Yuji Matsuzawa Talks about Metabolic Syndrome in Japan

Special Topic of Metabolic Syndrome Interview, August 2011

Yuji Matsuzawa

In our Special Topics analysis of Metabolic Syndrome research over the past decade, the work of Dr. Yuji Matsuzawa ranks at #10 by total papers and #16 by total cites, based on 58 papers cited a total of 3,339 times. His work ranks in the top 1% in the fields of Clinical Medicine and Biology & Biochemistry in Essential Science IndicatorsSM from Clarivate Analytics.

Matsuzawa is Director of Sumitomo Hospital in Osaka, Japan. He is also Professor Emeritus at Osaka University. He is also the President of the Japan Atherosclerosis Society, the Japan Society for the Study of Obesity, and the Japanese Society of Molecular Medicine.

In this interview, he talks with ScienceWatch.com about his highly cited work as it relates to metabolic syndrome.

SW: Please tell us about your educational background and research experiences.

I graduated from Osaka University Medical School in 1966 and joined a research group called the Lipid Research Laboratory of the Second Department of Internal Medicine, Osaka University, in 1969. I have long worked on hyperlipidemia and obesity. Previously, we discovered several novel disease entities, such as "Autoimmune hyperchylomicrolemia" (N. Engl. J. Med. 320[19]: 1255-9, 11 May 1989) and "HyperHDLcholesterolemia caused by cholesteryl ester transfer protein (CETP)" (Atherosclerosis 53[2]: 207-12, 1984; J. Clin. Invest. 92[4]: 2060-4, October 1993).

We are also interested in body fat distribution of obesity with respect to morbidity, because the prevalence of obesity-related diseases, such as type 2 diabetes and hypertension, is very high in Japan, whereas the prevalence of obesity is much lower than in western countries. Then we developed the method for adipose tissue analysis using CT scan in 1983 (Int. J. Obes. 7[5]: 437-45, 1983), which enabled us to determine visceral fat and subcutaneous fat separately. Then we found that visceral fat accumulation closely correlated to the development of type 2 diabetes, dyslipidemia, hypertension, and also cardiovascular disease, and proposed the concept of visceral fat syndrome (Metabolism 36[1]: 54-9, January 1987).

Based on these clinical studies, we started the investigation of expressed genes in adipocytes by large-scale random sequence analysis in order to clarify biological characteristics of both visceral adipose tissue and subcutaneous adipose tissue. This project revealed that adipose tissue abundantly expressed the genes encoding bioactive substances such as cytokines, growth factors, and complements, which were named "adipocytokines or adipokines" (Gene 190: 227, 1997; Nature Med. 2[7]: 800-3, 1996). During this project, we discovered a very important novel collagen-like protein and named "adiponectin." This protein became one of the key players in the mechanism of the metabolic syndrome later.

SW: What first drew you to work with metabolic syndrome?

The syndrome entity named metabolic syndrome was proposed by several groups as an atherogenic syndrome with multiple risk factors. However, there has not been consensus about the primary cause of the multiple risk factors and also cardiovascular disease, although obesity, especially abdominal obesity, and insulin resistance may be considered to play an important role.

"Although the prevalence of massive obesity is much lower in Japan than in western countries, the prevalence of obesity-related diseases such as type 2 diabetes or hypertension is very frequent with the increase of mild obese subjects with visceral fat accumulation."

We considered that metabolic syndrome should be classified as a multiple risk factor clustering syndrome caused by visceral fat accumulation from those in which multiple risk factors gather coincidently. Then we can choose the group in which the reduction of visceral fat by diet control and physical exercise becomes a very effective measure for the reduction of multiple risks. So we have emphasized the importance of visceral fat in metabolic syndrome.

SW: One of your highly cited original articles in the 2004 Circulation Journal paper you coauthored, "Adiponectin as a biomarker of the metabolic syndrome," (Ryo M, et al., 68[11]: 975-81, November 2004). Would you tell us a bit about this paper—your expectations going in, your findings, where this work has gone since this publication?

A total 661 Japanese adults (471 men, 53+/-10 years, 182 women, 56+/-10 years) who took an annual health examination were enrolled. Plasma adiponectin levels correlated negatively with waist circumference, visceral fat area determined by CT scan, serum triglyceride, fasting blood glucose, fasting plasma insulin, and blood pressure in both sexes.

A positive correlation was found between plasma adiponectin concentrations and high-density lipoprotein cholesterol in both sexes. The mean number of components of the metabolic syndrome increased as the metabolic syndrome increased as the plasma adiponectin concentration decreased: #2.57+/-1.34 for men and #2.00+/-1.54 for women with adiponectin concentrations < 4.0 µg/ml. In all, 52.8% of men and 37.5% of women with adiponectin concentration < 4.0 µg/ml fulfilled the criteria for metabolic syndrome.

From this paper and our previous clinical studies on adiponectin, I proposed the clinical disease entity hypoadiponectinemia be named as one of the major background factors for metabolic syndrome and also several lifestyle-related diseases. Recently, several health check laboratories in Japan have adopted adiponectin determination as well as plasma lipids or glucose determination.

SW: Last year, you coauthored a study in the Journal of Atherosclerosis and Thrombosis "Absolute value of bioelectrical impedance analysis measured visceral fat area with obesity-related cardiovascular risk factors in Japanese workers," (Okauchi Y, et al., 17[12]: 1237-45, 2010). Please tell us about this research.

We measured the visceral fat area of 2,870 middle-aged Japanese employees (males/females, 2,322/548) using a novel method for determination of abdominal visceral fat by bioelectric impedance developed by our group (Diabetes Care 28[2]: 451-3, February 2005) and analyzed its correlation to the prevalence of obesity-related cardiovascular risks.

In the receiver operating characteristics (ROC) curve, the cutoff levels yielding maximal sensitivity plus specificity for predicting of >2 risks were 111 cm2 for visceral fat area in males and 67 cm2 in females. However the average number of risk factor was over 1.0 in those with VFA over 100 cm2 in both males and females and it was around 1.0 with cutoff levels from ROC curve in males, but 0.6 with cutoff levels from ROC curve in females.

From these results we proposed the cutoff levels for visceral fat reduction should be set based on an absolute value of risk factors, rather than a calculated value in regular health check-ups because the prevalence of subjects with obesity and multiple risks was very low in Japanese females. We proposed in this paper that it may be practical and useful to set an absolute cutoff value for VFA at 100 cm2 in both sexes as criteria for multiple obesity-related cardiovascular risk factors.

SW: How big of a societal problem/threat is metabolic syndrome in Japan compared with the rest of the world?

Although the prevalence of massive obesity is much lower in Japan than in western countries, the prevalence of obesity-related diseases such as type 2 diabetes or hypertension is very frequent with the increase of mild obese subjects with visceral fat accumulation. So the prevalence of metabolic syndrome is estimated to be 25% in males and 10% in females.

"…we have emphasized the importance of visceral fat in metabolic syndrome."

The government started a national health policy against the metabolic syndrome in 2008 called "Tokutei Kenshin and Tokutei Shidou" (specific examination and specific counseling) and health insurers were made responsible for conducting a specific checkup and counseling. Through this policy, all Japanese aged 40-74 years (56 million people) covered by the public insurance scheme can take examination, including waist circumference, every year, and the subjects who are diagnosed to have metabolic syndrome should take the specific counseling for the modification of lifestyle to reduce waist circumference by specialists for metabolic syndrome.

We expect the reduction of lifestyle-related diseases including cardiovascular disease and the government expects to control the increased medical costs of lifestyle-related diseases with this nationwide project. One of our pilot studies performed in one urban city demonstrated that the extent of reduction of visceral adiposity clearly correlated with the improvement of risk factors (Diabetes Care 30[9]: 2392-4, September 2007).

SW: How the field as a whole changed over the past 10 years? Would you say we are in a better position today in terms of our knowledge of metabolic syndrome than we were in the 1990s? Why or why not?

The concept of metabolic syndrome was first proposed as a multiple risk factor clustering syndrome, such as Syndrome X, focusing on insulin resistance as a key player. Although it is true that insulin resistance plays an important role in this syndrome, it was not enough to explain the mechanism of a variety of cardiovascular risks.

Since visceral fat or abdominal fat has become noted as a key player for multiple risks and also atherosclerosis, many institutes, including ours, started the characterization of adipose tissue function as we mentioned previously. Then leptin and adiponectin were discovered, TNFa and PAI-1 were found to be secreted from adipose tissue in 1994-1997, and the concept of adipocytokines (adipokines) was proposed in the end of 1990s. After that, the mechanism of metabolic syndrome has become more clearly understood.

We call this kind of research strategy "Adiposcience," and we can say progress in Adiposcience has been remarkable in this decade.

SW: Where do you hope to see this research go in the next decade?

In the present, the management of the metabolic syndrome is to normalize adipocytokine secretion; for example, to reduce the secretion of TNFa or to increase the secretion of adiponectin by the reduction of visceral adiposity through diet control or physical exercise. But in the future, we hope that new therapeutic strategies for regulating adipocytokine secretion will be developed. In particular, drug treatments enhancing adiponectin formation and secretion will be developed in near future.End

Yuji Matsuzawa, M.D., Ph.D.
Sumitomo Hospital
Osaka University
Osaka, Japan


Weyer C, et al., "Hypoadiponectinemia in obesity and type 2 diabetes: Close association with insulin resistance and hyperinsulinemia," J. Clin. Endocrinol. Metab. 86(5): 1930-5, May 2001 with 1,483 cites. Source: Essential Science Indicators from Clarivate Analytics.



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