Deficiency of p62/Sequestosome 1 causes hyperphagia due to leptin resistance in the brain.

The cytoplasmic regulatory protein p62 (Sequestosome 1/A170) is known to modulate various receptor-mediated intracellular signaling pathways. p62 deficiency was shown to result in mature-onset obesity in mice, but the mechanisms underlying this abnormality remained unclear. Here we report that hyperphagia due to central leptin resistance is the cause of obesity in p62(-/-) mice. We found that these mice show hyperphagia. Restriction of food to the amount eaten by wild-type mice prevented excess body weight gain and fat accumulation, suggesting that overfeeding is the primary cause of obesity in p62(-/-) mice. Brain-specific p62 deficiency caused mature-onset obesity to the same extent as in p62(-/-) mice, further supporting a neuronal mechanism as the major cause of obesity in these mice. Immunohistochemical analysis revealed that p62 is highly expressed in hypothalamic neurons, including POMC neurons in the arcuate nucleus. Central leptin resistance was observed even in young preobese p62(-/-) mice. We found a defect in intracellular distribution of the transcription factor Stat3, which is essential for the action of leptin, in p62(-/-) mice. These results indicate that brain p62 plays an important role in bodyweight control by modulating the central leptin-signaling pathway and that lack of p62 in the brain causes leptin resistance, leading to hyperphagia. Thus, p62 could be a clinical target for treating obesity and metabolic syndrome.

Magnesium intake and risk of self-reported type 2 diabetes among Japanese.

OBJECTIVE: Dietary magnesium intake has been associated with a reduced risk of type 2 diabetes in western populations, but the evidence is limited in Asian populations. METHODS: We assessed the relationship between dietary magnesium intake and risk of diabetes in a cohort of 17,592 individuals (6480 men and 11,112 women) aged 40-65, free of a history of diabetes or other chronic disease at the time of the baseline lifestyle survey, who completed a 5-year follow-up questionnaire. Dietary magnesium was calculated by using a validated questionnaire, and the incidence of diabetes was defined by self-report of physician diagnosis. Associations between dietary magnesium and diabetes incidence were evaluated using a logistic regression model. RESULTS: We found 459 self-reported new cases of diabetes (237 men and 222 women) at the 5-year follow-up. Dietary intake of magnesium was inversely associated with age- and body mass index (BMI)-adjusted diabetes incidence in both sexes. In multivariable analysis that adjusted further for cardiovascular risk factors, the association was weakened in both sexes, but the association in total participants remained statistically significant. The odds ratios of diabetes with reference to the lowest quartile of magnesium intake were 0.83 (95% confidence interval [CI], 0.69 to 1.09) for the second quartile, 0.79 (95% CI, 0.59 to 1.07) for the third quartile, and 0.64 (95% CI, 0.44 to 0.94) for the highest quartile of magnesium intake (p for trend = 0.04). CONCLUSIONS: Dietary intake of magnesium was associated with a reduced risk of type 2 diabetes in Japanese populations.

Soy product and isoflavone intakes are associated with a lower risk of type 2 diabetes in overweight Japanese women.

Isoflavones have been shown to improve glucose metabolism, but epidemiologic data are limited. We prospectively investigated the relationship between soy product and isoflavone intake and the risk of developing type 2 diabetes among Japanese adults. Participants were 25,872 men and 33,919 women aged 45-75 y, who participated in the second survey of the Japan Public Health Center-Based Prospective Study and had no history of diabetes. Soy product and isoflavone intakes were ascertained using a 147-item FFQ. Odds ratios of self-reported, physician-diagnosed type 2 diabetes over 5 y were estimated using logistic regression analysis. A total of 1114 new cases of type 2 diabetes were self-reported. Intakes of soy products and isoflavones were not significantly associated with type 2 diabetes in either men or all women. However, among overweight women (BMI > or = 25 kg/m(2)), a higher intake of soy products was associated with a lower risk of type 2 diabetes; multivariable-adjusted odds ratios (95% CI) for the lowest through highest quintiles of soy product intake were 1.00 (reference), 0.78 (0.52-1.18), 0.79 (0.52-1.20), 0.62 (0.39-0.99), and 0.89 (0.55-1.44), respectively, and we found a similar risk pattern for daidzein and genistein intakes. Overall, our results suggest that there are no benefits of soy product or isoflavone intake with respect to risk of type 2 diabetes in either men or women. The possible protective associations of soy and isoflavone intakes among overweight women deserves further investigation.

Associations between cardiovascular risk factors and carotid atherosclerosis in middle-aged Japanese men with multiple risk factors.

To examine the relationship between cardiovascular risk factors and prevalence of carotid atherosclerosis in Japanese middle-aged men with multiple risk factors, 110 Japanese men aged 36 to 60 yr were recruited based on the presence of all of the following factors detected during a screening survey: 1) body mass index (BMI) > or = 25 kg/m2; 2) systolic blood pressure (SBP) > or = 140 mmHg and/or diastolic blood pressure > or = 90 mmHg; 3) serum levels of triglycerides (TG) > or = 150 mg/dl and/or total cholesterol (T-ChoL) levels > or = 220 mg/dl and/or high density lipoprotein cholesterol (HDL-C) levels < 40 mg/dl; and 4) fasting serum glucose > or = 110 mg/dl and/or hemoglobin A1C > or = 5.6%. After adjustment for age and cardiovascular risk factors, the odds ratio (95% confidence interval) of carotid atherosclerosis associated with a 1-SD increment in HDL-C was 0.4 (95%CI: 0.2 to 0.9). We also detected a borderline association for anti-hypertension medication use, an indicator for advanced hypertension, with an odds ratio of 2.7 (95%CI: 1.0 to 7.4) after multivariable adjustment. The other risk factors, i.e. BMI, SBP, T-ChoL, TG, diabetes, smoking and drinking status did not show significant associations with carotid atherosclerosis. In conclusion, low HDL-C and advanced hypertension were significant correlates of carotid atherosclerosis for middle-aged Japanese men with multiple risk factors.

Clinical significance of measurement of resting energy expenditure in childhood.

1. Biliary atresia (BA), as a common disease in Japan, and cystic fibrosis (CF), as an extremely uncommon disease in Japan, were selected to assess the clinical significance of measurement of energy expenditure (EE). 2. Energy expenditure was significantly higher in children with BA than in normal children. 3. Measurement of EE in BA lead to clues to resolving its mechanism by novel assessment of interleukin-6 and leptin. 4. Energy expenditure in children with CF is also higher, but this has been addressed by nutritional intervention with additional calories. 5. Individualization of EE measurement is necessary in the analysis of pathological mechanisms and nutritional management of patients with both common and uncommon diseases.

CLINICAL SIGNIFICANCE OF MEASUREMENT OF RESTING ENERGY EXPENDITURE IN CHILDHOOD.

1. Biliary atresia (BA), as a common disease in Japan, and cystic fibrosis (CF), as an extremely uncommon disease in Japan, were selected to assess the clinical significance of measurement of energy expenditure (EE). 2. Energy expenditure was significantly higher in children with BA than in normal children. 3. Measurement of EE in BA lead to clues to resolving its mechanism by novel assessment of interleukin-6 and leptin. 4. Energy expenditure in children with CF is also higher, but this has been addressed by nutritional intervention with additional calories. 5. Individualization of EE measurement is necessary in the analysis of pathological mechanisms and nutritional management of patients with both common and uncommon diseases.