What is leptin?
Leptin is a hormone produced by fat cells. The more fat there is in the body, the more leptin is produced (,). With its help, fat cells “communicate” with the brain.
Leptin tells you how much energy is stored in the body. When there is a lot of it, the brain understands that there is enough fat (energy) in the body. As a result, there is no severe hunger, and the metabolic rate is at a good level ().
When leptin is low, it is a signal that fat reserves (energy) are low, which means hunger and possible death. As a result, metabolism decreases and hunger increases.
Thus, the main role of leptin is the long-term management of energy balance (). It helps support the body during times of hunger by signaling the brain to turn on the appetite and reduce metabolism. It also protects against overeating, “turning off” hunger ().
Leptin resistance
Obese people have high levels of leptin () Logically, the brain should know that there is more than enough energy stored in the body, but sometimes the brain's sensitivity to leptin is impaired. This condition is called leptin resistance and is now considered the main biological cause of obesity ().
When the brain loses sensitivity to leptin, the control of energy balance is disrupted. There are a lot of fat reserves in the body, a lot of leptin is also produced, but the brain does not see it. Leptin resistance is when your body thinks you're starving (even though you're not) and adjusts your eating behavior and metabolism accordingly (11, , , ):
- A person may feel hungry all the time; food does not satisfy him, which is why he eats much more than normal.
- Activity decreases, calorie expenditure at rest decreases, and metabolism decreases.
A person eats too much, moves little, becomes lethargic, his metabolism and the activity of the thyroid gland are reduced, excess weight up to obesity is the result.
It's a vicious circle:
- He eats more and stores more fat.
- More body fat means more leptin is released.
- High levels of leptin cause the brain to reduce the sensitivity of its receptors to it.
- The brain stops receiving leptin and thinks that hunger has come and forces you to eat more and spend less.
- You eat more, spend less and accumulate even more fat.
- Even more leptin. And so on.
What Causes Leptin Resistance?
Inflammatory processes
Inflammation in the body can be asymptomatic. In obese people, similar processes can occur in the subcutaneous fat tissue with severe overcrowding of fat cells or in the intestines due to a passion for the “Western” diet, rich in refined, processed foods.
Immune cells called macrophages arrive at the site of inflammation and release inflammatory substances, some of which interfere with leptin's ability to work.
What to do:
- Increase omega-3 acids in food (fatty fish, flax, fish oil supplements).
- Bioflavonoids and carotenoids also show anti-inflammatory properties. They are rich in ginger, cherries, blueberries, currants, chokeberries and other dark berries, pomegranates.
- Decreased insulin levels (more on that below).
Fast food
Fast food and a Western diet with a lot of processed foods can also cause leptin resistance. The main culprit is thought to be fructose, which is widely available as an additive in foods and as a constituent of sugar ().
What to do:
- Avoid processed food ().
- Eat soluble fiber ().
Chronic stress
Chronically elevated stress hormone cortisol reduces the sensitivity of brain receptors to leptin.
Insulin insensitivity
When a lot of carbohydrates enter the body, a lot of insulin is released to remove glucose from the blood. If there is chronically too much insulin, cells lose sensitivity to it. Under these conditions, unused glucose is converted into fatty acids, which interferes with the transport of leptin to the brain ().
What to do:
- Strength training helps restore insulin sensitivity.
- Limit simple carbohydrates in your diet.
Overweight and obesity
The more fat you have in your body, the more leptin is produced. If there is too much leptin, the brain reduces the number of leptin receptors and its sensitivity to it decreases. So it's a vicious cycle: more fat = more leptin = more leptin resistance = more body fat.
What to do:
- Lose weight through proper nutrition and physical activity (,).
Genetics
Sometimes there is a genetically impaired sensitivity of the brain receptors to leptin or mutations in the structure of leptin itself, which prevent the brain from seeing it. It is believed that up to 20% of obese people have these problems.
Leptin: effect on lipid metabolism
Structure of leptin.
The leptin molecule is a three-dimensional 167-amino acid structure having four antiparallel α-helices that are linked by two long cross-links and one short loop forming a left-handed helical bundle forming a bilayer packing. The disulfide bond between two cysteine residues (Cys96 and Cys146) at the C-terminus of leptin and at the beginning of one of the loops is important for proper folding of the structure and binding of the receptor. Mutation of any of the cysteine residues makes the protein biologically inactive.
The structure of leptin, which influences biological activity in vivo and receptor binding activity in vitro, can be divided into three types:
(1) N-terminal amino acid sequence (22–115), which is important for biological and receptor binding activity;
(2) the C-terminal amino acid sequence (116–166) with a loop structure, which is also important for enhancing the activity of the N-terminal region;
(3) C-terminal disulfide bond, which is not required for leptin activity.
Receptors:
The receptors are highly expressed in the hypothalamus, as well as in T lymphocytes and vascular endothelial cells. These receptors belong to the class 1 cytokine receptor family, which contains extracellular ligand-binding, transmembrane, and cytoplasmic signaling domains. The leptin gene has several spliced isoforms: Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd and Ob-Re. Ob-Rb has the longest intracellular signaling domain and is highest concentrated in the hypothalamus, and it mediates the majority of leptin signaling. Ob-Ra is considered to be a leptin transporter, and Ob-Re is a soluble form of the transmembrane leptin receptor.
Leptin controls certain groups of neurons in the hypothalamus, brain stem and other areas of the central nervous system. High LRb expression is present in the arcuate, dorsomedial, ventromedial, and ventral premammillary nuclei of the hypothalamus, moderate LRb expression is present in the periventricular region and posterior nucleus of the hypothalamus, and low levels of LRb are expressed in the paraventricular nucleus (PVN) and lateral hypothalamic region. (LHA). LRb is also localized to the nucleus solitarius, lateral parabrachial nucleus, motor and sensory nuclei, and areas of the brainstem not typically associated with energy balance. Increasing leptin levels directly suppresses the orexigenic peptide, neuropeptide Y (NPY) and agouti-related peptide (AGRP) in the arcuate nucleus. Melanin concentrating hormone (MCH) and orexins expressed in the LHA are indirectly suppressed by leptin. Leptin increases the levels of anorectic peptides, pro-opiomelanocortin (POMC)-derived α-melanocyte-stimulating hormone (α-MSH), and cocaine- and amphetamine-regulated transcripts produced by neurons in the lateral arcuate nucleus. This project in PVN causes increased levels of corticotropin releasing hormone, thyrotropin releasing hormone and oxytocin. The net effects of leptin are to suppress appetite, stimulate thermogenesis, increase fatty acid oxidation, lower glucose levels, and reduce body weight and fat. Inhibition of AGRP by leptin attenuates the antagonism of α-MSH by AGRP to the melanocortin-4 receptor. The importance of these central neural circuits has been confirmed using neuroanatomical and genetic methods.
Mechanism of action.
Circulating leptin crosses the blood-brain barrier and mediates its action through the signal transducer and activator of transcription (STAT) pathway (JAK-STAT3) Janus kinase (JAK). Leptin binding to LRb leads to autophosphorylation of JAK1 and 2, and tyrosyl phosphorylation of the cytoplasmic domain of LRb leads to phosphorylation and activation of STAT3. Tyrosyl-phosphorylated STAT3 undergoes homodimerization, translocates to the nucleus, and regulates the expression of neuropeptides and other genes.
Leptin, acting through LRb, has also been shown to regulate insulin receptor substrate-1 and 2, mitogen-activated protein kinase, extracellular signal-regulated kinase, Akt, and PI3 kinase, raising the possibility of interaction between leptin and insulin. Leptin's ability to suppress feeding is associated with activation of PI3 kinase in the hypothalamus. Blockade of PI3 kinase activity prevents the anorectic effects of leptin. Leptin signaling is terminated by the induction of suppressors of cytokine signaling (SOCS)-3, a member of a family of proteins that inhibit JAK-STAT signaling. SOCS-3 haploinsufficiency increases leptin sensitivity and prevents obesity. More specifically, ablation of SOCS3 in neurons enhances leptin action, leading to STAT3 activation, increased hypothalamic POMC expression, and decreased food intake and weight. Protein tyrosine phosphatase-1B, which is known to terminate the action of insulin, also inhibits leptin signaling through inactivation of JAK2. Consistent with this, mice deficient in protein tyrosine phosphatase-1B exhibit greater leptin sensitivity, increased hypothalamic STAT3 phosphorylation, and resistance to obesity. AMP-activated protein kinase (AMPK) is another interesting target. AMPK is phosphorylated and activated in response to energy deficiency during fasting or cellular stress, resulting in stimulation of fatty acid oxidation. AMPK is colocalized with STAT3 and hypothalamic peptides involved in energy balance. Hypothalamic phosphorylation and AMPK activity are increased by fasting and decreased by leptin, insulin, and various anorectics.
Conclusions:
Adiponectin is a widely expressed adipokine that exhibits potent insulin-sensitizing effects through binding to its receptors AdipoR1 and AdipoR2, resulting in activation of AMPK, PPAR-α, and likely other as yet unknown signaling pathways. In obesity-associated insulin resistance, both adiponectin and adiponectin receptors are downregulated. Antidiabetic TZDs may be an interesting therapeutic strategy for insulin resistance. The new adiponectin sensitivity index (SA), defined as the percentage of HMW form/total circulating adiponectin, may become an important parameter of systemic insulin sensitivity. Leptin serves as a major adipostate, inhibiting food intake and promoting energy expenditure. Leptin improves peripheral (liver and skeletal muscle) insulin sensitivity and modulates pancreatic β-cell function. Leptin resistance is associated with decreased leptin-mediated JAK–STAT signaling and induction of suppressor of cytokine signaling-3 (SOCS-3).
What to do?
The best way to find out if you have leptin resistance is to know your body fat percentage. If you have a high percentage of fat, which indicates obesity, if you have a lot of excess weight especially in the abdominal area, there is a possibility.
Also, for the primary diagnosis of obesity, body mass index (BMI - body mass index) is used. It can be calculated using the formula:
BMI = body weight in kg: (height in sq.m.)
Example: 90 kg: (1.64 x 1.64) = 33.4
The good news is that leptin resistance is reversible in most cases. The bad news is that there is no easy way to do this yet, and there is no drug yet that can improve leptin sensitivity. For now, those who are losing weight have in their arsenal familiar tips for changing their lifestyle - a healthy diet, calorie control, strength training and increasing daily household activity.
Leptin is a satiety hormone
Leptin, or the satiety hormone, was discovered quite recently. This substance is produced by fat cells, it affects all types of metabolism, but the main effect of leptin is an anorexigenic effect, that is, it suppresses appetite. A decrease in leptin concentration in the blood or impaired cell sensitivity to it leads to excess body weight gain and obesity . In addition, today leptin is considered as a main factor in the pathogenesis of type 2 diabetes mellitus. After the discovery of this hormone in 1994, great hopes were placed on it, it was believed that leptin would be the key to defeating obesity and non-insulin-dependent diabetes . But, unfortunately, scientists until today have not been able to synthesize a drug that can force the body to produce leptin in the required amount or a drug that will increase the sensitivity of tissues to the hormone.
Therefore, the only way to influence the activity of leptin and its level in the blood is to reconsider your lifestyle and make it as close to healthy as possible.
Diagnosing leptin resistance in the body is very simple.
The main symptoms of this condition:
- overweight or obesity of varying degrees;
- after eating, a person experiences drowsiness and fatigue;
- difficulties in losing weight, rapid gain of lost pounds;
- increased appetite and chronic hunger, a tendency to snack between meals, nightly “raids” on the refrigerator;
- anxiety and chronic stress;
- addiction to sweets;
- various sleep problems;
- lack of breakfast habit;
- rapid fatigue even after minor physical activity.
Basic Tips for Improving Leptin Sensitivity
- Healthy sleep. Clinical studies have shown that fragmented and poor quality sleep leads to the development of leptin resistance. Therefore, by getting rid of insomnia, you can normalize the level of this hormone.
- Physical exercise. Regular exercise or simple exercise increases the sensitivity of cells to leptin and normalizes fat metabolism.
- Diet. There is no special diet, but there are several nutritional recommendations that will help bring leptin levels back to normal. Be sure to eat breakfast and make sure your breakfast includes protein foods. Limit your intake of simple and fast carbohydrates. Increase the amount of foods high in zinc, vitamin D and magnesium in your diet. Minimize your intake of saturated fats and increase the percentage of unsaturated fats.
- Hunger. During fasting, the sensitivity of cells to leptin increases. But this does not mean that you need to fast for a long time; it is enough to skip one meal a day 1-2 times a week.
- Do not disturb your biorhythm by consuming large amounts of coffee, sweets, energy drinks, or alcohol.
- Avoid any snacks between main meals.
- Don't eat at night. The last meal should be no later than 4 hours before bedtime.
These simple recommendations will help you not only lose extra pounds, but also prevent them from gaining back in the future, and will also allow you to remain a healthy and energetic person for many years of your life.
