Abstract
Over a decade passed between Friedman’s discovery of the mammalian leptin gene (1) and its cloning in fish (2) and amphibians (3). Since 2005, the concept of gene synteny conservation (vs. gene sequence homology) was instrumental in identifying leptin genes in dozens of species, and we now have leptin genes from all major classes of vertebrates. This database of LEP (leptin), LEPR (leptin receptor), and LEPROT (endospanin) genes has allowed protein structure modeling, stoichiometry predictions, and even functional predictions of leptin function for most vertebrate classes. Here, we apply functional genomics to model hundreds of LEP, LEPR, and LEPROT proteins from both vertebrates and invertebrates. We identify conserved structural motifs in each of the three leptin signaling proteins and demonstrate Drosophila Dome protein’s conservation with vertebrate leptin receptors. We model endospanin structure for the first time and identify endospanin paralogs in invertebrate genomes. Finally, we argue that leptin is not an adipostat in fishes and discuss emerging knockout models in fishes.
Highlights
In 1994, Friedman’s laboratory described leptin as a peptide hormone that is synthesized by adipose tissue [1] and soon after it was proposed to regulate appetite and metabolic rate by communicating energy stores to the central nervous system [4,5,6]
Leptin is synthesized by adipose tissue and released into the blood; there it travels to the hypothalamus and binds to the leptin receptor, which stimulates reduction of appetite and increased mobilization of lipid for metabolism
Comparative leptin endocrinology has matured in the 11 years since the first non-mammal leptin was cloned
Summary
In 1994, Friedman’s laboratory described leptin as a peptide hormone that is synthesized by adipose tissue [1] and soon after it was proposed to regulate appetite and metabolic rate by communicating energy stores to the central nervous system [4,5,6]. Leptin is synthesized by adipose tissue and released into the blood; there it travels to the hypothalamus and binds to the leptin receptor, which stimulates reduction of appetite and increased mobilization of lipid for metabolism. Through this feedback loop, the brain regulates energy stores to remain relatively constant [“adipostat control” [4,5,6]]. This review will focus on three areas: evolution of genes in the leptin signaling pathway, the status of leptin as an adipostat, and emerging non-mammal
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