Greetings and introduction to my research

I was recently added to the editorial board of Hypertension Research as an associate editor. It is a great honor, and I would like to express my deepest gratitude to Professor Kario and the members of the editorial committee for giving me this opportunity. My clinical and research activities to date have focused on the field of metabolic diseases, mainly obesity and diabetes. Therefore, I believe that I was invited to contribute to the journal as an expert in diabetes and metabolism. As a way of introducing myself to readers, I have been asked to briefly describe how my research experience is related to hypertension research.

My main research focus has been on the role of inflammatory changes in adipose tissue in the pathogenesis of insulin resistance observed in type 2 diabetes (T2D) and obesity. At the beginning of my research career, I performed several studies with cultured adipocytes that examined the mechanisms by which inflammatory cytokines suppress insulin signaling; for example, evaluating the role of some serine/threonine kinases and suppressor of cytokine signaling (SOCS) [1, 2]. At that time, I read about a study that found that in pathologically expanded adipose tissue in obesity, adipose tissue macrophages (ATMs) produce more inflammatory cytokines than large adipocytes do [3]. I was very interested in those findings and subsequently shifted my research to focus on the relationship between ATMs and metabolism.

Macrophages have a wide variety of phenotypes. Therefore, a classical taxonomy has long been used in which the characteristics of individual macrophages are represented between the typical inflammatory M1 and anti-inflammatory M2 polarities. When visceral adipose tissue exhibits pathological hypertrophy as obesity progresses, ATMs with inflammatory M1 polarity increase markedly in the tissue and promote the pathogenesis of insulin resistance and glucose intolerance. We found that flow cytometry can clearly separate ATMs into M1ATMs and M2ATMs by using the surface markers CD11c and CD206, respectively [4]. In addition, we also found that M1ATMs cluster to the hypoxic regions locally distributed in hypertrophic adipose tissue and that hypoxia-induced activation of HIF-1α signaling in ATMs is essential for the acquisition of inflammatory M1 polarity and promotion of insulin resistance [5, 6].

Furthermore, we analyzed the function of M2ATMs in adipose tissue. To comprehensively elucidate the function of M2ATMs, we generated and analyzed mice in which M2ATMs could be ablated. At that time, M2ATM was thought to play a role in maintaining and promoting insulin sensitivity due to its anti-inflammatory properties. Therefore, we expected that insulin resistance would be exacerbated by M2ATM ablation. Unexpectedly, M2ATM-ablated mice showed improved insulin resistance and glucose intolerance, and their visceral adipose tissue had an increased number of small adipocytes, which are known to have metabolically favorable functions. Our results revealed a novel function of M2ATMs, i.e., that M2ATMs suppress preadipocyte differentiation and reduce the number of small adipocytes, a function through which they are also involved in the regulation of glucose metabolism [7].

Obesity has a significant impact on the pathogenesis of hypertension, e.g., by promoting the development of hypertension and worsening blood pressure control [8]. In addition, hypertension and obesity synergistically exacerbate cardiovascular complications through common pathologies. For example, hypertension and obesity-associated heart failure together induce low-grade inflammatory changes in the myocardium and adverse cardiac remodeling. In the myocardium, M1 polarity is given to intramyocardial macrophages through mechanisms that include local hypoxia in myocardial tissue. M1 macrophages then impair myocardial contractile and diastolic functions by producing inflammatory cytokines [8]. These changes, which are seen in the process of heart failure, are highly similar to the pathological hypertrophy of visceral fat and accompanying chronic inflammation [3, 4, 9]. I hope that my above-mentioned research experience will be of some help to the further development of Hypertension Research.

Hiroshima study

Hypertension Research has published many original papers and reviews on the involvement of obesity, glucose metabolism disorders, and insulin signaling in the pathogenesis of hypertension. In 2022, Sasaki et al. published a very important article that revealed the newly discovered importance of insulin resistance in adipose tissue in the incidence and pathophysiology of hypertension [10].

Type 2 diabetes and hypertension often coexist on the background of obesity. The most accepted mechanism by which obesity leads to both conditions is that visceral fat accumulation and accompanying insulin resistance induce abnormal glucose metabolism and elevated blood pressure. Homeostatic Model Assessment- Insulin Resistance (HOMA-IR) and the Matsuda index have long been used as simple indices of insulin resistance. Their formulas include the product of glucose and insulin concentrations, i.e., HOMA-IR is fasting plasma glucose × fasting insulin divided by 405, and the Matsuda index is 10,000 divided by the square root of fasting plasma glucose × fasting insulin × 2-h post-load glucose × 2-h post-load insulin. These indices are based on the idea that insulin resistance is a state in which plasma glucose levels cannot be lowered even when the insulin concentration increases. The liver, skeletal muscle, and adipocytes are the target organs for glucose metabolism regulated by insulin. Plasma glucose concentrations in fasting conditions and after glucose load are mainly determined by hepatic gluconeogenesis and glucose uptake into skeletal muscle, respectively. Therefore, HOMA-IR, which is calculated from fasting blood glucose and insulin, is considered mainly to be an index of insulin resistance in the liver, whereas the Matsuda index, which is calculated from fasting and post-load glucose and insulin, is considered mainly to be an index of insulin resistance in the liver and muscle. Insulin resistance is assumed when the HOMA-IR value is high or the Matsuda index is low. On the other hand, the main actions of insulin in adipocytes are to promote lipogenesis and suppress lipolysis. When the actions of insulin in adipocytes decrease, lipolysis is enhanced and free fatty acids are released into the blood. Consequently, Adipo-IR (fasting insulin [μU/mL] × free fatty acid [mmol/L]) was developed as an index of the insulin resistance in adipose tissue.

In their article, Sasaki et al. investigated the significance of tissue-specific insulin resistance in predicting the onset of hypertension [10]. They used Adipo-IR as an index of adipose tissue insulin resistance, and HOMA-IR and the Matsuda index as indices of liver and liver + muscle insulin resistance. Their cross-sectional study analyzed 3,948 individuals without hypertension and cardiovascular diseases from a regional cohort (Hiroshima Study on Glucose Metabolism and Cardiovascular Disease). The group found that Adipo-IR correlated with systolic blood pressure as well as HOMA-IR and the Matsuda index, so they concluded that blood pressure control is associated with insulin resistance regardless of the tissue. The retrospective cohort study had a mean follow-up of 5.3 years, during which time 1310 people developed hypertension. The onset of hypertension correlated with high Adipo-IR values, but not with HOMA-IR or the Matsuda index. Furthermore, there was no difference in the odds of predicting hypertension when a high Adipo-IR value was combined with either a high HOMA-IR or a low Matsuda index. The authors concluded from these results that the risk of developing hypertension is associated with insulin resistance in adipose tissue but not liver or muscle. Interestingly, the high Adipo-IR group had a higher proportion of individuals with normal glucose tolerance at baseline and a lower proportion of individuals with prediabetes or diabetes than the high HOMA-IR and low Matsuda index groups. These results suggest that among the three indices compared in this study, Adipo-IR is the first to increase in patients with a history of glucose intolerance and that Adipo-IR can be used as a new and useful index that can identify people at high risk for developing hypertension before they develop impaired glucose tolerance [10].

Despite the interesting results of this study, it remains unclear how insulin resistance in adipose tissue is related to the later development of hypertension. The authors discussed that the formula for calculating Adipo-IR includes insulin and free fatty acids but suggested that hyperinsulinemia may be less involved in the process. One of the reasons for their hypothesis is that HOMA-IR and the Matsuda index, which include insulin levels in their formulas, did not predict the risk of developing hypertension in this study. On the other hand, the authors speculated that serum free fatty acid, which is included only in Adipo-IR and is an index of adipose tissue-specific actions of insulin, might contribute more to the development of hypertension.

In addition to hyperinsulinemia and high free fatty acid levels, various pathological changes inside and outside adipose tissue occur during the period when Adipo-IR is elevated. Personally, I am very interested in how those pathological changes might be related to the development of hypertension. Chronic inflammation of obese adipose tissue might also be a candidate. This article provided insights into a very important and interesting topic not only for hypertension specialists but also for metabolic specialists, especially those who study adipose tissue, and I look forward to the findings of future research that addresses the important issues and questions it raised.