Celebrating the 100^th anniversary of the Japan Endocrine Society: reflecting on my 50 years of hormone research

I. Introduction

As Japan enters the era of 100-year lifespans, the 100^th anniversary of the founding of the Japan Endocrine Society (JES) is just around the corner. Established in 1925, the JES has a history second only to Endocrine Society and has developed into one of the most prestigious societies in Japan. With over 9,000 members and approaching 10,000 (Fig. 1) (*Added in proof), the membership is expected to surpass 10,000 by its 100^th anniversary in 2026. The list of founding members, including Prof. Kwanji Tsuji (Fig. 2) [1], and their research fields at the time of JES’s establishment in 1925 (Fig. 3) provides an intriguing view into the research on hormones and endocrine organs during that period. The names of the founding members, their graduation years from Kyoto University, the names of the endocrine organs or hormones they were researching, and the years their papers were published are listed. Among the endocrine organs listed are the thyroid gland, adrenal glands, and gonads; the majority of the researchers focused on the thyroid gland, while none are listed for the pituitary and parathyroid glands. This reflects the early days of endocrinology when it was known that these endocrine organs secrete hormones, but the nature of the hormones was still unclear. Among the hormones, only insulin, which was discovered in 1921, was listed as a research topic, indicating the high level of interest in its discovery and the determination of its molecular structure. By 1925, only adrenaline, thyroxine, and insulin had been isolated, purified, and their structures determined (Fig. 4).

Fig. 1  The number of members of the Japan Endocrine Society (JES) will be more than ten thousand by 2026 (*Added in proof)

*The membership surpassed 10,000 in 2023.

Fig. 2  Prof. Kwanji Tsuji, who became Chief Professor of Internal Medicine, the First Division, Kyoto University School of Medicine

Fig. 3  Names of founding members of The Japan Endocrine Society in 1925

A. In Japanese

B. Names of founding members and their fields of study in endocrinology

Fig. 4  History of hormone discoveries and the JES foundation in the 20^th Century

II. Three Great Pioneers of the Early Days of the Japan Endocrine Society (JES)

Of course, looking back at the history of the isolation and purification of adrenaline in the early 20^th century [2], followed by the purification, discovery, and structural determination of hormones, it is clear that research on hormone-secreting endocrine organs has expanded. By the last quarter of the 20^th century, it became evident that organs throughout the body, such as the heart and adipose tissue, were also endocrine organs, in addition to the classical endocrine organs mentioned earlier. This progress has led to advancements in the elucidation of physiological functions and the clinical applications for diagnosis and treatment (Fig. 4). I would like to briefly touch on the encounter between Prof. Kwanji Tsuji (from Shimane Prefecture) (Fig. 2), who was studying in Germany and was forced to move to London due to the impact of World War I, and Prof. Ernest H. Starling, as well as the background of that time, since they are deeply intertwined with the history of the JES (Figs. 2–4).

Prof. Kwanji Tsuji, who had been studying in Berlin, Germany, as a student from a country that had become an enemy of Germany, was deported upon the outbreak of World War I in 1914 and moved to London. There, he discovered the textbook Principles of Human Physiology (J. & A. Churchill London 1912) by Prof. Ernest H. Starling (Fig. 5) [3] and began studying endocrinology in Prof. Starling’s laboratory. The outbreak of World War I, which triggered the fateful meeting between Prof. Ernest H. Starling, a pioneer in endocrinology and the person who coined the term “hormone,” and Prof. Kwanji Tsuji, who would later become a founder of the JES, may be considered a significant event for the JES. The thick physiology textbook is inscribed with the date of September 1, 1914, when Prof. Kwanji Tsuji purchased it in London (Fig. 5). For a student from a developing country like Japan at the time, it must have been an expensive textbook. It is presumed that this textbook was brought back to Japan and read repeatedly. The encounter of Prof. Kwanji Tsuji with endocrinology, the future of endocrinology as a medical field, and the significant influence this had on the founding of the JES 11 years later in 1925, make this textbook a valuable historical document (Fig. 5).

Fig. 5  Textbook of Human Physiology written by Prof. A. Starling which Prof. Kwanji Tsuji bought in London in 1914

In Chapter 20, titled ‘The Ductless Glands,’ Prof. Ernest H. Starling provides his definition of hormones as “chemical messengers” for intercellular communication and explains that the term “hormone” is derived from the Greek word meaning “I excite.” He details the mechanism of “internal secretion” and the role of hormones as chemical messengers, which transmit effects from endocrine organs to target organs through the bloodstream, contrasting this with the exocrine stimulation of the pancreas by secretin [3]. Furthermore, the textbook follows this description with a detailed account of the structure of the adrenal gland, a typical endocrine organ, covering both the cortex and medulla. It includes information on the purification of adrenaline, a pressor substance from the adrenal medulla, by Dr. Jokichi Takamine (1853–1922, from Toyama Prefecture) (Fig. 6) in 1901, along with the molecular formula that was revealed as a result [3]. In 1979, this textbook was passed from Prof. Kwanji Tsuji’s nephew, Prof. Shigeji Kijima, to my mentor, Prof. Hiroo Imura (Fig. 7). In March 1993, Prof. Imura presented it to me as my “cherished possession” to encourage me as his successor to lead the Second Department of Internal Medicine at Kyoto University (Fig. 5). The book bears the seal of Tsuji’s library. I recall the words of encouragement given to me by Prof. Shigeji Kijima, who was the deputy director of Kitano Hospital when I started my residency there. He said, “Kitano Hospital is famous for being busy and having low salaries, but because of the variety of illnesses and the overwhelming number of patients, think of the low salary as an investment in yourself as you train.” At the time, I did not know that he was Prof. Kwanji Tsuji’s nephew, but I respected him as a knowledgeable teacher.

Fig. 6  Dr. Jokichi Takamine and a sketch of adrenaline crystals recorded in the note in July 1900 by Dr. Keizo Uenaka, his co-worker

Fig. 7  With two great mentors, Prof. Hiroo Imura (Internal Medicine, Endocrinology and Metabolism) (left) and Prof. Hisayuki Matsuo (Biochemistry, Peptide Chemistry) (right)

The 1912 publication Principles of Human Physiology features only one Japanese achievement: Dr. Jokichi Takamine’s isolation and purification of adrenaline [2, 3]. In the textbook The Ductless Glands written by Prof. Ernest H. Starling, who coined the term “hormone,” the name Dr. Jokichi Takamine and the description of his isolation and purification of adrenaline are central in Chapter 20. Needless to say, adrenaline was the first hormone to be isolated and purified just prior to the definition and naming of hormones in 1904, and the first hormone to be crystallized, have its structure determined, and synthesized, marking it as a foundational achievement in endocrinology. Furthermore, Chapter 4, ‘Ferments,’ mentions Takadiastase, the commercial name for diastase, a digestive enzyme developed by Dr. Jokichi Takamine for clinical use. This clearly highlights the high international regard for his exceptional talent and achievements at the time.

Similarly, in The History of Clinical Endocrinology published in 1993 (V. C. Medvei, The Parthenon Publishing Group, Lancs, UK, 1993) [4], Dr. Jokichi Takamine and his isolation of adrenaline, referred to as ‘the blood-pressure-raising principle of the suprarenal glands,’ are described as brilliant achievements in the birth of endocrinology [2]. However, in A Biographical History of Endocrinology (D. Lynn Loriaux, Endocrine Society & Wiley Blackwell, Iowa, USA, 2016) [5], published by Endocrine Society, which celebrated its 100^th anniversary in 2016, Dr. Jokichi Takamine’s name is inexplicably absent from the list of 108 endocrinologists. On the other hand, Prof. John J. Abel, who was a worthy rival in the research on the isolation and purification of adrenaline, is mentioned under the subtitle ‘Isolation of hormones.’ The isolation and purification of adrenaline by Dr. Jokichi Takamine was a remarkable scientific achievement accomplished by a Japanese scientist in the United States in 1901, prior to the founding of the JES [2], and it is a scientific history shared by all members of the JES. Nonetheless, the absence of Dr. Jokichi Takamine’s name in A Biographical History of Endocrinology is utterly incomprehensible. Furthermore, in the United States, the name adrenaline, as isolated and purified by Dr. Jokichi Takamine, is not used, and Prof. John J. Abel’s term epinephrine is used instead. This is extremely regrettable. We believe that the generic name adrenaline, as isolated and purified by Dr. Jokichi Takamine, should also be used in the United States.

On my way back from attending the Endocrine Society meeting, I stopped in New York to search for the former residence of Dr. Jokichi Takamine near the Hudson River. I managed to visit his remaining villa (Shofuden) and his gravesite. The villa, befitting a successful entrepreneur in the United States, was a replica of the Shishinden of the Kyoto Imperial Palace. Originally the Japanese Pavilion at the World’s Fair held in St. Louis, it was relocated to a villa area in the suburbs of New York. I was also struck by the grand scale of his gravesite. While Dr. Jokichi Takamine may be remembered more for his success as a businessman in the U.S. than for his achievements as a scientist, it is worth noting that today many scientists in the U.S. own venture companies and have become wealthy. Dr. Jokichi Takamine could be considered one of the pioneering Japanese entrepreneurs who successfully established venture companies.

Among Japanese researchers, the only one selected among the 108 in A Biographical History of Endocrinology is Dr. Hakaru Hashimoto (from Mie Prefecture) (Fig. 8) [6]. The subtitle is ‘His Disease’ [5]. Chapter 61 on Dr. Hakaru Hashimoto (1881–1934) notes that after attending the Third High School in Kyoto, he advanced to Fukuoka Medical College, which was established as a branch of Kyoto Imperial University’s medical school. In the Department of Surgery, he discovered four rare cases of goiter that were distinct from Riedel’s struma. He conducted histological research and in 1912 submitted a lengthy paper to the German surgical journal Arch. Klin. Chir., which was accepted and published. This was the discovery of Struma lymphomatosa, clearly different from Riedel’s struma [6]. Subsequently, it seems that this German-language paper by a Japanese author did not attract the attention of leading endocrinologists in Europe and USA, and time passed. After submitting this paper, Dr. Hakaru Hashimoto studied at the University of Göttingen in Germany until 1914, focusing on tuberculosis of the gonads and urinary system. With the outbreak of World War I, he moved to the United Kingdom. The movement of Japanese students from Germany to the UK, as mentioned in the case of Prof. Kwanji Tsuji, happened during the same period. As a member of the JES, I find it historically significant that the two passionate young Japanese endocrinologists, Prof. Kwanji Tsuji, who would become a founder of the JES, and Dr. Hakaru Hashimoto, whose name would be immortalized in “Hashimoto’s disease,” were both relocated from Germany to the UK at the same time. Perhaps they met by chance on their way to the UK or in London and discussed goiters, hormones, and the future of endocrinology.

Fig. 8  Dr. Hakaru Hashimoto

Dr. Hakaru Hashimoto returned to Japan in 1916 and began practicing as a general practitioner in his hometown in Mie Prefecture. In 1917, he was awarded a degree from Kyushu University. However, in 1925, British pathologist Prof. G.S. Williamson published a paper on lymphomatous goiter, and it is said that he was unaware of Dr. Hakaru Hashimoto’s earlier paper. It was later discovered that this condition was the same as Hashimoto’s disease. The term “Hashimoto’s disease” was officially adopted at the International Goiter Conference held in Washington, DC, in 1938. However, after 1916, Dr. Hakaru Hashimoto focused on his practice as a general practitioner and did not continue his research in endocrinology. He passed away from typhoid fever in 1934 and likely never knew that his name would be used to refer to chronic thyroiditis as Hashimoto’s disease.

As we approach the centennial of the JES, it is essential that the names of Dr. Jokichi Takamine, Dr. Hakaru Hashimoto, and Prof. Kwanji Tsuji along with their contributions to endocrinology in Japan, be recognized and shared among the members of the JES so that we can carry on the mission and passion they have fulfilled. These three great pioneers and their achievements at the dawn of Japanese endocrinology should never be forgotten.

III. The Japan Endocrine Society (JES) and Me

In 1975, at the age of 27, I became a member of the JES. Therefore, the 100^th anniversary of the founding of the JES coincides with the 50^th anniversary of my membership. This means I have been active as a JES member during the latter half of JES’s 100-year history, which began in 1925. I take pride in having attended every Annual Congress without fail during this period. Needless to say, my research career would not have been possible without the JES.

Fortunately, during these years, I had opportunities to join the JES activities as Director and President.

My activities as the JES Director and President are filled with many memories. We decided to regularize the Annual Congresses and Summer Seminars (aimed at encouraging basic endocrinology and metabolism research), unify the clinical general assemblies that were divided into Eastern and Western regional meetings into a single autumn Clinical Update on Endocrinology & Metabolism (aimed at sharing updates in clinical endocrinology and metabolism), and hold annual meetings in each regional branch (aimed at promoting and practicing endocrinology and metabolism throughout the country). Additionally, we organized six member societies of the JES (the Japan Thyroid Association, Japan Neuroendocrine Society, Japan Endocrine Pathology Society, the Society of Cardiovascular Endocrinology and Metabolism, Japan Hormonal Steroid Society, and Japan Society of Reproductive Endocrinology), established a stable financial foundation (achieving administrative independence), and set up an awards system (JES Award, Meister Award, Best Endocrine Surgeon of the Year, Distinguished Endocrinologist Award, JES Research Award, and YIA). Furthermore, we planned commemorative events for the 80^th anniversary of the JES, held in Tokyo in 2007 with the participation of the six member societies and nine regional branches. In 2010, the JES hosted the 14^th International Congress of Endocrinology (ICE 2010) in Kyoto (the second time it was held in Japan since 1988), and I served as Chairman of the Local Organizing Committee. We promoted international exchange, particularly supporting the participation of endocrine societies from Asian countries in ICE 2010 (Fig. 9). Additionally, as part of collaborative activities with Endocrine Society and the Endocrine Society of Oceania, JES hosted the Trans-Pacific Symposium from 1997 to 2004 at Endocrine Society Annual Meetings (ENDO), supported by Shionogi & Co., Ltd. (Fig. 10) [7].

Fig. 9  The fourteenth International Congress of Endocrinology (ICE), Kyoto, in 2010

A. The poster of 14^th ICE (Kyoto)

B. My opening address in 14^th ICE (Kyoto) in 2010

Fig. 10  Trans-Pacific Symposium

Here, I will share some of the memorable moments from these activities.

The first was the creation of a logo for the JES (Fig. 11). At that time, the logo for the Japanese Society of Internal Medicine (JSIM) had just been created, and as one of the major member societies of the JSIM, I proposed creating a logo suitable for the JES. We pursued a design symbolizing the concept of hormones, defined as chemical intercellular signaling substances from endocrine cells to target cells. After considering many prospective designs and listening to the opinions of our members, we decided on the current logo (Fig. 11).

Fig. 11  The logo of the JES was made in 2001

The second was regarding the generic name of adrenaline. As previously mentioned, there was a fierce competition between Dr. Jokichi Takamine and Prof. J. J. Abel in the research on isolating adrenaline. In Japan, the generic name epinephrine had been used for many years instead of adrenaline. In collaboration with Professor Tomio Kanno, Professor Emeritus at Hokkaido University, and journalist Kazumasa Iinuma, who were actively working together to ensure that Dr. Jokichi Takamine’s achievements in the purification of adrenaline were correctly recognized, we signed a petition to the Ministry of Health, Labour and Welfare to change the generic name of the drug from epinephrine to adrenaline on behalf of the JES. In 2001, we successfully secured the change to adrenaline. This restored the name adrenaline in Japan in the 21^st century. However, in my paper on enkephalin production in pheochromocytoma published in the Journal of Clinical Investigation, adrenaline was typeset as epinephrine [8]. In contrast, in the UK, the name adrenaline has been consistently used since Prof. Ernest Starling’s time. We would like to express our high regard and respect for this [3].

The third, although not official, was the creation of the “Hormone Anthem.” Its beginning was in response to feedback from Kyoto University medical students who said, “Professor Nakao’s lectures on endocrinology and metabolism involve too many names of various hormones, making it overwhelming.” To address this, I wrote the lyrics for the “Hormone Anthem.” Singing the song allowed students to memorize the names of hormones in the order they were discovered, and also to remember important concepts and terms in endocrinology. The definition of hormones and the fact that the word “hormone” comes from the Greek word hormao meaning “I excite” were also included. I asked Ms. Yuriko Fuji, a staff member of the society office who had experience in composing music, to compose the music. It was a byproduct of the 80^th anniversary event of the JES. We created an English version of the CD for the ICE 2010 (Supplementary Fig. 1). At that time, only a few people knew about it, but I was secretly delighted to recently learn that it is being used in JES-related events. It is a nostalgic and somewhat embarrassing story. As I write this essay and listen to the song in the background, I find that it has a gentle melody that anyone can sing. It brings back memories of the people involved in its creation and the circumstances at the time, making me feel deeply moved.

IV. Expectations for JES and JES Members

The JES has provided us with an optimal platform for presenting and discussing translational research (TR) related to our “novel hormones” and has offered us numerous opportunities as a supportive society for the clinical application of diagnosis and treatment. During the latter half of JES’s 100-year history, which coincides with our active period, the JES has grown and developed into one of the world’s leading societies in the discovery of novel hormones, the promotion of TR for these hormones, and their practical application in diagnosis and treatment. I am confident and strongly hope that this tradition of the JES will continue to thrive in the future.

I would also like to express my heartfelt gratitude to the many pioneers who contributed to the founding of the JES, to the mentors of our generation such as Prof. Hiroo Imura, Prof. Hisayuki Matsuo, Prof. Osamu Hayaishi, Prof. Shousaku Numa, and others, to the JES members who engaged in rigorous yet enjoyable discussions at academic conferences, and to my co-researchers who worked tirelessly with us. Furthermore, I have high expectations for the JES members, who surpassed 9,800 at the end of 2022 (Fig. 1), to continue their “everlasting challenge” in hormone research. While we are all JES members, it goes without saying that our roles in research vary, including basic scientists, physician-scientists, clinical endocrinology and metabolism specialists, and clinical epidemiologists (Fig. 12). I hope that each member will leverage the unique characteristics of their respective roles to promote discoveries in endocrinology and metabolism and to advance the development and practical applications of these discoveries for clinical use and for patients. For the promotion of TR, I anticipate a further increase in the participation of basic scientists in the JES, who contribute to the discoveries that serve as the starting points for TR and to the development of new technologies to advance endocrinology and metabolism.

Fig. 12  Schematic presentation of the concept of translational research bridging between basic science and clinical medicine. Bidirectional approach, from bench to bedside, and from bedside to bench, is the best strategy to overcome “dead valley” between basic science and clinical medicine

As a physician-scientist who has dedicated myself to the TR of novel hormones (Figs. 4, 13, 14), I propose the following as fundamental strategies for TR in endocrinology and metabolism:

Fig. 13  Cardiovascular hormones secreted by the heart and blood vessel

Fig. 14  Adipocytes and adipokines secreted by adipocytes

1. Developing, selecting, and thoroughly analyzing excellent animal models of human diseases that replicate the pathologies of hormonal functional abnormalities in humans.

2. Establishing proof-of-concept (POC) for the clinical application of hormone action or the blockade of hormone action, targeting rare pathologies and diseases where hormone therapy is most effective.

3. Expanding the targets of hormone clinical applications from rare diseases to common diseases in humans.

4. Recognizing the importance of persistent verification from a bidirectional perspective, from basic research to clinical application and vice versa, in all processes of TR of these hormones (Fig. 12) [9].

Furthermore, as a fundamental strategy for research on “novel hormones,” I believe that developing accurate methods for measuring blood hormone concentrations and precisely quantifying circulating blood hormone concentrations based on the resulting measurements, along with estimating local concentrations of paracrine and autocrine factors in synapses and production organs, and pursuing rigorous analysis of their binding to receptors, comprise the immutable first step in elucidating the significance of hormones in endocrinology and metabolism (Fig. 15) [6, 9-13], as pointed out by Professor Albright in his special lecture in 1944 [14].

Fig. 15  The “do’s” and “do-not’s” along the road leading to the castle of success in clinical investigation in plenary lecture by Prof. Fuller Albright in the annual meeting of American Society for Clinical Investigation in 1944 (modified)

The day I finalize this essay happens to be the 100^th anniversary of the Great Kanto Earthquake of 1924. It goes without saying that we have not experienced the Great Kanto Earthquake, but we have lived through the Great Hanshin Earthquake of 1995 and the Great East Japan Earthquake of 2011. I have heard that during the Great Kanto Earthquake, various pieces of false information circulated widely and that Japan, which was then a developing country, was in extreme chaos. It was shortly after this period of chaos that the JES, with the aim of pursuing the truth in endocrinology and metabolism, was founded in Kyoto. As we reaffirm the mission of the JES, including the presentation and discussion of scientific research results in endocrinology, international exchange, and the nurturing of the next generation, and wholeheartedly celebrate the 100^th anniversary of the JES, which has matured and developed, I sincerely congratulate the JES on its centennial and entrust the continued development of the JES in the hands of all of its over 10,000 members.

V. My Research in Endocrinology

My research in endocrinology can be summarized as ‘the promotion of TR of novel hormones and the achievement of their clinical application in diagnosis and treatment’ [9-13]. TR is the research that bridges the gap between basic research and clinical application (Fig. 12). However, its success is a challenging path that requires not only the development from basic to clinical research but also detailed considerations for feedback from clinical activities to basic research [9].

“Novel hormones” refer to hormones that were discovered after I became a JES member in 1975 and whose significance sparked my interest. Specifically, these include opioid peptides (β-endorphin, enkephalin, leumorphin, etc.), the natriuretic peptide family of cardiovascular hormones (ANP, BNP, CNP), and the adipokine leptin (Fig. 4). I have devoted myself to research day and night.

Let us reflect on the past half-century of my activities from the beginning of my research activities in endocrinology and metabolism to the present, focusing on my encounters with novel hormones and researchers I met through these opportunities.

1.  Medical Student Days: Cyclic AMP [9]

As a first-year student at the Kyoto University School of Medicine, I visited the biochemistry laboratory of Prof. Osamu Hayaishi (Fig. 16A), who was at the forefront of international medical chemistry research, with my classmate Mr. Shu Narumiya (later Professor of Pharmacology at Kyoto University) (Fig. 16B), and began assisting with biochemical research. My assigned task was to conduct research on protein kinases activated by cyclic AMP, an intracellular second messenger of hormones. Cyclic AMP was mentioned in our biochemistry textbooks along with the name of its discoverer, Prof. E. W. Sutherland.

Fig. 16  Prof. Osamu Hayaishi (A), Prof. of Biochemistry, Kyoto University School of Medicine. “You should get the Nobel Price” was his encouraging words for students including us. Prof. Shu Narumiya (center) and me (right) at practice of anatomy (B) We were medical students and started learning biochemistry at the Department of Medical Chemistry of Prof. Osamu Hayaishi.

Growing up in a family of teachers in an environment that sometimes resembled a village without a doctor, I had no opportunity to meet basic researchers or consider becoming a researcher until I entered the Kyoto University School of Medicine. My original intention for entering medical school was to become a physician contributing to healthcare in remote areas. However, in the Hayaishi lab, I was captivated by the allure of cutting-edge international medical chemistry research. Reading newly published papers, designing experiments, and discussing the results were endlessly enjoyable.

Around that time, I attended a symposium on cyclic AMP held at Osaka University, where I heard a lecture on ACTH and cyclic AMP by the up-and-coming clinician and researcher Prof. Hiroo Imura (then in his late 30s and an Associate Professor of Internal Medicine at Kyoto University) (Fig. 7). This lecture made me aware of the path of a clinical investigator or physician-scientist, which differed from the basic research conducted by Prof. Osamu Hayaishi. It was an encounter with my lifelong mentor. The introduction to cyclic AMP research during my medical student days, under the guidance of Prof. Osamu Hayaishi (Fig. 16A), was a fateful event that would lead to my subsequent career in hormone research.

2.  Graduate School Days: β-Endorphin, Enkephalin, Leumorphin [8, 15-26]

Prof. Hiroo Imura transferred to Kobe University as a professor before he started giving clinical lectures to us, but in the autumn before I entered graduate school, he returned to Kyoto University and was appointed Professor of the Second Department of Internal Medicine. With this fortunate turn of events, I became a graduate student in the Second Department of Internal Medicine at Kyoto University without hesitation. My research theme in graduate school was ‘The Clinical Significance of β-Endorphin,’ one of the opioid peptides that was attracting attention at the time, and I enthusiastically devoted myself to the research. This was right after the entire structure of the common precursor protein of ACTH and β-endorphin, proopiomelanocortin (POMC) mRNA, was elucidated through cloning by Prof. Shosaku Numa (Fig. 17A) and Prof. Shigetada Nakanishi (Fig. 17B) in the Department of Medical Chemistry at Kyoto University [15]. This cloning attracted attention not only within Kyoto University but also internationally. Around that time, our laboratory had completed a high-sensitivity RIA for β-endorphin, making it possible to measure β-endorphin concentrations in human blood. Just as we were beginning to study the regulatory mechanisms of secretion and the physiological functions by accurately measuring blood concentrations, a paper was published in Science by a U.S. research group stating that ‘β-endorphin is not detectable in blood from normal human subjects’ [16], dampening our enthusiasm. It was the first time I experienced the harshness of international research competition.

Fig. 17  Prof. Shosaku Numa (A), who succeeded in cloning the precursor of ACTH/βLPH or proopiomelanocortin (POPC) (B) with Prof. Shigetada Nakanishi in 1979

However, I was confident in the high sensitivity and reproducibility of the β-endorphin assay we developed. I was also slightly confident in the research results using biochemical techniques honed at the Hayaishi Lab. Since CRH had not yet been discovered, I planned to collect blood samples under conditions where concentrations of blood ACTH derived from POMC, a precursor protein in common with β-endorphin, would increase. I conducted a single-dose metyrapone loading test on myself to test the presence and increase of β-endorphin. I still vividly remember an unforgettable experience. In the late-night laboratory, after taking metyrapone and preparing for the next morning’s blood collection and experiments, I realized I had fallen asleep face down on the lab table and had drooled onto the table. In hindsight, it was likely that I fell asleep due to a combination of fatigue and low cortisol levels. However, as a result, the β-endorphin concentration in my blood collected the next morning unexpectedly spiked along with the ACTH concentration, and gel chromatography detected an immunoreactive peak corresponding to the molecular weight of β-endorphin in the elution fraction. I submitted a rapid communication paper to Journal of Clinical Investigation in September, which was accepted with no revisions [17]. I felt exhilarated and on top of the world.

However, after two or three days, a subtle change in my state of mind occurred—I began to feel an anxiety that I could not suppress. I worried that the detection of β-endorphin might be an artifact from β-LPH. The words ‘β-endorphin is not detectable in blood from normal human subjects’ from the paper published in Science came to mind [16]. Although I had not fabricated anything, if the β-endorphin that I had joyfully detected in human blood was a product of proteolytic enzymes, it would tarnish the reputation of Prof. Hiroo Imura and other co-authors. I spent sleepless nights until I could reconfirm the presence of β-endorphin in human blood. When I finally reconfirmed it with confidence, I was honestly relieved. I also later found out after returning to Japan that the gray-haired researcher who persistently questioned me about the presence of β-endorphin during my poster presentation at that year’s Endocrine Society meeting was Prof. W. H. Daughaday, the then Chief Editor of the Journal of Clinical Investigation. Until I confirmed the publication of my paper in the Journal of Clinical Investigation, I was secretly worried that he might send a letter overturning the decision to accept my paper.

Even now I can’t forget the joy and sense of fulfillment I felt when I confirmed my paper’s publication in the December issue of the Journal of Clinical Investigation at the Kyoto University Medical Library in 1978. I was able to quickly write subsequent reports on the increase in blood β-endorphin concentration during the insulin tolerance test (ITT) [18] and the analysis of β-endorphin concentration in human cerebrospinal fluid [19, 20] since they were extensions of this research. Furthermore, I was able to report that a peptide containing the γ-MSH structure at the N-terminal of POMC was present in human blood and that its secretion occurred in parallel with ACTH and β-endorphin [21]. I was able to immerse myself every day in my research without being tied down at home even when I was newly married. As a result, I was blessed with three sons and one daughter (Fig. 18). Although not from that time, a photograph of my children from 1989 remains, which I used during an international symposium on the natriuretic peptide family held in Germany. This was around the time I was researching the potential of CNP, which would be discovered following ANP and BNP.

Fig. 18  My four children in 1988. ANP and BNP were known, however, CNP was not known

3.  Postdoctoral Period: Enkephalin and Leumorphin

During my postdoctoral period, I continued to spend my research life thinking about which path to take, whether to give up endorphin research to study abroad in the United States or remain in Japan to form a research group and continue my clinical medical research. In the field of neuroendocrinology, I was invited to study growth hormones at Harvard University and posterior pituitary hormones at the NIH. Around that time, opioid peptide research was further accelerated by the cloning of the enkephalin precursor Proenkephalin A [22] and the Dynorphin/Neoendorphin precursor Proenkephalin B [23] in Prof. Shosaku Numa’s lab [8, 24, 25]. I started to lead a small group in a tiny lab with broken glass windows, where we made steady progress in opioid peptide research, including the synthesis of enkephalin in humans and the identification of a novel endogenous opioid peptide, leumorphin, derived from Proenkephalin B in the posterior pituitary gland [25, 26]. During our investigation of the relationship between catecholamine synthesis in the adrenal medulla and enkephalin production [8, 24], I learned about the history of the intense competition between Dr. Jokichi Takamine and Prof. John J. Abel in the purification of adrenaline. I was deeply impressed by the success of Dr. Jokichi Takamine’s purification of adrenaline in the early 20^th century, and my admiration for his activities grew stronger during this time. During a business trip to the U.S. for an Endocrine Society meeting, I visited New York and the Shofuden, Dr. Jokichi Takamine’s villa in the suburbs. Inspired by his great achievements, I reconfirmed my desire to continue hormone research. Around this time in Japan, there were successive discoveries of the natriuretic peptide family, endothelin family, and adrenomedullin from the cardiovascular system (Fig. 13). We organized domestic workshops and established the Society of Cardiovascular Endocrinology and Metabolism (CVEM) in the field of cardiovascular endocrinology and metabolism. This society later grew into a member society of the JES, and the name of its award was decided without hesitation to be the Jokichi Takamine Award.

I have an unforgettable memory about leumorphin. As the researcher responsible for the joint research conducted by Prof. Shosaku Numa (Fig. 17) and Prof. Hiroo Imura (Fig. 7), I submitted a paper, which was accepted for publication [25], on the discovery of leumorphin, a novel endogenous opioid peptide located at the C-terminal of proenkephalin B, before presenting my findings at an international symposium. Just before my overseas trip to present my findings, I visited Prof. Shosaku Numa’s office to report that the paper was accepted. His reaction to my report was completely unexpected, and he immediately ordered me to have the paper withdrawn. When I nervously asked the reason, he sternly replied, “Experiments done hastily before a presentation at a symposium raise questions about their reliability. If you can reconfirm the results after redoing the experiments, then you can resubmit the paper.” Enduring jet lag after returning to Japan, I redid the experiments. Having the same paper accepted twice is a unique and unforgettable experience that will never happen again [25]. Around this time, I also met Prof. Kenji Kangawa (Fig. 19) and Prof. Hisayuki Matsuo (Fig. 7) from the Department of Biochemistry at the Medical College of Miyazaki, who isolated neoendorphin. There was a strong rivalry between our group, which explored new opioid peptides based on genetic information through cloning of precursor protein mRNA in Prof. Shosaku Numa’s lab, and the Matsuo-Kangawa group, which explored new peptides using bioassays.

Fig. 19  Dr. Kenji Kangawa in Kyoto Symposium on ANP in 1988

Meanwhile, I began to feel the limitation in the prospects of clinical application of opioid peptides in the field of endocrinology and metabolism. I couldn’t come up with any bright ideas for developing research due to the differences between the use of opioids themselves in pain treatment (therapy) and the clinical application of opioid peptides, and I felt the limitation in their usability. I hadn’t yet thought of studying the relationship between opioid peptides and lifestyle habit such as eating and exercise, which would later be elucidated, and I struggled to continue my research. Even though it was a small research group, as its leader, I faced the daily responsibility of deciding the direction of our research and worried about the future of my co-researchers. I carried the burden of concern in my research life as to whether continuing research on opioid peptides in the field of clinical endocrinology and metabolism would open future prospects for both myself and my co-researchers—in other words, whether we could survive in the field. I agonized over the differences between endocrinology and metabolism in internal medicine and basic pharmacology.

4.  Assistant Professor and Lecturer Period: ANP, BNP, CNP, and Endothelin (Fig. 13) [9]

In late 1983, I was summoned to Professor Hiroo Imura’s office and handed a preprint copy of the Biochemical and Biophysical Research Communications Journal. “Are you interested?” he asked. It was a paper on the isolation and structural determination of ANP from the human atrium, and it stated that its diuretic activity was 1,000 times that of furosemide [27]. The first author was Professor Kenji Kangawa, who had isolated Neoendorphin, and the last author was Professor Hisayuki Matsuo. “The heart is an endocrine organ and secretes ANP? Research on hormone action usually begins with the removal of the producing organ, but what happens if the heart is removed?” Despite these thoughts running through my mind, I immediately replied, “I’ll do it.” Although the term “translational research” (TR) didn’t exist at the time, various ideas for clinical applications came to mind. This marked the beginning of my research on natriuretic peptides. On January 1, 1984, I was officially appointed as an assistant professor. I held concurrent positions as an assistant professor at the Kyoto University Radioisotope Research Center and the Second Department of Internal Medicine at the Kyoto University School of Medicine.

As a first step, it was necessary to develop a method for measuring ANP, so we began preparing antibodies. Prioritizing speed and drawing on my experience of creating an antibody for enkephalin, which has five amino acid residues, I was confident in preparing antibodies if I could obtain a fragment of 7–8 amino acids from the C-terminus of ANP. We had the C-terminal peptide synthesized in a short time and attempted to create the antibody in the shortest possible time. I recall that we were able to establish the radioimmunoassay (RIA) around March. Although the RIA could not be considered sufficiently sensitive since speed was prioritized, it was sufficient for measuring the high concentrations of ANP present in the atria of humans and rats. Compared to the peptide content in the hypothalamus, which I had previously studied, I was astonished by the extremely high ANP content in the atria [28]. It seemed curious that such high ANP content in the atria had not been discovered until the 1980s, in the latter half of the 20^th century [9, 28]. Applying selective blood sampling, a method used in endocrinology and metabolism for localizing hormone-producing tumors, we discovered during cardiac catheterization that ANP secreted from the heart had concentrations in the coronary veins an order of magnitude higher than in other regions, indicating that ANP enters systemic circulation from the coronary veins [29]. Alongside the report by Prof. De Bold’s group from Canada on the isolation and structural determination of rat ANP, the report by Prof. Kenji Kangawa’s group on the isolation and structural determination of human ANP was a groundbreaking discovery that attracted global attention. In addition to the groups led by Prof. Hisayuki Matsuo, Prof. Kenji Kangawa, and Prof. De Bold, distinguished researchers from institutions such as Heidelberg University in Germany, Cornell University, Washington University, Vanderbilt University in the United States, and the Montreal Clinical Research Institute in Canada were fiercely competing. In 1989, five years later, a photo was taken at an international symposium held at Myoshinji Temple in Kyoto, featuring researchers gathered from around the world who were studying the natriuretic peptide family (Fig. 20). To make our presence known among these prominent researchers, we had no choice but to continuously publish rapid communication papers. Although there was only one publication on the development of a radioimmunoassay for ANP in 1984 [28], we continued to publish over ten rapid communication papers each year in 1985 and 1986. We even heard remarks ridiculing us about being a ‘group that could only write rapid communication papers.’ It was not until 1986 and 1987 that we were able to publish two full papers [30, 31]. I fondly remember that we discovered ANP, which had attracted attention as a cardiac hormone, also existed in the nervous system, and investigated its functions under the hypothesis of contrasting them with renin-angiotensin system amid intense international competition [9-13]. It was truly a series of cutthroat competition.

Fig. 20  Participants of Myoshinji Temple Symposium on natriuretic peptide family

Since ethics committees had not yet been established in Japan, before conducting research by administering ANP to humans, we decided to investigate the safety and diuretic antihypertensive effects of ANP by intravenously injecting filtered ANP dissolved in saline into myself and my co-researchers. I was the first subject for the human administration trial, fitted with a urethral catheter for precise measurements of urine output while my blood pressure was monitored. The plan was to gradually increase the amount of ANP injected from one-tenth of the effective dose predicted by rat experiments, and we were able to determine the effective dose in humans [32]. I still remember the excitement when my urine output significantly increased with the intravenous injection of an appropriate dose of ANP. This marked the first step toward the clinical application of ANP as a heart failure treatment [31, 32]. I fondly recall the challenges of submitting to journals of the American Heart Association (AHA), such as Circulation, Circulation Research, and Hypertension, while learning how to use the specialized terminology from the Journal of Clinical Endocrinology & Metabolism, and Endocrinology, which are the leading journals in endocrinology and metabolism published by Endocrine Society [30, 31]. We struggled with the differences in terminology. Considering the short half-life of peptide hormones, we avoided bolus injection and chose drip infusion, which was the correct decision based on an understanding of physiological effects and an emphasis on safety [31-34]. Later, in clinical trials in the U.S., bolus injections of BNP, which has a relative longer half-life compared to ANP [34], revealed side effects such as acute kidney failure, resulting in the discontinuation of BNP products. This outcome was predictable and was something we feared based on our experience [32, 33]. While both ANP and BNP act on the same receptor, Guanylate Cyclase A, the successful clinical application of ANP therapy in Japan and the discontinuation of BNP therapy in Western countries likely were caused by considerations regarding physiological concentration in dose settings and choices in administration methods [31-34].

I have many memories of developing the BNP assay [34-36]. Although BNP was discovered in pig brains, it was barely detected in the brains of humans, rats, or mice. Across species, BNP was primarily detected in the heart ventricles [9-13, 34-38]. The initial discovery that the ventricles, rather than the brain, were the main organ producing BNP strongly highlighted the importance of considering species differences in BNP distribution in the body, and relates to its name (BNP, where “B” stands for brain) [9, 13, 37]. Furthermore, the amino acid sequence of BNP was found to vary significantly among species, resulting in differences in the number of constituent amino acids depending on the species [9]. This variability necessitated the development of species-specific assays [9]. The naming of CNP (where “C” stands for C-type), discovered in the brain after BNP, does not include the name of an organ. This reflects the research process for BNP described earlier, where the organ in which it was discovered differed from the primary production organ [9, 37]. Additionally, the BNP content in ventricular tissue is considerably lower compared to the ANP content in atrial tissue. Particularly in normal conditions, the BNP concentration in the ventricles is significantly lower than the ANP concentration in the atria (about one-hundredth), making it initially unexpected that blood BNP concentration would serve as an excellent biomarker reflecting the severity of heart failure. However, in patients with heart failure, blood BNP concentrations increased up to 1,000 times [9, 34-36]. It was determined that there are two types of hormone synthesis and secretion mechanisms: Regulated Secretion, where the hormone is concentrated in secretory granules after synthesis and secreted in response to a secretion stimulus, and Constitutive Secretion, where the hormone is secreted without being concentrated in secretory granules after synthesis. The atria primarily use Regulated Secretion, while the ventricles primarily use Constitutive Secretion [9].

Additionally, based on the general characteristics of endocrine organs, we initially expected that cardiac hormones might decrease or become deficient in cases of heart failure, which is a state of organ dysfunction. However, this prediction was completely disproved as we discovered that the blood BNP concentration increased dramatically in proportion to the severity of heart failure, with concentrations in severe cases reaching up to 1,000 times the normal value [34-36]. At first, we even misinterpreted this significant increase as a measurement error caused by incorrect reagents. I still remember the excitement when we confirmed the reproducibility of this drastic increase. The rise in BNP concentration was so pronounced that we thought we had failed in our measurements. We published our findings in letters to The Lancet and the New England Journal of Medicine, and a full paper in the Journal of Clinical Investigation [34-36]. Subsequently, ANP became a therapeutic drug for heart failure, and the measurement methods for ANP and BNP, particularly BNP, became indispensable diagnostic tools for heart failure in routine clinical practice and are now widely used around the world [9, 34-36].

By around this time, our laboratory had also become proficient in gene manipulation techniques using molecular biological methods, leading to the development and analysis of mice overexpressing BNP [38, 39], BNP knockout mice [40], CNP knockout mice [41], and mice overexpressing CNP [42, 43]. Then, we discovered the powerful effect of CNP on promoting endochondral bone formation [41-43]. The effect was so strong that we were unsure how to describe the phenotype in our papers, and I even brought X-ray photographs to an international conference to discretely show bone experts and seek their comments. Furthermore, in contrast to BNP, there was little species difference in the distribution of CNP in the body. The discovery of CNP as the main natriuretic peptide in the brain [9, 44] and its production by vascular endothelial cells [9, 45-47], as well as research on the physiological significance of CNP as an endothelial cell-derived vasorelaxant peptide, were unexpected developments early in our research [9, 13, 44-51]. The rigorous analysis of CNP’s significance as a hypotensive factor [48], its roles in vascular remodeling [49-51], and the pathophysiological significance of reduced CNP in atherosclerotic lesions [9, 51] are very interesting topics for future research. In particular, the severe dwarfism in systemic knockout (KO) mice made it difficult to perform detailed analysis. The development and practical application of methods for high-sensitivity measurements of CNP in blood are expected to provide insights for future investigations [52, 53].

As we proposed, CNP analogs were approved as a treatment for achondroplasia in Europe and the United States in 2021, and in Japan in 2022 [9, 42, 43]. The effect of CNP on promoting endochondral bone formation is extremely powerful [41-43], and in clinical application, emphasis is placed on safety, with treatment expected to cover a sufficiently long period corresponding to the growth phase.

The fact that we survived the intense cutthroat competition in the TR on the NP family described above was due to the hard work of our co-researchers and fortunate encounters. Around this time, the term TR had become widespread, and our clinical medical research activities as Physician-Scientists, focusing on animal models and patients aiming for clinical application, had become the most suitable term for us (Fig. 12) [9, 13].

We developed a hypothesis based on a summary of our research findings on the NP system. By elucidating the detailed distribution of the NP system as a cardiovascular hormone and as a neuropeptide [9-13], as well as their complementary physiological significance, we were able to propose the antagonistic relationship between the NP system and the renin-angiotensin system (RA system) in regulating blood pressure and fluid volume [9-13]. We were invited to present this hypothesis at the Gordon Conference (Fig. 21).

Fig. 21  Gordon Research Conference in 1989 entitled by Angiotensin Central and Peripheral Mechanism of Action, Oxnard, California. USA

Besides research on the significance of the opioid peptide and NP systems, I was also in charge of posterior pituitary gland disorders in neuroendocrine diseases. Although idiopathic diabetes insipidus is a rare disease, there were frequent cases at Kyoto University Hospital, and we focused on it as an idiopathic diabetes insipidus (of unknown cause). Many of the patients were from Osaka Prefecture, and I recall a middle-aged female patient who complained that she couldn’t commute or go out using private railways due to frequent urination because there were no toilets on their trains. Although her condition was diagnosed as idiopathic, a tendency for enlargement of the infundibulum was found on MRI. As her attending physician, I was concerned about how much further testing should be conducted, and eventually consulted a neurosurgeon. The consultation was about whether the patient should undergo a biopsy. After a lengthy discussion, the decision was made to proceed with the biopsy. The histological findings showed characteristic lymphocytic infiltration, and I intuitively felt that it was essentially similar to the lesion found in the chronic thyroiditis discovered by Dr. Hakaru Hashimoto. The results compiled from cases collected at the Second Department of Internal Medicine were published in the New England Journal of Medicine with Professor Imura as the lead author [54].

5.  Appointment as Professor, and Research on ANP, BNP, CNP, and Leptin

In October 1992, at the age of 44, I was selected as a professor of the Second Department of Internal Medicine at Kyoto University and assumed the position in December. In addition to TR on the natriuretic peptide (NP) family, I explored novel hormones that could be targets for related new TR fields. In 1994, the discovery by Prof. J. M. Friedman of leptin, a hormone derived from fat cells having anti-obesity effects, from the analysis of the etiologic gene of genetically obese mice (ob/ob mice), became an attractive “novel hormone” for concurrent research alongside the NP family (Fig. 14) [9, 55]. This was due to the global rise in obesity (or obesity-related conditions) and the need to overcome it, as obesity is now attracting attention as a risk factor for atherosclerosis and as a fundamental pathology of lifestyle-related diseases. Genetically deficient mice, such as hereditary obese mice (ob/ob and db/db) and hereditary obese rats (fa/fa rat, Koretsky rat), were highly valued as disease model animals. Furthermore, since ob/ob and db/db mice were deficient in the leptin gene and leptin receptor gene, respectively, there was no need to develop new knockout model mice. We began by creating leptin overexpressing transgenic mice [56]. Furthermore, to analyze rat disease models, we first cloned the rat leptin gene and confirmed the leptin gene mutation and significant overexpression in Zucker obese rats (fa/fa) [57]. We extensively studied the distribution of leptin in the bodies of humans, mice, and rats, discovering leptin production from the human placenta [58], and reporting its production and elevated blood leptin concentrations in choriocarcinoma [59]. Additionally, we discovered that spontaneously hypertensive rats (SHR) exhibiting obesity (Koretsky rat) had a nonsense mutation in the leptin receptor [60].

For the purpose of breeding with disease model mice, similar to the NP family, we decided to use the liver as the organ for leptin gene expression in leptin overexpressing transgenic mice (Tg). The liver was suitable for processing precursor proteins and regulating hormone expression, allowing us to develop mouse strains with blood leptin concentrations comparable to those of obese human individuals [56]. The phenotype of the Tg mice was also remarkable. Upon dissection, all body fat was absent, resulting in literally skinny mice that we named “skinny mice” [57]. Although easier said than done, without careful observation or weight measurement, it was difficult to identify the phenotype in furred mice unless they were dissected.

These skinny mice gradually developed leptin resistance and became obese when subjected to a high-fat diet [9, 61], which is consistent with human obesity, where leptin action is diminished and leptin resistance is observed [9]. In the leptin Tg skinny mice, we observed anti-diabetic effects [57], blood pressure elevation due to sympathetic nervous system activation [62], enhanced lipid metabolism [63], and precocious puberty followed by hypogonadism [64]. Furthermore, in crossbreeding experiments between generalized lipodystrophy (GLD) model mice and “skinny mice,” the severe insulin resistance, impaired glucose tolerance, dyslipidemia, and fatty liver observed in GLD model mice were remarkably normalized [65].

At this point, we shifted the target disease for a potential breakthrough in leptin TR from obesity to lipodystrophy (Fig. 22) [9, 65]. After the publication of the paper on the normalization of insulin-resistant diabetes in GLD model mice through crossbreeding with skinny mice [65], we began to receive an increasing number of patient referrals from within Japan. Following a six-month review by the ethics committee, we were able to start leptin replacement therapy for lipodystrophy in a 12-year-old GLD patient, who showed dramatic improvements in diabetes, hypertriglyceridemia, and fatty liver [66, 67]. Although it was just one case, the dramatic improvement in diabetes provided a sense of success in clinical application that I had never experienced before [66, 67]. Subsequently, the number of cases increased, and stable clinical effects were evident over a five-year period. In addition to GLD, leptin replacement was also effective for diabetes and dyslipidemia in partial lipodystrophy (PLD) [67], and we obtained approval from the Pharmaceuticals and Medical Devices Agency (PMDA) for leptin replacement therapy for both GLD and PLD. In March 2014, I retired as professor of Endocrinology and Metabolism at Kyoto University (Fig. 23). Furthermore, the expansion from rare diseases to common diseases has become one of our main strategies for TR of novel hormones, which I also advocated in my final lecture and retirement speech [9].

Fig. 22  Comparison in pathophysiology between obesity and generalized lipodystrophy (GLD)

Fig. 23  In 2014, I retired from Chief Professor, Department of Medicine and Clinical Science, Endocrinology and Metabolism, Kyoto University

6.  Professor Emeritus

Upon retiring at age 64 from my position as a professor of internal medicine at Kyoto University, I considered deciding my future path based on my own aptitude. Typically, clinical professors are appointed as hospital directors at affiliated hospitals of Kyoto University after retirement. However, this requires a sense of management, which I felt I lacked, given my career managing only a university laboratory and being dedicated to clinical practice, education, and research. While my 20 years as the head professor of internal medicine was by no means a short period, I felt that my time as a professor was consumed by administrative duties, leaving me without a sense of accomplishment in my research. Therefore, I decided to remain at the university after retirement to continue my unfinished research.

In order to enhance the CNP treatment method for achondroplasia, which has been successfully applied clinically, we believed it was necessary to develop a high-sensitivity CNP assay without extraction. However, compared to the blood concentrations of ANP and BNP, which are cardiac hormones [9], the blood concentration of CNP, a local regulatory factor, is estimated to be low. Therefore, the minimum sensitivity needed to be increased tenfold. Although papers on CNP blood concentration have been reported from overseas, the sensitivity of the CNP blood concentration assays that were used was clearly insufficient. Thus, the high concentration of blood CNP reported could not be considered accurate measurements. Therefore, we embarked on developing a high-sensitivity assay for CNP without extraction. To create a suitable antibody for this development, we started with three experts: Dr. Makoto Matsuyama (Shigei Medical Research Institute, Okayama), a researcher specializing in monoclonal antibody production; Dr. Naoto Minamino (Protein Research Foundation, Suita), an expert biochemist in CNP research and assay development; and myself, with extensive experience in the development and clinical application of hormone assays as biomarkers. Currently, the CNP chemiluminescent enzyme immunoassay (CLEIA) is nearly complete and was presented at the 97^th Annual Congress of the JES (2024, Yokohama) [52, 53]. I believe that the development of CNP CLEIA will be a valuable research and analysis tool, useful not only for selecting cases suitable for CNP analog treatment, which was approved last year, and monitoring treatment progress for achondroplasia, but also for elucidating the clinical significance of CNP derived from vascular endothelial cells. Of course, it will undoubtedly be useful for analyzing the clinical significance of CNP in the brain as well [9, 52, 53].

The results of leptin TR led to the approval of leptin replacement therapy for GLD and PLD in 2013 (Fig. 22) [9]. An important remaining issue is clinical research on PLD, particularly the creation of diagnostic criteria, and conducting epidemiological studies on the prevalence of this disease in Japan [68]. This is necessary to accurately understand the clinical presentation of PLD in Japanese patients, who have different lifestyles compared to Westerners, and to clarify the prevalence of PLD among Japanese diabetes patients. In PLD, Koebberling type (FPLD1) and Dunnigan type (FPLD2) are known as familial (congenital) FPLD, and other forms of FPLD caused by recessive gene mutations, such as PPAR-γ, are also known [68]. Other known acquired forms include PLD of the limbs (PLL), acquired partial lipodystrophy (APL), HIV-related PLD, and PLD associated with progeroid syndromes and autoinflammatory syndromes [69]. We discovered that the prevalence of Koebberling type FPLD1 is considerably higher than previously expected [7]. Serum leptin concentrations in all cases of GLD are below the normal reference value regardless of BMI. While serum leptin concentrations in PLD range from below normal to normal, leptin replacement therapy was effective in PLD cases with lower-than-normal leptin concentrations [66, 67, 69]. Therefore, we clarified the correlation between BMI and serum leptin values in 549 Japanese adult males and females to estimate serum leptin values corresponding to BMI. We devised a Leptin Secretion Index (LSI), calculated as the ratio of measured leptin values to estimated serum leptin values, expressed as a percentage. In the PLD group with a normal BMI (18.5–25), serum leptin values ranged from below normal to normal-low, but the LSI averaged 35%, with all cases showing an LSI below 100%. In the PLD group that exhibited obesity (BMI: 25–30) due to truncal obesity, the average LSI was 58%, indicating an upward trend compared to the PLD group with a normal BMI. However, even in this PLD group, all individuals had an LSI below 100%. The presence of these two BMI-based PLD groups suggests an intriguing pathophysiological significance regarding leptin secretion deficiency and leptin sensitivity in PLD, as indicated by the LSI. Considering these results, GLD exhibits a pathology of absolute leptin deficiency, whereas PLD corresponds to a pathology of relative leptin deficiency [7, 9, 69]. The prevalence of this condition is unexpectedly high compared to the number of patients estimated from previous case reports, suggesting a potential prevalence of at least about 1% of the total number of Japanese diabetes patients [68]. Further large-scale epidemiological studies should be conducted in the future, but PLD is likely a major disease among diabetes in the third category, excluding type 1 and type 2 diabetes [68, 69].

While I have previously focused my research on lifestyle-related diseases as risk factors for atherosclerosis and have proposed countermeasures, I have recently turned my attention to the numerous lifestyle-related risk factors for Alzheimer’s disease (AD) [70]. Obesity, hypertension, diabetes, smoking, lack of exercise, and excessive alcohol consumption are known risk factors for AD. These factors overlap with the components of metabolic syndrome that we have addressed as risk factors for atherosclerosis and for which we have proposed interventions. I believe that NP and leptin TR can be applied in interventions for lifestyle diseases and dementia [9]. This is because the antihypertensive and diuretic effects of NP, its effect in suppressing vascular remodeling, and the anti-obesity and anti-diabetic effects of leptin [9] suggest the relevance of a neuroendocrine metabolic approach (e.g., oxytocin treatment) to the prevention and treatment of AD, which is characterized by metabolic abnormalities in brain amyloid proteins [71].

On New Year’s Day in 2024, while I was doing the final check of this essay, the Noto Peninsula Earthquake struck. This is the third major earthquake with a magnitude of 7 or more that we’ve experienced in the past 30 years. The 100-year history of the JES, founded shortly after the Great Kanto Earthquake, and the exemplary and resilient stress response shown by JES members in the face of such a significant earthquake stressor, alongside the cumulative efforts of all JES members over the past century, come vividly to mind.

Supplementary Fig. 1  Song lyrics of “Song in praise of hormones”

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Biographies

Kazuwa Nakao

13^th, 17^th President/Honorary Member

Professor Emeritus, Kyoto University

Medical Innovation Center, Kyoto University Graduate School of Medicine

Director, Glocal Institute of Medicine, Culture and Economy, Hyogo, Japan

E-mail: [e-mail]

Careers in JES

2018– Honorary Member

2015– Senior Councilor

2011–2015 Director (General Affairs)

2009–2011 Director (Academic Affairs and Publication)

2007–2009 17^th President

2003–2007 Director (General Affairs)

2001–2003 Director (Finance)

1999–2001 13^th President

1997–1999 Director (Finance)

1985– Councilor

1975– Member

Activities in JES

2010 Chairman, Local Organizing Committee, 14^th International Congress of Endocrinology, International Society of Endocrinology

2004 Chair, 77^th Annual Congress of JES

2000 Chair, 1^st Kinki Naibunpi Taisha Forum (Annual Meeting of JES Kinki Regional Branch)

JES Awards

2003 2^nd JES Award

1987 7^th JES Research Award

Contributions to EJ

1999–2012 Associate Editor-in-Chief