- Email: [email protected]
MCH: From melanin-concentration to mega-consumption
Peptides 30 (2009) 1967–1968
Contents lists available at ScienceDirect
Peptides journal homepage: www.elsevier.com/locate/peptides
Preface
MCH: From melanin-concentration to mega-consumption
The melanin-concentrating hormone (MCH) had a prolonged and laborious delivery compared with the easy birth of its pigmentary opponent, MSH. It was discovered and named because of its very obvious ability to cause concentration of the melanin granules within pigment cells of teleost fish, resulting in skin pallor. While this name is perhaps annoying to those who study its roles in mammals, it is a useful reminder of how any hormone has multiple functions and that its predominant function can change during evolution. It is well known that many cold-blooded vertebrates will readily adapt their skin color to match that of the environment, and the ability of pituitary extracts to cause skin darkening in frogs led to the early identification of MSH in the intermediate lobe and its role in adaptive color change. At about the same time, in the 1930s, it was also observed that extracts made from teleost fish pituitaries, while causing skin darkening in frogs and some fish, induced skin pallor when injected into many species of teleost. This naturally suggested the existence of a paling, or melaninconcentrating, hormone and led to the concept of dual, antagonistic hormonal control of pigment cells. My interest in these hormones developed in the late 1950s, as a research student in Bedford College, London University. In the same department was Dr E.G. Healey, who worked on the neural control of fish pigment cells and who showed that while denervated melanophores could still show adaptive color change, this ability was lost after hypophysectomy. Hoping to identify the pituitary cellular origin of MCH, I examined the secretory activity of the cells in the intermediate lobe of fishes adapted to either black or white backgrounds. In contrast to other vertebrates, teleost fish have an intermediate lobe with two cell-types. We now know that these cell-types secrete POMC/MSH and somatolactin 0196-9781/$ – see front matter ß 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2009.04.005
but at that time we had no idea of their individual functions. My studies showed that, depending on the species, either one or other of the cells became increasingly active in fish kept in illuminated black-colored tanks but neither were activated by adaptation to a white background when MCH synthesis and release were presumably enhanced. Experiments by other workers similarly failed to identify the source of MCH and its very existence was refuted by some reviewers who attributed the pallor induced by pituitary extracts to some ‘‘contaminant’’. My research subsequently took another turn but I returned to the problem more than ten years later. Working first with John Ball at Sheffield University and then with an astute and tenacious research assistant, Teresa Rance at Bath University, we confirmed that a melanin-concentrating hormone is indeed essential to achieve full skin pallor in fish and that its abundance within the pituitary and, more significantly, within the hypothalamus can be manipulated by the color of the tank and the demands for its secretion. It was thus revealed to be a neurohypophysial hormone—a conclusion, we were shocked to discover, that had already been postulated 20 years beforehand by Masashi Enami but whose work had been ignored. Progress on MCH research gathered speed when the hormone attracted the attention of Hiroshi Kawauchi who was at that time embarked on purifying and sequencing all the fish pituitary hormones. When we met in 1981 at a comparative endocrinology conference in Hong Kong we described to him our in vitro MCH bioassay and discussed how best to proceed. With a team of students, he collected many hundreds of salmonid pituitaries and it was not long before he had purified, sequenced and synthesized the peptide and raised antibodies against it. Immunocytochemistry confirmed the neurohypophysial nature of MCH in fish and revealed MCH perikarya and fibres also in mammalian brains. It has since been identified in central neurones of all vertebrate classes. Hiroshi Kawauchi, Masao Ono and colleagues subsequently established the structure of MCH cDNA and its gene in chum salmon and this was later established also for the coho and Chinook salmon by Jean-Louis Nahon and others and then by us for the rainbow trout. Physiological and molecular studies of MCH could now proceed apace: Alex Eberle in Switzerland, and Victor Hruby and Mac Hadley in Arizona were among the first to synthesize MCH fragments and analogues to investigate their interaction with melanophores. We at Bath applied ourselves largely to the biological effects of MCH in fish and the response of the MCH neurones to environmental perturbations such as changes of tank color, photoperiodicity and a variety of stresses. Much of this
1968
Preface / Peptides 30 (2009) 1967–1968
involved collaboration with people from other labs—not only Hiroshi Kawauchi in Japan but also Alex Eberle in Basel, Julia Buckingham from London and Andy Levy from Bristol to name but a few who encouraged and helped us enormously and with whom it was such fun to work. Intrigued by our findings that MCH has a repressive effect on ACTH and cortisol secretion in teleosts, and that MCH secretion was itself affected by stress, Wylie Vale and Jean Rivier at the Salk Institute decided to sequence MCH and its gene in rats. Knowledge of this sequence subsequently hastened the identification of MCH as a novel orexigenic peptide in mice: using differential display PCR, researchers in Eleftheria Maratos-Flier’s lab showed that it was one of a limited number of genes showing enhanced mRNA expression in the hypothalamus of ob/ob mice. Its surprising role as a potent appetite enhancer in rodents has now been amply validated. In mammals, MCH probably plays no role as a neurohypophysial hormone; indeed, our work and that of others suggests that its release as a neurohypophysial hormone and use in color change is an evolutionary novelty restricted to the higher groups of fish, and is not apparent in agnathans or primitive fish. It is interesting, though, that mammalian pigment cells and keratinocytes express MCH receptors while the peptide itself seems to be produced within skin cells where it could exert a paracrine effect. Indeed, it is noteworthy that several effects of MCH in mammals – for instance a role in appetite or an influence on immune cells – have been reported also in fish and may have a long history.
Most of the research done on MCH today is focussed on mammals in which there are different populations of MCH neurones within the brains (as is true for probably all vertebrates), and in which the peptide seems to be involved in a multiplicity of functions. Given the increasing incidence of obesity in our society, the peptide’s appetite-enhancing effect has attracted considerable attention and an antagonist to one of its receptors is reported to be an effective anorectic. An awareness of the full spectrum of MCH influences, whether gained from mammals or lower vertebrates, and the receptor types through which it acts is of obvious importance if MCH is to be used clinically. The past 50 years have been an exciting period for biological research and the availability, today, of investigative tools that were not even dreamed of at the start of my career in the 1950s, means that research on MCH and its various effects can progress rather faster than in the early days. This volume considers some of the most recent studies on this intriguing neuropeptide. Bridget Baker* School of Biological Sciences, University of Bath, Claverton Down, Bath BA2 7AY, UK *Tel.: +44 1225 386407 E-mail address: [email protected]
18 December 2008 Available online 19 April 2009
Contents lists available at ScienceDirect
Peptides journal homepage: www.elsevier.com/locate/peptides
Preface
MCH: From melanin-concentration to mega-consumption
The melanin-concentrating hormone (MCH) had a prolonged and laborious delivery compared with the easy birth of its pigmentary opponent, MSH. It was discovered and named because of its very obvious ability to cause concentration of the melanin granules within pigment cells of teleost fish, resulting in skin pallor. While this name is perhaps annoying to those who study its roles in mammals, it is a useful reminder of how any hormone has multiple functions and that its predominant function can change during evolution. It is well known that many cold-blooded vertebrates will readily adapt their skin color to match that of the environment, and the ability of pituitary extracts to cause skin darkening in frogs led to the early identification of MSH in the intermediate lobe and its role in adaptive color change. At about the same time, in the 1930s, it was also observed that extracts made from teleost fish pituitaries, while causing skin darkening in frogs and some fish, induced skin pallor when injected into many species of teleost. This naturally suggested the existence of a paling, or melaninconcentrating, hormone and led to the concept of dual, antagonistic hormonal control of pigment cells. My interest in these hormones developed in the late 1950s, as a research student in Bedford College, London University. In the same department was Dr E.G. Healey, who worked on the neural control of fish pigment cells and who showed that while denervated melanophores could still show adaptive color change, this ability was lost after hypophysectomy. Hoping to identify the pituitary cellular origin of MCH, I examined the secretory activity of the cells in the intermediate lobe of fishes adapted to either black or white backgrounds. In contrast to other vertebrates, teleost fish have an intermediate lobe with two cell-types. We now know that these cell-types secrete POMC/MSH and somatolactin 0196-9781/$ – see front matter ß 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2009.04.005
but at that time we had no idea of their individual functions. My studies showed that, depending on the species, either one or other of the cells became increasingly active in fish kept in illuminated black-colored tanks but neither were activated by adaptation to a white background when MCH synthesis and release were presumably enhanced. Experiments by other workers similarly failed to identify the source of MCH and its very existence was refuted by some reviewers who attributed the pallor induced by pituitary extracts to some ‘‘contaminant’’. My research subsequently took another turn but I returned to the problem more than ten years later. Working first with John Ball at Sheffield University and then with an astute and tenacious research assistant, Teresa Rance at Bath University, we confirmed that a melanin-concentrating hormone is indeed essential to achieve full skin pallor in fish and that its abundance within the pituitary and, more significantly, within the hypothalamus can be manipulated by the color of the tank and the demands for its secretion. It was thus revealed to be a neurohypophysial hormone—a conclusion, we were shocked to discover, that had already been postulated 20 years beforehand by Masashi Enami but whose work had been ignored. Progress on MCH research gathered speed when the hormone attracted the attention of Hiroshi Kawauchi who was at that time embarked on purifying and sequencing all the fish pituitary hormones. When we met in 1981 at a comparative endocrinology conference in Hong Kong we described to him our in vitro MCH bioassay and discussed how best to proceed. With a team of students, he collected many hundreds of salmonid pituitaries and it was not long before he had purified, sequenced and synthesized the peptide and raised antibodies against it. Immunocytochemistry confirmed the neurohypophysial nature of MCH in fish and revealed MCH perikarya and fibres also in mammalian brains. It has since been identified in central neurones of all vertebrate classes. Hiroshi Kawauchi, Masao Ono and colleagues subsequently established the structure of MCH cDNA and its gene in chum salmon and this was later established also for the coho and Chinook salmon by Jean-Louis Nahon and others and then by us for the rainbow trout. Physiological and molecular studies of MCH could now proceed apace: Alex Eberle in Switzerland, and Victor Hruby and Mac Hadley in Arizona were among the first to synthesize MCH fragments and analogues to investigate their interaction with melanophores. We at Bath applied ourselves largely to the biological effects of MCH in fish and the response of the MCH neurones to environmental perturbations such as changes of tank color, photoperiodicity and a variety of stresses. Much of this
1968
Preface / Peptides 30 (2009) 1967–1968
involved collaboration with people from other labs—not only Hiroshi Kawauchi in Japan but also Alex Eberle in Basel, Julia Buckingham from London and Andy Levy from Bristol to name but a few who encouraged and helped us enormously and with whom it was such fun to work. Intrigued by our findings that MCH has a repressive effect on ACTH and cortisol secretion in teleosts, and that MCH secretion was itself affected by stress, Wylie Vale and Jean Rivier at the Salk Institute decided to sequence MCH and its gene in rats. Knowledge of this sequence subsequently hastened the identification of MCH as a novel orexigenic peptide in mice: using differential display PCR, researchers in Eleftheria Maratos-Flier’s lab showed that it was one of a limited number of genes showing enhanced mRNA expression in the hypothalamus of ob/ob mice. Its surprising role as a potent appetite enhancer in rodents has now been amply validated. In mammals, MCH probably plays no role as a neurohypophysial hormone; indeed, our work and that of others suggests that its release as a neurohypophysial hormone and use in color change is an evolutionary novelty restricted to the higher groups of fish, and is not apparent in agnathans or primitive fish. It is interesting, though, that mammalian pigment cells and keratinocytes express MCH receptors while the peptide itself seems to be produced within skin cells where it could exert a paracrine effect. Indeed, it is noteworthy that several effects of MCH in mammals – for instance a role in appetite or an influence on immune cells – have been reported also in fish and may have a long history.
Most of the research done on MCH today is focussed on mammals in which there are different populations of MCH neurones within the brains (as is true for probably all vertebrates), and in which the peptide seems to be involved in a multiplicity of functions. Given the increasing incidence of obesity in our society, the peptide’s appetite-enhancing effect has attracted considerable attention and an antagonist to one of its receptors is reported to be an effective anorectic. An awareness of the full spectrum of MCH influences, whether gained from mammals or lower vertebrates, and the receptor types through which it acts is of obvious importance if MCH is to be used clinically. The past 50 years have been an exciting period for biological research and the availability, today, of investigative tools that were not even dreamed of at the start of my career in the 1950s, means that research on MCH and its various effects can progress rather faster than in the early days. This volume considers some of the most recent studies on this intriguing neuropeptide. Bridget Baker* School of Biological Sciences, University of Bath, Claverton Down, Bath BA2 7AY, UK *Tel.: +44 1225 386407 E-mail address: [email protected]
18 December 2008 Available online 19 April 2009