Leptin Deficiency: Causes, Effects, and Management

March 14, 2025

Leptin Deficiency, also known as Congenital leptin deficiency (CLD), is a rare inherited disorder that causes early-onset obesity (in infants). Patients are born with normal weight, but they become obese over time because there is dysregulation of appetite, which leads to excessive eating. Deficiency of the leptin hormone can interfere with the production of sex hormones as well, which may lead to hypogonadism (a condition of insufficient sex hormones). Worldwide data suggest that only 14 cases of leptin deficiency have been reported. However, there is a high frequency of leptin gene mutations (and consequent leptin deficiency) in Pakistani children.¹. Doctors manage the condition with leptin replacement therapy, which helps regulate appetite and promotes weight loss.

What Is Leptin?

Leptin is a peptide hormone, mainly produced by the adipocytes (fat cells), and is responsible for maintenance of the body weight and energy levels.² Therefore, it is also called the obese protein. This particular hormone also regulates the appetite and oversees the amount of energy reserves of the body.

Leptin Deficiency Symptoms

The most common symptoms of leptin deficiency include:

Hyperphagia:

Infants suffering from hormonal deficiency experience extreme hunger that invokes them to eat excessively, i.e., hyperphagia. The hunger drive is so strong that the affected individuals, in their early childhood, become ferocious for food and are often seen fighting (with other children) over it. You may see your child hoarding food or secretively eating out of the home. Studies reveal that low (or zero) serum leptin levels directly contribute to pediatric binge eating or loss of control (LOC) eating, which ultimately leads to weight gain and obesity. ³

Obesity:

The ultimate consequence of uncontrolled feeding is weight gain. Clinicians note acute weight gain during the first postnatal year. Being overweight and obesity are direct complications of hormone deficiency and replacement therapies have been shown to effectively reverse them.⁴

Hypogonadotropic Hypogonadism:

Hypogonadotropic hypogonadism is characterized by the production of inadequate sex hormones. The leptin hormone plays an important role in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis, a co-ordinating system that involves the hypothalamus of the brain, pituitary gland, and the gonads i.e., testes and ovaries. This system is responsible for the production of sex hormones. Therefore, in cases of leptin deficiency, there is dysregulation of sex hormone production and hypogonadism arises secondary to the hormone deficiency. Patients present with late or absent puberty. Without proper treatment, individuals may even experience infertility. In addition to the hormonal imbalances, obesity also contributes to hypogonadism.⁵

Leptin Deficiency Causes

Genetic experts identify mutations in the LEP gene as the major cause of congenital leptin deficiency. This gene is responsible for providing instructions to produce the leptin hormone. In a normal individual, the fat cells produce the hormone leptin according to their size. When more fat cells are stored, there is a greater production of leptin. This leptin binds to leptin receptors present in the hypothalamus (and different parts of the body). This binding triggers a cascade of chemical actions/signals that control:

Hunger
Feelings of satiety (fullness)

A deficiency of the hormone leads to dysregulation in feelings of hunger and fullness, leading to uncontrolled hunger and weight gain. Moreover, leptin signaling is also believed to be responsible for the regulation of sex hormone production which explains the associated hypogonadism.
Leptin deficiency is inherited in an autosomal recessive pattern. This means that two copies of the mutated gene (one from each parent) are required for an individual to develop the disorder. Therefore, it is very rare.
Deficiency of the leptin hormone may also arise secondary to other health issues like:

HIV-AIDS: The HIV virus may induce a lack of adipose tissues in the body, a condition called HIV-associated lipodystrophy syndrome (HALS). This leads to a partial or complete loss of leptin.
Anorexia Nervosa: Patients suffering from eating disorders like anorexia nervosa have low body fat and associated low leptin levels.

Other conditions that can diminish serum leptin levels include:

Insulin resistance
Glucose tolerance abnormalities
Hepatic steatosis
Dyslipidemia

Leptin Deficiency Diagnosis

How to test for Leptin Deficiency?

The diagnosis of leptin deficiency relies on clinical examination and specific tests.

History taking & Evaluation of Symptoms

Severe obesity which begins in the first few months after birth is the hallmark of the deficiency disorder. Your doctor will evaluate symptoms like hyperphagia, uncontrolled eating, delayed/absent puberty, etc.

Diagnostic Tests

Serum leptin levels are low (or even undetectable) in individuals with congenital leptin deficiency. It is an easy and quick test to diagnose leptin deficiency.⁶

Growth hormone levels may also be suboptimal in patients with hormone deficiency.
Genetic testing helps identify if the condition is caused by a mutation in the LEP gene.

Leptin Deficiency Treatment

Management of leptin deficiency requires a multi-disciplinary approach. Usually, there is a team of specialists including nutritionists, endocrinologists, gastroenterologists, and mental health experts working together to alter the behavior and curb the cravings.

Leptin Replacement Therapy:

Mainstay of the treatment is hormone replacement therapy with metreleptin/recombinant methionyl human leptin (r-methHuLeptin) i.e., a recombinant form of human leptin. It helps reverse the symptoms of CLD. treatment results in fast loss of weight and regaining of sex hormone levels.⁷
Metreleptin therapy induces remarkable weight loss in CLD patients. Owing to its positive results, the hormone treatment can potentially be beneficial in managing common obesity and obese diabetics, etc.⁸

Lifestyle Changes:

In addition to the drug therapy, doctors advise changes in lifestyle habits. Dietary changes with patient-tailored exercise programs are proven to help reduce weight. As patients can develop frantic eating habits, behavioral modification may also be indicated in some cases.

Surgery:

Bariatric surgery (surgical removal of excess fat) is reserved for severe cases where excess fat interferes with daily life and/or becomes a serious threat to a patient’s life.

Final Word

Leptin deficiency is a very rare disorder in which there is a congenital deficiency of the leptin hormone (produced by fat cells of the body). This lack of the hormone leads to excessive hunger, binge eating, and excessive weight gain in infants (during the first year of life). Untreated CLD can also induce hypogonadotropic hypogonadism which results in delayed puberty or even infertility. Doctors diagnose it by checking serum leptin levels. Treatment involves hormone replacement therapy with a recombinant human form of leptin, i.e., metreleptin.

Refrences

1
Fatima, W., Shahid, A., Imran, M., Manzoor, J., Hasnain, S., Rana, S., & Mahmood, S. (2011). Leptin deficiency and leptin gene mutations in obese children from Pakistan. International journal of pediatric obesity, 6(5-6), 419-427
2
Dornbush, S., & Aeddula, N. R. (2019). Physiology, leptin.
3
Miller, R., Tanofsky-Kraff, M., Shomaker, L. B., Field, S. E., Hannallah, L., Reina, S. A., … & Yanovski, J. A. (2014). Serum leptin and loss of control eating in children and adolescents. International journal of obesity, 38(3), 397-403.
4
Wasim, M., Awan, F. R., Najam, S. S., Khan, A. R., & Khan, H. N. (2016). Role of leptin deficiency, inefficiency, and leptin receptors in obesity. Biochemical Genetics, 54, 565-572.
5
Wong, H. K., Hoermann, R., & Grossmann, M. (2019). Reversible male hypogonadotropic hypogonadism due to energy deficit. Clinical endocrinology, 91(1), 3-9.
6
ElSaeed, G., Mousa, N., El‐Mougy, F., Hafez, M., Khodeera, S., Alhelbawy, M., … & Elsharkawy, M. (2020). Monogenic leptin deficiency in early childhood obesity. Pediatric obesity, 15(1), e12574.
7
Blüher, S., Shah, S., & Mantzoros, C. S. (2009). Leptin deficiency: clinical implications and opportunities for therapeutic interventions. Journal of Investigative Medicine, 57(7), 784-788.
8
Paz-Filho, G., Mastronardi, C. A., & Licinio, J. (2015). Leptin treatment: facts and expectations. Metabolism, 64(1), 146-156.

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