The global obesity burden—spotlight on Japan

According to current estimates, 1.1 billion adults worldwide are overweight. More than 300 million people are obese.1 Western countries have been at the forefront of the obesity pandemic. In the United States, more than 60% of the population are overweight whereas 30% are obese.2, 3 However, the prevalence of overweight and obesity also increased in Japan albeit to a lesser degree than in Western countries. The National Health and Nutrition Survey Japan 2006 assessed the prevalence of lifestyle related diseases including overweight and obesity. The obesity prevalence in men had gradually increased over 20 years across all age groups. For example, in men aged 30–39 years, the obesity prevalence was 19% in 1986, 24% in 1996 and 34% in 2006. Remarkably, over 20 years, obesity prevalence had not changed in women.

Obesity is associated with markedly increased morbidity and mortality. In an analysis from the Framingham Heart Study, obesity at the age of 40 years shortened life expectancy by 5.8 years in men and 7.1 years in women.4 The Ohsaki National Health Insurance Cohort Study followed 43 972 Japanese participants aged 40–79 years.5 Of those, 5707 died during the 12 years follow-up period. After adjustment for several important confounding variables, including cigarette smoking, alcohol consumption and physical activity, excessive adiposity was associated with increased mortality in middle-aged men. The authors observed a similar trend in middle-aged women. An earlier study conducted in the Ibaraki prefecture in Japan arrived at similar conclusions.6 Finally, individuals who were normal weight at 20 years of age and subsequently became obese showed a marked increase in total mortality compared with individuals who remained weight stable.7

Cardiovascular and metabolic disease is an important but not the sole cause of excess mortality associated with overweight and obesity. The ‘Asia–Pacific Cohort Studies Collaboration’ showed that in 14 countries of the region, overweight and obesity contributed substantially to excess mortality due to stroke or myocardial infarction.8 However, the individual cardiometabolic risk varies markedly between subjects. Apparently, the same increase in adipose tissue mass can elicit different secondary cardiovascular and metabolic responses. Metabolic syndrome criteria, which are comprised of abdominal obesity, dyslipidemia, raised blood pressure and impaired glucose metabolism, identify high-risk individuals. Genetic mechanisms likely contribute to the variable expression of metabolic syndrome components among overweight and obese subjects. For example, Pima Indians show a profound increase in diabetes risk with increasing adiposity. Yet, sympathetic nervous system activity and blood pressure respond less to adiposity compared with other populations.9 Japanese people are sensitive to increased adiposity as evidenced by a recent study in children. The prevalence of the metabolic syndrome in overweight Japanese children was virtually identical to the prevalence of the metabolic syndrome in overweight children in the United States.10 Abdominal obesity increased the risk of developing arterial hypertension by 2.33-times in the Tanno–Sobetsu study.11 Moreover, in this rural population, subjects fulfilling metabolic syndrome criteria exhibited a 2.2-times greater risk of developing cardiac disease compared with subjects without the metabolic syndrome.12

Together, all these findings suggest that in Japanese people, cardiovascular and metabolic risk factors associated with excess adiposity are potentially preventable causes of increased morbidity and mortality. Indeed, the study by Masuo et al.13 in this issue supports the idea that increased physical activity and healthy nutrition may be beneficial in this setting.

A dismal kidney brain connection in obesity?

Pathophysiological and epidemiological studies suggest that obesity and metabolic syndrome are renal risk factors throughout the transition from subclinical early stages to end-stage renal disease requiring dialysis or renal transplantation. Various mechanisms may be involved. In addition to increasing the risk for arterial hypertension and diabetes mellitus, two widely appreciated risk factors for renal disease, obesity elicits an activation of the sympathetic nervous system and the renin–angiotensin system in many patients.14, 15, 16 Neurohumoral activation may elicit vascular damage and promote fibrosis in the kidney and elsewhere in the body.17 Masuo et al.13 showed that plasma norepinephrine levels were reduced following a 12-month period with mild caloric restriction and exercise. Dyslipidemia, a core feature of the metabolic syndrome, may also contribute to the progression of renal disease.18 Lipotoxicity through ectopic fat storage in the kidney as well as systemic inflammation and oxidative stress might further exacerbate renal damage in this setting.19

Increased albumin excretion is an early sign of obesity and metabolic syndrome associated renal disease. In a Japanese population based study, prevalence of microalbuminuria was positively associated with the number of metabolic syndrome criteria.20 In early stage renal disease, glomerular filtration rate is maintained or may even increase, a phenomenon commonly referred to as hyperfiltration. When renal damage progresses further, glomerular filtration rate starts to decline. In the event, presence of the metabolic syndrome increases the risk for chronic renal failure in various populations.21, 22, 23

End-stage renal disease is a catastrophic event, both, from an individual and from a societal perspective. However, most patients with obesity-associated renal disease will die from cardiovascular causes rather than from progressive renal disease. Indeed, microalbuminuria and impaired glomerular filtration rate herald poor cardiovascular outcomes. One possible explanation is that risk factors for renal disease are also associated with increased vascular damage elsewhere in the body. Furthermore, it is unlikely that target organ damage is restricted to one organ. Animal studies support this point of view as diabetes, which leads to impaired barrier function for albumin in the glomerulus, also increases albumin extravasation in the heart and in the brain.

Compared with Western countries, coronary artery disease incidence in Japan is relatively low whereas stroke incidence is remarkably high. In one study, metabolic syndrome was positively correlated with stroke risk.24 In another study, each 1 kg m−2 increase in body mass index was associated with a 4% relative risk increase experiencing a stroke.25 Ischemic stroke and renal dysfunction often occur in the same patient.26 Thus pathophysiological as well as epidemiological studies suggest that there may be an unholy alliance of renal damage and cerebrovascular disease in obese patients, particularly in those with metabolic syndrome. Lee et al.27 assessed consistency and strength of the association between microalbuminuria and stroke risk. In their meta-analysis, the authors identified 12 studies with a total of 48 596 participants and 1263 stroke events. Overall, presence of microalbuminuria, the first marker of renal impairment, was associated with greater stroke risk. Thus, frail vessels in the kidney are associated with frail vessels in the brain and vice versa.

Implications for clinical research

As renal dysfunction is more than a risk marker for end-stage renal disease, the work by Masuo et al.13 may have clinical implications beyond the nephrology community. First, the study reminds us that glomerular filtration rate is an important intermediate phenotype linking obesity and cardiovascular disease. Thus, glomerular filtration rate should be more widely adopted in obesity research.

Glomerular filtration rate can be measured in several ways. Classically, exogenous or endogenous molecules, such as creatinine, that are freely filtrated in the glomerulus and that do not undergo tubular net reabsorption or only to a limited degree are measured in urine and in plasma. Plasma and urinary concentrations and urine volume can then be applied to estimate clearance. Inulin or iothalamate infusion may be the gold standard for glomerular filtration estimates. Recently, investigators applied the so-called steady-state methodology to estimate inulin clearance based on plasma concentration and infusion rate, thus, obviating urine sampling.28 Yet, inulin infusions are time consuming and therefore difficult to apply for routine diagnostics or for larger scale clinical studies. Hence, glomerular filtration rate estimates in clinical practice are usually based on the endogenous marker creatinine and cystatin C. In practice, the collection of urine is time-consuming and fraught with errors. Indeed, collection of a complete 24-h urine sample appears to be one of the least successful clinical endeavors. Therefore, formulas have been developed that allow to estimate glomerular filtration rate from serum creatinine. The Cockcroft–Gault formula and modification of diet in renal disease have been widely applied for this purpose. However, other equations might provide an even better glomerular filtration rate estimate.29 Masuo et al.13 applied the Cockcroft–Gault formula in their study. At the end of the day, all these formulas rely on serum creatinine measurements with all its limitations. For example, muscle mass changes, which strongly affect creatinine production and may, therefore, lead to faulty glomerular filtration estimates.

Glomerular filtration rate is sometimes equated with renal function, which is an oversimplification. Indeed, kidneys have many physiological functions including the release of erythropoietin and renin, as well as finely regulated filtration, reabsorption and secretion of many important endogenous and exogenous molecules. We suggest that future studies on renal function in obesity should take into account the wide variety of renal functions.

Clinical and societal implications

It is tempting to speculate that lifestyle interventions improving glomerular filtration rate will prevent future renal and cardiovascular events including strokes. Yet, most people have difficulties maintaining weight loss in the long term with lifestyle interventions alone. So far, weight loss medications have been fraught with side effects, and disappointing in terms of risk reduction.30, 31 Bariatric surgery leads to massive weight loss but can only be applied to a small patient group.

Perhaps, changing the environment that created the obesity pandemic is a good idea. The important contribution of the environment is illustrated by a study in Okinawan immigrants. Obesity, arterial hypertension and cardiovascular damage were much less common in Okinawans living in Okinawa compared with Okinawan immigrants living in Brazil.32 Observations on childhood obesity in Japan suggest that the environment may be amenable to interventions. Obese children and adolescents are likely to become obese adults, thus, accruing cardiometabolic risk for many years. In contrast to most other countries, the obesity prevalence in Japanese children and adolescents tended to decrease in recent years.33 Japan may serve as an important role model in terms of obesity prevention early in life. Clearly, the number of obese patients requiring our attention will remain unacceptably high in years to come even in Japan. Yet, prevention rather than treatment will lead to long-term improvements in obesity prevalence and subsequently to reductions in associated diseases. An environment promoting physical activity and healthy eating is a goal worth pursuing.