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  • Writer's pictureDr Edin Hamzić

🧬 All You Need To Know About the LEPR Gene

Updated: Jan 24

📒 A Short Introduction! TL;DR

As the post's title says, this post aims to cover all the key things you need to know about the LEPR gene. So, the post essentially covers the following topics:

  • 1️⃣ Basic information about the LEPR gene and what it encodes? What is the function of the proteins it encodes?

  • 2️⃣ What are the most common health conditions related to genetic mutations in the gene, more specifically, obesity

  • 3️⃣ How can one do genetic testing for the LEPR gene?

🙋🏽 What Does the LEPR Gene Encode?

  • The LEPR gene encodes the leptin receptor.

  • Leptin was cloned for the first time in 1994, but Douglas et al. predicted the existence of the leptin gene in studies done on ob/ob (leptin-deficient) and db/db (leptin receptor-deficient) mice by [citation].

  • The LEPR gene is located on chromosome 1p31.3 and contains 18 coding exons [citation]. The LEPR gene encodes the protein that serves as a receptor for the leptin hormone, which regulates body weight.

🧑🏾‍🏫 About Leptin Receptor

  • The leptin receptor has six isoforms as a result of alternative RNA splicing. These isoforms are further divided into three classes:

    • Long isoforms

    • Short isoforms

    • Secretory isoforms

  • Long isoforms are mostly expressed in the hypothalamus and participate in homeostasis and in the regulation of secretory organ activity. Apart from that, it is present in the immune cells and involved in innate and adaptive immunity [citation].

  • Short leptin isoforms (Ob-Ra, Ob-Rc, Ob-Rd, and Ob-Re) bind to Janus kinases and activate other signal cascades [citation].

  • Secretory isoforms regulate serum leptin concentration, serve as carrier proteins, and activate signal transduction cascades [citation].

  • Leptin activates the six isoforms of leptin receptors as it uses a complex transport system due to its inability to cross the blood-brain barrier [citation]. Leptin binds to the leptin binding domain in all its receptors [citation].

Where is leptin produced? Can I take leptin to lose weight? What are the side effects of leptin?

Leptin is produced mainly in adipocytes [citation]. Therefore, taking leptin rarely helps one lose weight as most obese people develop leptin resistance. Side effects of leptin can include hypoglycemia, weight loss, headaches, ovarian cysts, fatigue, dizziness, and abdominal pain. You can find a detailed list of side effects here.

What are leptin deficiency symptoms? What causes a lack of leptin? How is leptin receptor deficiency treated? What disease is leptin involved in? What foods are good for leptin resistance?

Leptin deficiency symptoms are extreme obesity in childhood, hypogonadism, and a family history of obesity [citation]. Low leptin levels can be caused by mutations either in leptin or leptin receptor genes [citation]. Leptin deficiency is treated by administering leptin replacement doses [citation]. Generally, leptin increases susceptibility to infection, hypothalamic hypothyroidism, growth delay, pituitary dysfunction, and obesity [citation]. When it comes to leptin and diet, the best diet to practice is the energy-restricted diet that avoids foods high in fat and sugar [citation]. The LEPR mutations can lead either to leptin deficiency or leptin resistance.

The LEPR Gene's Mutations & Leptin Deficiency

  • Wild type (wt/wt) that are monoallelic (wt/-) or biallelic (-/-) pathogenic variants cause fundamental failure in LEP in LEPR signaling that leads to lower leptin levels that go on to further lead to severe early-onset obesity and fertility issues [citation].

  • There are 13 mutations of the LEPR gene that lead to single amino acid changes and 25 deletions, duplications, insertions, or nonsense mutations that were predicted to result in truncated LEPR proteins, most of which cause deficiency and obesity. A detailed overview of mutations can be found in this here.

🧪 How to Detect the LEPR Deficiency Caused Obesity?

  • The POMC / PCSK1 / LEPR CDx Panel from PreventionGenetic LLC is a type of Setmelanotide eligibility gene variant detection system [citation].

  • The POMC / PCSK1 / LEPR CDx test uses sequencing technology to detect germline variants in DNA from human clinical specimens [citation]. This panel tests for missense, nonsense, frameshift, splicing, and copy number variants (CNVs) [citation].

  • The POMC / PCSK1 / LEPR CDx test is a qualitative in vitro diagnostic device intended to detect germline variants within genes isolated from human specimens for the purpose of identifying patients with obesity who may benefit from treatment with setmelanotide by the approved therapeutic product labeling [citation].

  • Patients with early-onset of obesity should take this test.

  • Setmelanotide is a melanocortin-4 (MC4) receptor agonist, meaning setmelanotide is used to treat obesity arising from:

    • Proopiomelanocortin (POMC)

    • Proprotein convertase subtilisin/kexin type 1 (PCSK1), or

    • Leptin receptor (LEPR) deficiency

  • The potential patient might benefit from treatment with setmelanotide if one of these three genes harbors (POMC, PCSK1, and LEPR) a mutation.

Testing for Leptin Levels

  • Leptin levels can be measured using blood tests and ELISA [citation]. The lab test results take roughly 2-4 days to be ready.

Leptin As Therapy

  • One can take leptin pills, but most do not actually contain the hormone, and they only increase leptin sensitivity. Furthermore, leptin pills are still not sufficiently investigated, and therefore, their use remains controversial.

  • Leptin replacement therapy treats leptin-deficient patients with recombinant leptin hormone injections [citation].

Leptin & Diet

  • When it comes to leptin and diet, the best diet to practice is the energy-restricted diet that avoids foods high in fat and sugar, which will boost leptin levels, or one can use leptin replacement therapy [citation].

  • Lack of leptin hormone increases appetite while higher concentrations of the hormone decrease it unless we are dealing with the case of leptin resistance.

  • While taking leptin might help lose weight, some obese people develop tolerance to leptin, causing it to have no effect.

  • Leptin is transferred into the cerebrospinal fluid (CSF) through tanycytes, from where it further diffuses into the mediobasal hypothalamus [citation].

Like many other genes, the LEPR gene is also prone to mutations. The LERP mutations include missense and nonsense mutations, as well as substitutions. They are primarily associated with childhood and morbid obesity, impaired glucose tolerance, and pituitary gland dysfunction [citation].


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