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General Information
Name
leptin deficiency or dysfunction
FlyBase ID
FBhh0000503
Disease Ontology Term
Parent Disease
Overview

This report describes morbid obesity caused by leptin deficiency or dysfunction (LEPD); LEPD exhibits autosomal recessive inheritance. There is a single leptin gene (LEP) in humans; one of its major functions is nutrient regulation as part of a signaling pathway that inhibits food intake and/or regulates energy expenditure to maintain constancy of the adipose mass. Based on the observation of heterologous rescue, the Drosophila upd2 gene has been described as functionally equivalent to LEP in terms of its nutrient regulation function. Classical amorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\upd2.

A UAS construct of the wild-type human gene Hsap\LEP has been introduced into flies. Heterologous rescue (functional complementation) is observed: when expressed in fat body, Hsap\LEP rescues the reduced wing area and reduced triacylglycerol levels seen in amorphic mutations of Dmel\upd2.

Recent work on the molecular evolution of leptin and leptin receptor identifies similar structural motifs in Dmel\upd2 vs. human LEP and in the fly transmembrane receptor dome vs. the human leptin receptor, LEPR. Another ligand of Dmel\dome, Dmel\upd1, has been shown to act in the brain (rather than in the fat body) to control attraction to food cues, food intake, and weight gain.

Adult animals homozygous or hemizygous for an amorphic mutation of upd2 exhibit decreased body size, reduced wing area, a significant reduction in triacylglycerol levels, a significant increase in circulating glucose levels, and increased resistance to starvation. Expression upd2 increases under a high-fat diet and decreases under starvation conditions. Experiments using tissue-specific drivers to assess degree of rescue by a wild-type copy of the fly gene or by the human leptin gene support the hypothesis that upd2 expression is required only in the fat body. Genetic and physical interactions of Dmel\upd2 have been described; see below and in the gene report for upd2.

[updated Jan. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: leptin deficiency or dysfunction
OMIM report

[LEPTIN DEFICIENCY OR DYSFUNCTION; LEPD](https://omim.org/entry/614962)

Human gene(s) implicated

[LEPTIN; LEP](https://omim.org/entry/164160)

Symptoms and phenotype

Defects in leptin production cause severe hereditary obesity. Affected individuals are of normal weight at birth, but they are constantly hungry and quickly gain weight. Without treatment, the extreme hunger continues and leads to chronic excessive eating (hyperphagia) and obesity. Individuals with congenital leptin deficiency also have hypogonadotropic hypogonadism, caused by reduced production of hormones that direct sexual development. Without treatment, affected individuals experience delayed puberty or do not go through puberty, and may be infertile. [Genetics Home Reference, congenital leptin deficiency; 2017.02.24]

Genetics

Nonsyndromic morbid obesity can be caused by homozygous mutation in the leptin gene (autosomalrecessive). [from OMIM:614962; 2017.02.24]

Cellular phenotype and pathology
Molecular information

The leptin protein plays a critical role in the regulation of body weight by inhibiting food intake and stimulating energy expenditure. In addition to its effects on body weight, leptin has a variety of other functions, including the regulation of hematopoiesis, angiogenesis, wound healing, and the immune and inflammatory response. [from OMIM:164160; 2017.02.24]

The leptin protein is secreted by white adipocytes, and which plays a major role in the regulation of body weight. Acting through the leptin receptor, leptin functions as part of a signaling pathway that can inhibit food intake and/or regulate energy expenditure to maintain constancy of the adipose mass; it also also has several endocrine functions, and is involved in the regulation of immune and inflammatory responses, hematopoiesis, angiogenesis and wound healing. [Gene Cards, LEP; 2017.02.24]

External links
Disease synonyms
congenital leptin deficiency
LEPD
obesity, morbid, due to leptin deficiency
obesity, morbid, nonsyndromic 1
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

There is evidence for functional equivalence of Dmel\upd2 and human LEP. (FBrf0219535)

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (2)
    Gene Snapshot
    unpaired 2 (upd2) encodes a secreted molecule that acts at a distance as a ligand for the JAK/STAT signal transduction pathway. upd2 mutants are viable due to redundancy with other Upd-family genes. [Date last reviewed: 2019-03-21]
    Molecular function (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)

    Based on heterologous rescue of upd2 loss-of-function phenotypes by the human gene, Dmel\upd2 appears to be functionally equivalent to human LEP (leptin). (FBrf0219535)

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Gene Snapshot
    unpaired 1 (upd1) encodes a secreted glycoprotein that is able to act at a distance as the primary ligand for the JAK/STAT signaling pathway. Although semi-redundant with upd2 and upd3, upd1 depletion results in embryonic lethality with an atypical gap gene-like segmentation phenotype. [Date last reviewed: 2019-03-21]
    Gene Groups / Pathways
    Comments on ortholog(s)

    One of several ligands of the transmembrane receptor dome, which is a probable ortholog of the human leptin receptor.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (8 groups)
      RNA-RNA
      Interacting group
      Assay
      References
      quantitative reverse transcription pcr
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, anti tag western blot
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot, affinity technology, fluorescence microscopy, inferred by author
      RNA-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, quantitative reverse transcription pcr, pull down, anti tag western blot, primer specific pcr
      anti tag coimmunoprecipitation, quantitative reverse transcription pcr
      RNA-RNA
      Interacting group
      Assay
      References
      quantitative reverse transcription pcr, luminiscence technology, necessary binding region
      quantitative reverse transcription pcr
      Alleles Reported to Model Human Disease (Disease Ontology) (8 alleles)
      Models Based on Experimental Evidence ( 2 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 3 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 2 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      loss of function allele
      ethyl methanesulfonate
      P-element activity
      amorphic allele - molecular evidence
      FLPase
      References (16)