Melanin-Concentrating Hormones and Related Peptides、黑色素濃縮激素及相關(guān)肽

Definition

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide. It regulates skin color in teleost fish in the induction of melanin aggregation in the melanocytes.

Discovery

Enami in 1955 observed pigment aggregation in catfish Parasilurus asotus mela nophores after injecting crude extracts ofthe pituitary ofthe same species. He named it as elanophore-concentratihnogrmone1. Baker and Rance in 1983 reported that “melanin-concentratihnogrmone” a peptide with a molecular weight of less than 2000, and that most of its bioactivity occurs in the hypothalamus, favouring the hypothalamic origin of the hormone theory 2.

Structural Characteristics

MCH is a heptadecapeptide, Asp-Thr-Met-Arg-Cys-Met-Val-Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-Glu-Val, synthesized in the brain and secreted from the pars nervosa of teleost fish 3. Valérie et al., investigated 57 analogues of MCH stably expressed in HEK293 cells. The dodecapeptide MCH-(6–17), MCH ring between Cys7 and Cys16, with a single extra amino acid at the N terminus (Arg6) and at the C terminus (Trp17)) was found to be the minimal sequence required for a full and potent agonistic response on cAMP formation and [35S]- GTP?S binding. They scanned this dodecapeptide and found that only 3 of 8 amino acids of the ring, namely Met8, Arg11, and Tyr13, were essential to elicit full and potent responses in both tests. Deletions inside the ring led either to inactivity or to poor antagonists with potencies in the micromolar range. Cys7 and Cys16 were substituted by Asp and Lys or one of their analogues, in an attempt to replace the disulfide bridge by an amide bond 4.

Mode of Action

MCH is involved in the regulation of feeding behavior, which acts through a G protein-coupled receptor (SLC-1) inhibiting adenylcyclase activity. This hormone stimulates melanosome (melanin granule) aggregation within integumental melanocytes of fishes but, in contrast, stimulates melanosome dispersion within tetrapod (frog and lizard) melanocytes. The message sequence of the primary structure of MCH was determined which is responsible for its MSH-like (melanocyte stimulating hormone) component of activity. Removal of the N-terminal amino acid results in an almost total loss of MSH-like activity. The C-terminal amino acid is also essential for full activity since the analogue, MCH (1-16), is about 100 times less active than MCH. Therefore, the entire heptadecapeptide sequence of MCH appears to contribute to the MSH-like activity of MCH. Ring-contracted analogues of MCH are almost devoid of any melanosome aggregating activity but generally possess considerable or as great an MSH-like activity as MCH 2.

Functions

It regulates skin color in teleost fish in the induction of melanin aggregation in the melanocytes. Mammalian MCH is present in neurons of both the central and peripheral nervous systems, with predominant expression in the lateral hypothalamus and zona incerta. Its central role is in the control of feeding behaviors and energy metabolism. When administered centrally, MCH promotes food intake. Its expression in the lateral hypothalamus is induced by starvation. MCH knockout mice are lean and hypophagic and have increased metabolic rates and reduced body weight. Overexpression of MCH in transgenic mice leads to obesity. MCH and components of MCH signaling pathways are therefore very attractive as potential antiobesity drug targets 5.

Mice lacking MCH (MCH-KO) showed a significant reduction in beta-cell mass. MCH enhanced insulin secretion in human and mouse islets and rodent beta-cell lines in a dose-dependent manner. Real-time PCR analyses of islet RNA derived from MCH-KO revealed altered expression of islet-enriched genes such as glucagon, forkhead homeobox A2, hepatocyte nuclear factor (HNF) 4alpha, and HNF1alpha. These data provide novel evidence for an autocrine role for MCH in the regulation of beta-cell mass dynamics and in islet secretory function and suggest that MCH is part of a hypothalamic-islet (pancreatic) axis 6. In human intestinal xenografts grown in mice, changes in the expression of MCH and its receptors following treatment with Clostridium difficile toxin A, the causative agent of antibiotic-associated diarrhoea in hospitalised patients. Results suggest that MCH as a mediator of C difficile-associated enteritis and possibly of additional gut pathogens. MCH may mediate its proinflammatory effects at least in part by acting on epithelial cells in the intestine 7.
References

1.Baker BI, Rance TA (1983). Further observations on the distribution and properties of teleost melanin concentrating hormone. Gen Comp EndocrinoL., 50:423-431.

2.Enami M (1955). Melanophore-concentrating hormone (MCH) of possible hypothalamic origin in the catfish Parasilurus. Science, 121(3132): 36-37.

3.Matsunaga TO, Hruby VJ, Lebl M, Castrucci AM, Hadley ME (1989). Melanin concentrating hormone (MCH): structure-function aspects of its melanocyte stimulating hormone-like (MSH-like) activity. Peptides, 10(4):773-778.

4.Audinot V, Beauverger P, Lahaye C, Suply T, Rodriguez M, Ouvry C, Lamamy V, Imbert J, Rique H, Nahon JL, Galizzi JP, Canet E, Levens N, Fauchere JL, Boutin JA (2001). Structure-Activity Relationship Studies of Melanin-concentrating Hormone (MCH)-related Peptide Ligands at SLC-1, the Human MCH Receptor.  The Journal of Biological Chemistry, 276(17):13554-13562.

5.Wilson CA, Cavalla D (1998). Update on antiobesity drugs. Drug News Perspect., 11(4):240-247.

6.Pissios P, Ozcan U, Kokkotou E, Okada T, Liew CW, Liu S, Peters JN, Dahlgren G, Karamchandani J, Kudva YC, Kurpad AJ, Kennedy RT, Maratos-Flier E, Kulkarni RN (2007).  Melanin concentrating hormone is a novel regulator of islet function and growth. Diabetes, 56(2):311-319.

7.Kokkotou E, Espinoza DO, Torres D, Karagiannides I, Kosteletos S, Savidge T, O'Brien M, Pothoulakis C (2009). Melanin-concentrating hormone (MCH) modulates C difficile toxin A-mediated enteritis. Gut, 58:34-40.