did not only correlate negatively with cortisol levels.

The observations, with other studies, led to the conclusion that lack of quality sleep can reduce leptin rhythm and its levels, with further results of higher ghrelin and hence more appetite.

Hypothalamic Activity

In the lateral hypothalamus, leptin neutralizes the effects of neuropeptide Y and anandamide to inhibit hunger, and in the middle, it helps produce ⍺-melanocyte-stimulating hormone (a hunger-suppressing, melanocortin peptide) to stimulate satiety.

These inhibitions last longer than the effects of cholecystokinin (rapid inhibitor) or PYY (slow indirect suppressant) between meals.

At the base of the medial hypothalamus, leptin activates its receptors for the primary function: control on food intake and energy spent.

Emotional State

Leptin levels can influence our mood when they are too high or too low. Leptin levels that remain high over long periods increase the risk for depression and anxiety.^[17]

Leptin neurotransmission depends on levels of serum leptin, which increase with weight gain, suggesting that high leptin levels may induce depression.^[18]

Levels that drop below a healthy range can cause temporary weight gain and associated mood issues.^[19] A severe shortage can also cause temporary feelings of malaise or apathy, among symptoms of neurodegeneration.

Regarding leptin and its receptors in the brain, it has a protective effect on dopaminergic neurons by enhancing dopamine synthesis/secretion through STAT proteins (signal transduction and activator of transcription).^[19]

Fetal Lung Development

Leptin develops in alveolar interstitial fibroblasts (lipofibroblasts) in the fetal lungs with the help of PTHrP secreted by the formative alveolar epithelium (endoderm) under mild stretch.^[20]

The (animal embryonic tissue) leptin, thus, responds at the lepR contained by the alveolar type II pneumocytes of the epithelium and causes surfactant expression, as one of their principal functions.

Without enough surfactant, we would observe high rates of IRDS, but the risk gets mitigated from 35 weeks of gestation.^[21]

Reproductive Health

Puberty

Leptin is important in reproductive health since it affects kisspeptins,^[22] estrogen, and the epiphyseal plate^[23] (growth plate on the rounded end of a long bone like the femur).

Kisspeptin neurons are sensitive to circulating leptin^[24] and estrogen levels^[25] (due to their estrogen receptor beta, ERβ).

Leptin secretion occurs in menarche and puberty. Its levels rise in both sexes at the onset of puberty due to increased body fat composition.^[26]

Like kisspeptin, it regulates neuroendocrine functions such as GnRH secretion, giving rise to premature menstruation/menarche.^[27] The latter is liable for the estrogenic, short heights, and early closure of the plates.^[28]

Ovulation

Leptin can control and stimulate fertility hormones, an essential part of fertility treatment programmes for women who suffer from fertility problems.

To conceive, a woman must have enough fertility hormones in her body, and leptin acts on the hypothalamus to control fertility hormones.^[29]

This hormone also affects energy balance and flux, thus impacting the ovulatory cycle and fertility of either sex.

When the energy balance goes deep down below the threshold (as in starvation and weight loss) or the energy flux is high (as in high-intensity workouts burning extra calories), both the ovarian and menstrual cycles come to an end.

Menstruation may decline, at low body fat levels and undesirably high leptin, leading to an in vitro formation of low-quality eggs.^[30]

Therefore when fertility is not a problem and energy balance can be controlled by dieting or exercising, women who suffer from fertility problems may have success conceiving during their ovulatory cycle.

The condition is if they take fertility treatment programmes with leptin hormone therapy alongside other related programmes.

Pregnancy

Produced by the placenta,^[31] leptin rises through pregnancy and declines post delivery. It contributes to an unhealthy supply of fat and energy for the gestation period.

We can find its expressions in fetal membranes and uterine tissues (where leptin inhibits contractions).^[32]

Leptin has a role to play in reproductive disorders, namely:

• Severe morning sickness (NVP/HG): With serious nausea and fainting symptoms, such disorder can worsen with low leptin and estrogen.^[33]
• PCOS: Since leptin regulates the HPG axis and fertility hormone secretion, its adequacy ensures immunity against reproductive pathologies.^[34]

Lactation

A review on leptin present in human breast milk pointed to infant growth, appetite, and nutrition regulation during the lactation period.

Then, the production of breast tissue leptin by epithelial cells will depend on feeding necessity and the infant’s state.

Bone Strength

Leptin plays a role in bone strength because it helps regulate the immune system and inflammation. It also mediates the body’s ability to rebuild bone tissue.

Leptin deficiency can induce pro-inflammatory cytokine levels, eventually accumulating leptin and inflammatory proteins in white adipose tissues.^[36]

From these tissues, leptin may then find its way into circulating blood and tissue fluids, altering calcium homeostasis and increasing free radical production while increasing cortisol release.^[37]

Cases of high-leptin obesity with leptin resistance have correlated leptin to reduced bone mass, as much as those of low-leptin extreme leanness.

When injected into obese mice with inferior bone mass, leptin multiplied bone osteoblasts (bone developing cells) and inhibited the formation of osteoclasts (cells for breakdown and resorption of bone tissue).^[38]

Hence, the new bone formed can have an ensured higher density and low fracture risk.

Immune System

Leptin can affect our immune system in many ways.

It provides the body with the necessary nutritional information to maintain a healthy weight and promote sufficient healing of damaged cells.

It interacts with our immune system and the production of white blood cells.

Experiments with mice have shown that it and its receptors play an essential role in modulating:

• The inborn immune system.
• The activity of T cells (type of lymphocytes making a quarter of white blood cells).^[40]
• The immune response to atherosclerosis^[41] (fatty deposits thickening brain arterial wall tissues). Here, corpulence increases while exercise decreases the risk.

Leptin exhibits some properties which draw concern here:

• pro-angiogenic: can develop new blood cells
• pro-inflammatory: positively mediates inflammation

  Example:

  
  It exacerbates lung inflammation by enhancing inflammatory disease development via induction of nuclear factor-κB/p38 mitogen-activated protein kinase (MAPK) signaling pathways and oxidative stress.^[42]
• mitogenic: induces or stimulates mitosis (i.e., equal bicellular division of parent nucleus)

Such actions get amplified along with other cytokines that stimulate the immune system and aid in tumor progression.

There exist yet many other pro-inflammatory factors influencing leptin, such as:

• sleep
• emotional stress
• testosterone
• caloric restriction
• body fat levels

After a caloric intake, leptin level increments function as an intense pro-inflammatory response system^[43] to prevent unrestrained cellular stress due to overeating.

A high caloric intake will overcharge fat cell proliferation, where the resulting stress reaction will cause cellular inflammation and unhealthy fat storage within arteries, organs, and muscles.

In this case, we can draw out an insulin-leptin relationship, similar to the effect of insulin on interleukin 6 expression and fat cell secretion.^[44]

The caloric weight increases insulin, which triggers a different rise in leptin per dose, easily enhanced by high cortisol.^[45]

This observation brings us to the irrefutable fact that a leptin surge due to high calories causes an adipose-derived inflammation as a signal to stop further food intake against harmful, abnormally stored fat in obese people.^[47]

Diseases

Without leptin or its receptors, we are bound to uncontrolled hunger and thus obesity. When fasting or consuming low-calorie meals, leptin levels drop.

There are more significant fluctuations in the levels when eating less than more. A drastic change in energy balance can affect leptin variation concerning appetite and how much we eat.

Lipodystrophy

Lipodystrophy accumulates all surrounding fatty tissue in the torso, often with an abnormally big, swollen upper back hump or thoracic obesity.

Firstly, the level of cellular lipid, for instance, fatty acids, plays some part in leptin gene expression.

It is not just the total adipose tissue mass that plays a role but rather its location.

It appears that, by increasing leptin gene expression, there is an increase in fat breakdown and fat burning that is proportional to the number of fat cell lipids.^[48]

Some study results help further the understanding of the dependency of leptin and other adipocyte genes on the adipogenic and lipodystrophic Nuclear Factor-Y.

Obesity

Leptin release varies in proportion to your fat storage, so its levels can be high when you have stored much fat.

In that case, a person is likely to turn obese with high cardiovascular risks and several metabolic diseases, correlating differently with several factors to leptin.

There are no other reasons found for these elevated levels of leptin than leptin resistance. As the name denotes, so much of the hormone will counteract its effects.

People with more fat cells will resist extra leptin, which will conversely make them crave more food and increase their resistance.

But there’s a lot you can do to reduce leptin resistance. Dr. Michelle Sands
hormone, metabolism and epigenetics expert - endocrineweb.com

Changes and remedies you can adopt are as follows:

• Turn to healthy fats (from vegetable/fruit oils to fish and livestock)
• Reject foods with added sugar
• Adjust your circadian clock for adequate sleep time. This enhances leptin sensitivity, satiety levels, hunger balance, and homeostatic hormones.
• Practice exercises, especially aerobic ones, for less leptin resistance.

Otherwise, since leptin levels can also be low in obese people,^[49] the hormone may solve weight loss for obese people.

Leptin shots can help treat leptin-deficient patients who are not able to produce enough leptin on their own.

Leptin causes weight loss because it tells the brain that the body is satiated, which reduces hunger (thus food intake) and slows down fat storage. It also helps regulate metabolism, so energy stays balanced in the body.

This hormone can help you lose weight by making it easier for your cells to use glucose for energy instead of storing more fat.

Since it also inhibits ghrelin,^[50] leptin promotes weight loss by decreasing appetite and increasing energy expenditure.

Leptin helps control our weight by giving us more energy when we need it and keeping the body from accumulating too much fat.

How do leptin levels affect weight control?

A study showed that the people who ate a diet high in protein lost more weight than those who ate a lower protein diet.

Leptin levels were higher in the group that lost weight, which indicates their success with leptin’s effects on weight control.

Leptin also modulates the expression of some transporters^[51] in astrocytes, which are highly abundant cells found in the nervous system.

Their chief role is to maintain extracellular ion homeostasis and supply nutrients such as lactate, pyruvate, or glutamate to neurons.

The hormone has antioxidant properties too. It modulates the reaction of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase in brain regions critical for its antioxidant properties.

Osteoarthritis With Obesity

We know that obesity can worsen osteoarthritis since the excess weight on joint cartilage and bones, causing pain and stiffness. The biomechanism engaging the two diseases is nonetheless not the only reason.

There may not be as much weight-bearing risk in hand joints as in the knee,^[52] but in the presence of a metabolic component like leptin, weight loss solely will not be an efficient solution compared to body fat loss.^[53]

Some obesity-related conditions in favor of joint degeneration are surprisingly those caused by leptin:

• pro-inflammatory mediation
• irregular adipokine production^[54]
• high blood lipid concentration^[55]
• a rise in systemic oxidative stress

Then, to upkeep cartilage and other joint tissues and adipose tissues, regulation factors got involved. Any changes to these would mean a regression to the problematic state.

The Connection with Leptin

Adipocytes produce and secrete various signaling molecules, including adipokines, to interact with other cells.

Certain adipokines, viewed as hormones, regulate the organ functions from afar, and many of them help treat joint diseases from the brain.

Such is leptin, which is present in the synovial fluid (joint lubricant in the flexible membrane around joints) of people with osteoarthritis.

We can then accredit leptin production to joint tissues like chondrocytes, the synovial tissue, the meniscus, and bone.^[56]

Circulating synovial leptin levels correlate positively with fat mass, BMI, and joint disease severity.^[57] LepR sites are identifiable on human cartilage cells.

It may play a role in Joint Disease development because leptin is involved in modulating cartilage metabolism. Leptin can stimulate chondrocytes (cells producing cartilage) to proliferate and keep them upregulated.^[58]

It exacerbates inflammation by suppressing nuclear factor-κB via induction of p38 mitogen-activated protein kinase (MAPK) signaling pathways.

Leptin thus decreases aggrecan through up-regulation of pro-inflammatory cytokines and degrading enzymes in the cartilage.^[59]

Our hormone has also manifested its ability to inhibit autophagy^[60] (metabolic consumption of own tissues while short of calories).

Some evidence, however, points to leptin as a potential identifier and factor degrading cartilage in osteoarthritis development.^[61]

With the high number of signaling soluble factors, like leptin and pro-inflammatory cytokines, joint inflammation and cartilage destruction will not remain a temporary issue in obese individuals.

Besides leptin-induced unwanted responses due to leptin resistance, leptin still carries out its role being:

• pro-apoptotic: induces programmed cell death in organism development
• an energy homeostasis regulator
• a neuroendocrine communicator
• a stimulant for GnRH in fertility and weight loss during pregnancy
• pro-angiogenic
• pro-osteoblastic: contributing to the formation of bone cells

Therapeutic Use

Injections

Leptin shots may be a good idea for anyone who has low levels of leptin. Since it can also help regulate metabolism, increasing leptin levels could positively affect weight loss and energy level balance.

Why does leptin administration fail to reverse the majority of obesity cases?

Such attempts are unreliable as leptin resistance develops with prolonged leptin overexposure. Leptin has only proven effective in obese individuals with leptin deficiency due to LepR mutations and leptinemia.

• Leptin resistance also leads to weight gain by increasing food intake and decreasing fat oxidation.
• The injections work because they introduce more leptin into the body, but that can’t break down the leptin resistance for those who have already developed it.

  The process that breaks down leptins is called leptinolysis, which is susceptible to genetic or acquired factors and can lead to long-term weight gain and obesity due to its effects on energy expenditure and increased food intake.

• Leptin resistance is the outcome of inflammatory cytokines like TNF-α and interleukin-16, resulting from obesity.^[64]

Immune System Health

Leptin serves as a target in treating osteoarthritis in nutritive and physical ways.

Proper nutrition and exercise can be a way to treat osteoarthritis as well as leptin.^[65] The latter also has the support of its direct injection instead of oral intake.

The following are some examples^[66] known for long to help reduce pain from arthritis:

• Green Tea

  Drinking green tea will help you fight inflammation, and it may even help reduce arthritis pain. It also contains antioxidants that can help prevent or slow down the early aging of the body’s cells and tissues, which may be a factor in helping to relieve osteoarthritis symptoms.

• Fish

  Fish oil supplements have shown their ability to ease arthritic joint pain by reducing inflammation and preventing cartilage breakdown from oxidative stress.

• Flaxseed

  Flaxseeds and flaxseed oil contain a significant amount of essential omega-three fatty acids, which help reduce inflammation in the body. They may also help reduce arthritis pain associated with osteoarthritis.

• Turmeric

  Turmeric has reliably treated inflammation for thousands of years and cured arthritis symptoms. Some studies have shown that curcumin is an effective natural treatment for osteoarthritis pain.

• Chamomile

  Chamomile contains anti-inflammatory properties that may aid in reducing the swelling associated with certain types of arthritis, especially rheumatoid arthritis.

• Probiotics

  Probiotics are beneficial bacteria that live in the digestive system and help to maintain good health. They may also mitigate symptoms of osteoarthritis caused by inflammation within the body, which can lead to pain.

Children’s Growth

Some leptin treatments are currently going through assessment but not in actual use.

The hormone can be effective for some children with growth issues^[67] but with side effects worth discussing with your doctor before beginning any fertility treatments.

Currently, there are no treatments in use for fertility related to leptin. However, some studies have shown leptin to affect fetal and neonatal growth.

Supplementation

Leptin supplementation is effective for weight loss in some individuals.

However, leptin supplementation is not effective in all cases of obesity because the body becomes resistant to its effects over time. As we have seen, it only helps leptin-deficient obese individuals.

In progestational cases, the best way to keep your fertility up while supplementing with this hormone would be through exercise and healthy eating habits conducive to fertility.^[68]

These include avoiding processed foods, low-fiber carbohydrates (like white bread), and high-protein diets.

A fertility diet is rich in:

• whole grains
• fruits & vegetables
• lean meats like poultry or fish (avoiding processed meat if possible)
• beans/legumes
• calcium-rich foods like yogurt or cheese (also dairy)
• healthy fats like avocado or flax oil^[69]

But not:

• skim milk products due to low-fat content which can lower fertility by affecting fertility hormones

Which amino acid substitution will potentially upregulate leptin signaling?

The deprivation of dietary leucine can regulate leptin signaling.^[70] The dearth of this amino acid increases energy expenditure to stimulate fat loss though it activates leptin expression in other cases.

A unique topology with a cysteine knot revealed that a disulphide-bridge promoted receptor binding to mediate stress-reducing biological activity from a distance.^[71]

Natural Boost – What foods are high in leptin?

Since food is not a direct source of leptin for the brain, a repleting drug recommended by your medical practitioner could fit into your routine while also adapting to a better lifestyle to boost your leptin levels.

The other influencing factors to consider are:

• Sleep: low quality sleep increases ghrelin and decreases leptin.
• Triglycerides: known as lipids, can induce hypothalamic leptin resistance and impede incoming leptin since they also cross the blood-brain barrier.^[72]

To stop these triglycerides from impacting leptin’s work in your body, you can integrate these foods^[4] into your diet:

• Berries (blue, black, and straw)
• Sugar-free beverages (herbal, black, or green teas; or other infusions)
• Healthy oils
• Specific vegetables, legumes, and salad greens
• Lean meat, poultry, and fish
• Mushrooms

Takeaway

Now that you are no stranger to leptin, the product of fat cells regulating food consumption, energy expenditure, weight gain or loss, fertility, among other bodily functions, you can be more mindful of your lifestyle choices.

Dependent on factors like diet quality (more lean meat), sleep quality (longer sleep), physical activity level (regular exercising), stress levels (relaxing with friends), and others, leptin is responsible for many bodily functions.

That qualifies it as an effective tool in the fight against obesity and other metabolic disorders, besides maintaining shape and condition internally.

So you can be thankful for the optimal levels you have!

Andreea Doireann

Researcher and Writer

Andreea is a fitness enthusiast with a keen interest in nutrition. She has gone from 98Kg to 70Kg through relentless hard work and getting her nutrition right with the help of a personal trainer.

She writes articles to empower anyone to take control and not let go of their mental and physical health.

Read More Articles from Andreea