Evolution of appetite regulating systems

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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 alpha melanocyte stimulating hormone (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 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 (corticotropin-like intermediate lobe peptide) and γ-LPH to β-MSH.

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

The POMC gene is expressed in number of tissues in man and animals. These include the anterior, and intermediate (only in rodents) pituitary of the central nervous system. It is also present in the nucleus tractus solitarius of the caudal medulla, and the hypothalamus, specifically the arcuate nucleus. Its expression has also been noted in the skin and the immune system,as well as other peripheral tissues.

The final products from the cleavage of POMC have a variety of functions. The melanocortins act on melanocortin receptors (MCRs) in different tissues. There are five types of MCR and melanocortin peptides bind to these with varying affinities, for example, mainly ACTH binds to MC2R.

TABLE

β-endorphin, on the other hand, is involved in the pain pathway by acting as an inhibitory neurotransmitter in the central nervous system. Here it binds to opioid receptors, leading to an analgesic effect .

CLIP has been found in many areas of the brain, especially in nerve fibres. It has been shown that it plays an important role in REM sleep, which in turn helps with the consolidation of memories .

The functions of β- and γ-LPH however, are still uncertain, although lipotropins are known for their role in lipolysis, mobilizing lipids for energy production, and their importance has been implicated in haematopoiesis.

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

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