NFIA differentially controls adipogenic and myogenic gene program through distinct pathways to ensure brown and beige adipocyte differentiation.

The transcription factor nuclear factor I-A (NFIA) is a regulator of brown adipocyte differentiation. Here we show that the C-terminal 17 amino acid residues of NFIA (which we call pro#3 domain) are required for the transcriptional activity of NFIA. Full-length NFIA-but not deletion mutant lacking pro#3 domain-rescued impaired expression of PPARγ, the master transcriptional regulator of adipogenesis and impaired adipocyte differentiation in NFIA-knockout cells. Mechanistically, the ability of NFIA to penetrate chromatin and bind to the crucial Pparg enhancer is mediated through pro#3 domain. However, the deletion mutant still binds to Myod1 enhancer to repress expression of MyoD, the master transcriptional regulator of myogenesis as well as proximally transcribed non-coding RNA called DRReRNA, via competition with KLF5 in terms of enhancer binding, leading to suppression of myogenic gene program. Therefore, the negative effect of NFIA on the myogenic gene program is, at least partly, independent of the positive effect on PPARγ expression and its downstream adipogenic gene program. These results uncover multiple ways of action of NFIA to ensure optimal regulation of brown and beige adipocyte differentiation.

Multifactorial intervention has a significant effect on diabetic kidney disease in patients with type 2 diabetes.

To evaluate the effect of multifactorial intervention on the onset and progression of diabetic kidney disease in the patients with type 2 diabetes, we analyzed the effects of intensified multifactorial intervention by step-wise intensification of medications and life-style modifications (intensive therapy treatment targets; HbA1c under 6.2%, blood pressure under 120/75 mmHg, low-density lipoprotein cholesterol under 80 mg/dL) comparing with the guideline-based standard care (conventional therapy treatment targets: HbA1c under 6.9%, blood pressure under 130/80 mmHg, low-density lipoprotein cholesterol under 120 mg/dL) on diabetic kidney disease. A total of 2540 eligible patients in the Japan Diabetes Optimal Integrated Treatment for three major risk factors of cardiovascular diseases (J-DOIT3) cohort were randomly assigned to intensive therapy (1269) and conventional therapy (1271) and treated for a median of 8.5 years. The prespecified kidney outcome measure was a composite of progression from normoalbuminuria to microalbuminuria or progression from normoalbuminuria to macroalbuminuria or progression from microalbuminuria to macroalbuminuria, serum creatinine levels elevated by two-fold or more compared to baseline, or kidney failure. Primary analysis was carried out on the intention-to-treat population. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. A total of 438 kidney events occurred (181 in the intensive therapy group and 257 in the conventional therapy group). Intensive therapy was associated with a significant 32% reduction in kidney events compared to conventional therapy and was associated with a change in HbA1c at one year from study initiation. Thus, prespecified analysis shows that intensified multifactorial intervention significantly reduced the onset and progression of diabetic kidney disease compared to currently recommended care.

Providing Practical Knowledge and Skills to Handle Real-World Data? Lessons Learned from Med RWD Program.

Both lectures and hands-on education are essential for the development of human resources that can use real-world data (RWD). The University of Tokyo has launched a new hybrid-style RWD educational program entitled "Medical Real World Data Utilization Human Resource Development Project" from FY2019 onwards. We present an overview of the overall picture of the project, including the development process of the educational program and the challenges associated with it.

Effectiveness of DialBetesPlus, a self-management support system for diabetic kidney disease: Randomized controlled trial.

We evaluated the effectiveness of a mobile health (mHealth) intervention for diabetic kidney disease patients by conducting a 12-month randomized controlled trial among 126 type 2 diabetes mellitus patients with moderately increased albuminuria (urinary albumin-to-creatinine ratio (UACR): 30-299 mg/g creatinine) recruited from eight clinical sites in Japan. Using a Theory of Planned Behavior (TPB) behavior change theory framework, the intervention provides patients detailed information in order to improve patient control over exercise and dietary behaviors. In addition to standard care, the intervention group received DialBetesPlus, a self-management support system allowing patients to monitor exercise, blood glucose, diet, blood pressure, and body weight via a smartphone application. The primary outcome, change in UACR after 12 months (used as a surrogate measure of renal function), was 28.8% better than the control group's change (P = 0.029). Secondary outcomes also improved in the intervention group, including a 0.32-point better change in HbA1c percentage (P = 0.041). These improvements persisted when models were adjusted to account for the impacts of coadministration of drugs targeting albuminuria (GLP-1 receptor agonists, SGLT-2 inhibitors, ACE inhibitors, and ARBs) (UACR: -32.3% [95% CI: -49.2%, -9.8%] between-group difference in change, P = 0.008). Exploratory multivariate regression analysis suggests that the improvements were primarily due to levels of exercise. This is the first trial to show that a lifestyle intervention via mHealth achieved a clinically-significant improvement in moderately increased albuminuria.

Preliminary Efficacy, Feasibility, and Perceived Usefulness of a Smartphone-Based Self-Management System With Personalized Goal Setting and Feedback to Increase Step Count Among Workers With High Blood Pressure: Before-and-After Study.

BACKGROUND: High blood pressure (BP) and physical inactivity are the major risk factors for cardiovascular diseases. Mobile health is expected to support patients' self-management for improving cardiovascular health; the development of fully automated systems is necessary to minimize the workloads of health care providers. OBJECTIVE: The objective of our study was to evaluate the preliminary efficacy, feasibility, and perceived usefulness of an intervention using a novel smartphone-based self-management system (DialBetes Step) in increasing steps per day among workers with high BP. METHODS: On the basis of the Social Cognitive Theory, we developed personalized goal-setting and feedback functions and information delivery functions for increasing step count. Personalized goal setting and feedback consist of 4 components to support users' self-regulation and enhance their self-efficacy: goal setting for daily steps, positive feedback, action planning, and barrier identification and problem-solving. In the goal-setting component, users set their own step goals weekly in gradual increments based on the system's suggestion. We added these fully automated functions to an extant system with the function of self-monitoring daily step count, BP, body weight, blood glucose, exercise, and diet. We conducted a single-arm before-and-after study of workers with high BP who were willing to increase their physical activity. After an educational group session, participants used only the self-monitoring function for 2 weeks (baseline) and all functions of DialBetes Step for 24 weeks. We evaluated changes in steps per day, self-reported frequencies of self-regulation and self-management behavior, self-efficacy, and biomedical characteristics (home BP, BMI, visceral fat area, and glucose and lipid parameters) around week 6 (P1) of using the new functions and at the end of the intervention (P2). Participants rated the usefulness of the system using a paper-based questionnaire. RESULTS: We analyzed 30 participants (n=19, 63% male; mean age 52.9, SD 5.3 years); 1 (3%) participant dropped out of the intervention. The median percentage of step measurement was 97%. Compared with baseline (median 10,084 steps per day), steps per day significantly increased at P1 (median +1493 steps per day; P<.001), but the increase attenuated at P2 (median +1056 steps per day; P=.04). Frequencies of self-regulation and self-management behavior increased at P1 and P2. Goal-related self-efficacy tended to increase at P2 (median +5%; P=.05). Home BP substantially decreased only at P2. Of the other biomedical characteristics, BMI decreased significantly at P1 (P<.001) and P2 (P=.001), and high-density lipoprotein cholesterol increased significantly only at P1 (P<.001). DialBetes Step was rated as useful or moderately useful by 97% (28/29) of the participants. CONCLUSIONS: DialBetes Step intervention might be a feasible and useful way of increasing workers' step count for a short period and, consequently, improving their BP and BMI; self-efficacy-enhancing techniques of the system should be improved.

The Use of Information and Communication Technology-Based Self-management System DialBeticsLite in Treating Abdominal Obesity in Japanese Office Workers: Prospective Single-Arm Pilot Intervention Study.

BACKGROUND: Making lifestyle changes is an essential element of abdominal obesity (AO) reduction. To support lifestyle modification and self-management, we developed an information and communication technology-based self-management system-DialBeticsLite-with a fully automated dietary evaluation function for the treatment of AO. OBJECTIVE: The objective of this study was to evaluate the preliminary efficacy and feasibility of DialBeticsLite among Japanese office workers with AO. METHODS: A 2- to 3-month prospective single-arm pilot intervention study was designed to assess the effects of the intervention using DialBeticsLite. The information and communication technology system was composed of 4 modules: data transmission (body weight, blood pressure, blood glucose, and pedometer count); data evaluation; exercise input; and food recording and dietary evaluation. Eligible participants were workers who were aged ≥20 years and with AO (waist circumference ≥85 cm for men and ≥90 cm for women). Physical parameters, blood tests, nutritional intake, and self-care behavior were compared at baseline and after the intervention. RESULTS: A total of 48 participants provided completed data for analysis, which yielded a study retention rate of 100%. The average age was 46.8 (SD 6.8) years, and 92% (44/48) of participants were male. The overall average measurement rate of DialBeticsLite, calculated by dividing the number of days with at least one measurement by the number of days of the intervention, was 98.6% (SD 3.4%). In total, 85% (41/48) of the participants reported that their participation in the study helped them to improve their lifestyle. BMI, waist circumference, and visceral fat area decreased significantly after the intervention (P<.001). In addition, the daily calorie intake reduced significantly (P=.02). There was a significant improvement in self-care behavior in terms of exercise and diet (P=.001). CONCLUSIONS: Using DialBeticsLite was shown to be a feasible and potentially effective method for reducing AO by providing users with a motivational framework to evaluate their lifestyle behaviors.

Chronic oestrogen replacement in ovariectomised rats attenuates food intake and augments c-Fos expression in the suprachiasmatic nucleus specifically during the light phase.

Oestrogen replacement in ovariectomised (OVX) rats has been reported to attenuate food intake, especially during the light phase. To gain better insight into the central mechanism of oestrogen-induced reduction of food intake, we examined the effect of chronic oestrogen replacement in OVX rats on c-Fos expression in the suprachiasmatic nucleus (SCN) and on food intake during the light and dark phases. Eight-week-old female rats were ovariectomised and implanted with either an oestradiol (E2) or a vehicle pellet (Veh) subcutaneously. The animals were housed in an environment with a 12 h light-12 h dark cycle with the lights on at 07.00 hours. The amount of spontaneous food intake relative to each animal's body weight was significantly less for the E2 group than for the Veh group during the light phase, but there were no differences shown between these groups during the dark phase. There were no differences shown in the number of c-Fos-immunoreactive cells in the SCN in the E2 group compared with the Veh group during the early dark phase (22.00 hours; Zeitgeber time 15.00 (ZT15)), but the number was significantly higher than in the Veh group during the early light phase (10.00 hours; ZT3). This finding suggests that chronic oestrogen replacement chronically enhances SCN activity, specifically during the light phase. The oestrogen-induced enhancement of SCN activity during the light phase is possibly involved in the light phase-specific attenuation of food intake by oestrogen replacement in OVX rats.

Effect of a Multifactorial Intervention on Fracture in Patients With Type 2 Diabetes: Subanalysis of the J-DOIT3 Study.

AIMS: To evaluate the effects of an intensified multifactorial intervention and patient characteristics on the incidence of fractures comorbid with type 2 diabetes. METHODS: Fracture events were identified and analyzed among adverse events reported in the J-DOIT3 study, a multicenter, open-label, randomized, parallel-group trial that was conducted in Japan, in which patients with type 2 diabetes were randomly assigned to receive conventional therapy for glucose, blood pressure, and lipids (targets: HbA1c < 6.9%, blood pressure <130/80 mm Hg, LDL-cholesterol <120mg/dL) or intensive therapy (HbA1c < 6.2%, blood pressure <120/75 mm Hg, LDL-cholesterol <80mg/dL) (ClinicalTrials.gov registration no. NCT00300976). RESULTS: The cumulative incidence of fractures did not differ between those receiving conventional therapy and those receiving intensive therapy (hazard ratio (HR) 1.15; 95% CI, 0.91-1.47; P = 0.241). Among the potential risk factors, only history of smoking at baseline was significantly associated with the incidence of fractures in men (HR 1.96; 95% CI, 1.04-3.07; P = 0.038). In contrast, the incidence of fractures in women was associated with the FRAX score [%/10 years] at baseline (HR 1.04; 95% CI, 1.02-1.07; P < 0.001) and administration of pioglitazone at 1 year after randomization (HR 1.59; 95% CI, 1.06-2.38; P = 0.025). CONCLUSIONS: Intensified multifactorial intervention may be implemented without increasing the fracture risk in patients with type 2 diabetes. The fracture risk is elevated in those with a history of smoking in men, whereas it is predicted by the FRAX score and is independently elevated with administration of pioglitazone in women.

Efficacy of the Self-management Support System DialBetesPlus for Diabetic Kidney Disease: Protocol for a Randomized Controlled Trial.

BACKGROUND: Diabetic kidney disease (DKD) is one of the main complications of type 2 diabetes mellitus (T2DM). DKD is a known risk factor for end-stage renal disease, cardiovascular disease, and all-cause death. Effective intervention for early-stage DKD is vital to slowing down the progression of kidney disease and improve prognoses. Mobile health (mHealth) is reportedly effective in supporting patients' self-care and improving glycemic control, but the impact of mHealth on DKD has yet to be shown. OBJECTIVE: The purpose of this study is to evaluate the efficacy of standard therapy with the addition of a self-management support system, DialBetesPlus, in patients with DKD and microalbuminuria. METHODS: This study is a prospective, randomized, open-label, multicenter clinical trial. The target population consists of 160 patients diagnosed with T2DM accompanied by microalbuminuria. We randomly assigned the patients to 2 groups-the intervention group using DialBetesPlus in addition to conventional therapy and the control group using conventional therapy alone. DialBetesPlus is a smartphone application that supports patients' self-management of T2DM. The study period was 12 months, with a follow-up survey at 18 months. The primary outcome was a change in albuminuria levels at 12 months. Secondary outcomes included changes in physical parameters, blood test results (glycemic control, renal function, and lipid metabolism), lifestyle habits, self-management scores, medication therapy, and quality of life. RESULTS: The study was approved in April 2018. We began recruiting patients in July 2018 and completed recruiting in August 2019. The final 18-month follow-up was conducted in March 2021. We recruited 159 patients and randomly allocated 70 into the intervention group and 61 into the control group, with 28 exclusions due to withdrawal of consent, refusal to continue, or ineligibility. The first results are expected to be available in 2021. CONCLUSIONS: This is the first randomized controlled trial assessing the efficacy of mHealth on early-stage DKD. We expect that albuminuria levels will decrease significantly in the intervention group due to improved glycemic control with ameliorated self-care behaviors. TRIAL REGISTRATION: UMIN-CTR UMIN000033261; https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000037924. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31061.

NFIA co-localizes with PPARγ and transcriptionally controls the brown fat gene program.

Brown fat dissipates energy as heat and protects against obesity. Here, we identified nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of brown-fat-specific open chromatin regions. NFIA and the master transcriptional regulator of adipogenesis, PPARγ, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARγ, leading to increased chromatin accessibility and active transcription. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA-knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Finally, expression of NFIA and the brown-fat-specific genes is positively correlated in human brown fat. These results indicate that NFIA activates the cell-type-specific enhancers and facilitates the binding of PPARγ to control the brown fat gene program.