Evolution of appetite regulating systems

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Introduction

Recently, there has been extensive research into the neuroendocrine mechanisms controlling appetite. The pro-opiomelanocortin (POMC) gene has been identified as playing an important role in these mechanisms, particularly through production of the peptide alpha-MSH. POMC and its end-products have not only been identified in humans, but also in a large range of other vertebrates. This has lead to further research into the origins of the POMC gene and the evolution of appetite regulating systems. This article details the structure and function of the POMC gene. It highlights variations between species, allowing a potential evolutionary route, originating at a common ancestral gene, to be mapped out.

Human POMC

The human pro-opiomelanocortin (POMC) gene encodes a hormone precursor protein, which itself is then cleaved, with the help of prohormone convertase enzymes, into a number of different peptides. These include the melanocyte-stimulating hormones (alpha-, beta-, gamma- MSH), adrenocorticotropic hormone (ACTH), the lipotropins, and beta-endorphin . ACTH and the MSHs are referred to as the melanocortins and all have the same core amino acid sequence, HFRW .

The POMC gene is found on chromosome 2p23, and is made up of three exons and two “large” introns. Only exons two and three are translated however. Exon two codes for the signal peptide and the initial N-terminal amino acids, while exon three codes for “most of the translated mRNA” .

POMC and its post-translational processing, adapted from Millington, and Raffin-Sanson et al.

After excision of the introns to form a “parent” POMC, this molecule is then cleaved into its various peptides, as mentioned above, by PCs, specifically PC1 and PC2. These enzymes act at cleavage sites consisting of paired basic residues, arginine and lysine, and end-products of their action depend on which sites are used. As PC1 and PC2 act on different sites, and their expression varies in different tissues, processing of POMC’s peptides is tissue-specific . For example, the anterior pituitary corticotroph cells only express PC1, which results in the cleavage of POMC into the NH2-terminal peptide (N-term), joining peptide (JP), ACTH, β-LPH, and some γ-LPH and β-endorphin (β-end) - See "POMC cleavage by PC1" diagram. The latter two peptides are produced because the “last cleavage site is only partially used”. However, in melanotroph cells, found in the intermediate lobe of the rodent pituitary, and the human hypothalamus, and placenta, both PC1 and PC2 are expressed. This means that all the cleavage sites are used and smaller peptides are produced ). N-term is therefore cleaved to the γ-MSHs, ACTH gives rise to α-MSH and CLIP (corticotrophinlike intermediate lobe peptide) and γ-LPH to β-MSH.

The cleavage of POMC by PC1, adapted from Raffin-Sanson et al.

POMC is expressed in the hypothalamus in the central nervous system, specifically the arcuate nucleus, as well as the nucleus tractus solitarius of the caudal medulla. It is also found in the anterior and intermediate pituitary, the immune system, and the skin.

Wot all the end products of pomc do
Where they act

Physiology and relation to appetite regulation

Evidence for POMC related to food regulating systems Relationship between POMC and other hormones eg leptin *diagram*

A-msh
Mc receptors
Pomc neurons and arc nucleus
Leptin, grhelin, npy et
diagram

Species Variation in POMC Gene

evolutionary tree diagram Chordata (vertebrates)

   ~ Agnatha – Lamprey
   ~ Gnathostomes
         ~ Chondrichthyes (cartilaginous fish)
         ~ Osteichthyes (bony fish) 
              ~ Subclass Actinopterygii (ray-finned fish;) - paddlefish
              ~ Subclass Sarcopterygii (lobe-finned fish)
                    ~ Tetrapods (mammals, birds, reptiles?)

Invertebrates

Summary/Conclusion

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