Comparative endocrinology of leptin: assessing function in a phylogenetic context

Abstract

As we approach the end of two decades of leptin research, the comparative biology of leptin is just beginning. We now have several leptin orthologs described from nearly every major clade among vertebrates, and are moving beyond gene descriptions to functional studies. Even at this early stage, it is clear that non-mammals display clear functional similarities and differences with their better-studied mammalian counterparts. This review assesses what we know about leptin function in mammals and non-mammals, and gives examples of how these data can inform leptin biology in humans.

Keywords: Amphibians; Fish; Immunology; Leptin; Phylogeny; Vertebrates.

Figure 1. Phylogenetic tree of 29 boney fish and representative tetrapod leptins

The evolutionary history was inferred by using the Maximum Likelihood method based on the JTT matrix-based model (Jones et al., 1992) as conducted in MEGA5 (Tamura et al., 2011). Numbers at nodes represent percentage of 100 bootstrap replicates. Notes with no number indicate bootstrap support of less than 50%. Inferred leptin amino acid sequences were manually aligned in MEGA5 informed by protein structural homologies. GenBank accession numbers in parentheses represent protein accessions.

Figure 2. Diversity of organisms in which leptin physiology has been studied from 1990s on-ward

We resolved the number of published studies on leptin in non-model organisms and agricultural organisms resulting from searches conducted in Web of Science. More than 15,000 articles involving biomedical model organisms (rat, mouse, human, non-human primate). When searching for articles involving leptin in non-model and agricultural organisms, each article that was listed using various search terms was inspected to verify the primary organism(s) studied. We did not include zebrafish or Xenopus in biomedical models even though they are genetic and developmental model organisms, nor did we include chicken or fishes reared in fisheries or chicken as agricultural organisms because these organisms better reflect phylogenetic diversity of leptin in this context. For non-model organisms, we included studies that used both homologous and heterologous leptins or leptin probes in our lists.

Figure 3. Diversity of leptin functions studied in biomedical model organisms, agricultural species, and non-model organisms

(see definition of categories in Figure 1). Articles retrieved by Web of Science searches were saved to EndNote and categorized by their various general animal names as represented in the figures of the papers. For the non-model and agricultural organisms the articles were reviewed individually and organized into their specific research area. We included studies investigating the role of leptin in the timing of puberty in the Life History Transitions category. Due to the large numbers of biomedical studies, they were sorted into categories based on keywords associated with the article.

Figure 4. Effect of leptin knockdown on bone mineralization in zebrafish

A) Fourteen day post-fertilization (DPF) zebrafish stained with calcein, which stains mineralized bone (Du et al., 2001). Eye is depicted by blue circle for orientation, bracket indicates area magnified in B-D. Mineralized bone stains bright green (there is also a bright signal from ingested stain because the embryos are stained live). B) Control fish 9 DPF showing the first vertebrae to mineralize immediately caudal to the cranium C) 9 DPF fish treated with anti-leptin A morpholino oligonucleotide lepMO1 as in Liu et al., (2012). No mineralization is evident. D) 9DPF fish coinjected with anti-leptin A morpholino oligonucleotide lepMO1 and recombinant zebrafish leptin A as in Liu et al., (2012). Bone mineralization is rescued.