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]
[LEPTIN DEFICIENCY OR DYSFUNCTION; LEPD](https://omim.org/entry/614962)
[LEPTIN; LEP](https://omim.org/entry/164160)
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]
Nonsyndromic morbid obesity can be caused by homozygous mutation in the leptin gene (autosomalrecessive). [from MIM:614962; 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]
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 MIM:164160; 2017.02.24]
There is evidence for functional equivalence of Dmel\upd2 and human LEP. (FBrf0219535)
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)
One of several ligands of the transmembrane receptor dome, which is a probable ortholog of the human leptin receptor.
