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Reprogrammed Functional Brown Adipocytes Ameliorate Insulin Resistance and Dyslipidemia in Diet-Induced Obesity and Type 2 Diabetes.

ABSTRACT: Brown adipocytes (BAs) play important roles in body temperature regulation, energy balance, and carbohydrate and lipid metabolism. Activities of BAs are remarkably diminished in obese and diabetic patients, providing possibilities of transplanting functional BAs resulting in therapeutic benefit. Here, we show generation of functional BAs by cellular reprogramming procedures. Transduction of the PRDM16 gene into iPSC-derived embryoid bodies induced BA phenotypes (iBAs). Moreover, normal human fibroblasts were directly converted into BAs (dBAs) by C/EBP-β and C-MYC gene transduction. Approximately 90% of the fibroblasts were successfully converted within 12 days. The dBAs were highly active in mitochondrial biogenesis and oxidative metabolism. Mouse dBAs were induced by Prdm16, C/ebp-β, and L-myc genes, and after transplantation, they significantly reduced diet-induced obesity and insulin resistance in an UCP1-dependent manner. Thus, highly functional BAs can be generated by cellular reprogramming, suggesting a promising tailor-made cell therapy against metabolic disorders including type 2 diabetes mellitus.

SUBMITTER: Kishida T

PROVIDER: S-EPMC4624936 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThere is emerging evidence that background exposure to persistent organic pollutants (POPs) are important in the development of conditions predisposing to diabetes as well as of type 2 diabetes itself. We recently reported that low dose POPs predicted incident type 2 diabetes in a nested case-control study. The current study examined if low dose POPs predicted future adiposity, dyslipidemia, and insulin resistance among controls without diabetes in that study.Methodology/principal findingsThe 90 controls were diabetes-free during 20 years follow-up. They were a stratified random sample, enriched with overweight and obese persons. POPs measured in 1987-88 (year 2) sera included 8 organochlorine (OC) pesticides, 22 polychlorinated biphenyls (PCBs), and 1 polybrominated biphenyl (PBB). Body mass index (BMI), triglycerides, HDL-cholesterol, LDL-cholesterol, and homeostasis model assessment value for insulin resistance (HOMA-IR) were study outcomes at 2005-06 (year 20). The evolution of study outcomes during 18 years by categories of serum concentrations of POPs at year 2 was evaluated by adjusting for the baseline values of outcomes plus potential confounders. Parallel to prediction of type 2 diabetes, many statistically significant associations of POPs with dysmetabolic conditions appeared at low dose, forming inverted U-shaped dose-response relations. Among OC pesticides, p,p'-DDE most consistently predicted higher BMI, triglycerides, and HOMA-IR and lower HDL-cholesterol at year 20 after adjusting for baseline values. Oxychlordane, trans-nonachlor, and hexachlorobenzene also significantly predicted higher triglycerides. Persistent PCBs with ?7 chlorides predicted higher BMI, triglycerides, and HOMA-IR and lower HDL-cholesterol at year 20 with similar dose-response curves.Conclusions/significanceSimultaneous exposure to various POPs in the general population may contribute to development of obesity, dyslipidemia, and insulin resistance, common precursors of type 2 diabetes and cardiovascular diseases. Although obesity is a primary cause of these metabolic abnormalities, POPs exposure may contribute to excess adiposity and other features of dysmetabolism.

Project description:Objectives: Diet quality may be a key modifiable factor for the prevention of non-communicable disease. We aimed to investigate the association between diet quality and prevalence of obesity, dyslipidemia, and insulin resistance among Filipino immigrant women in Korea. Methods: A total of 413 participants from the 2014-2016 baseline population of the Filipino Women's Diet and Health Study (FiLWHEL) were examined. Individual dietary intakes were evaluated through 24-h recalls and then converted into two dietary quality assessments: Minimum Dietary Diversity for Women (MDD-W) developed by the Food and Agriculture Organization (FAO) and the Data Derived Inflammation Index (DDII) originally developed by our group. Fasting blood levels of triglycerides, high-density lipoprotein cholesterols, glucose, and insulin were measured. We used logistic regression models for odds ratios (ORs) with 95% confidence intervals (CIs). Results: We found a statistically significant association between MDD-W scores and decreased prevalence of abdominal obesity; ORs (95% CIs) of the 3rd vs. 1st tertiles were 0.58 (0.36-0.94; p for trend = 0.029). Increased DDII was associated with elevated prevalence of dyslipidemia and insulin resistance; ORs (95% CIs) of the 5th vs. 1-3rd quintiles were 6.44 (2.56-16.20) for triglycerides (TG), 3.90 (1.92-7.90) for low-density lipoprotein (LDL) cholesterol, 3.36 (1.81-6.24) for total cholesterol (TC), 6.25 (2.53-15.41) for abnormal TG/HDL ratios, 3.59 (1.96-6.59) for HbA1c, 2.61 (1.11-6.17) for fasting blood glucose levels, 9.67 (4.16-22.48) for insulin levels, and 9.73 (4.46-21.25) for homeostasis model assessment of insulin resistance (HOMA-IR) (p for trend <0.001 for all, except 0.033 for fasting blood glucose). Conclusions: Greater dietary diversity was inversely associated with the prevalence of abdominal obesity in Filipino immigrant women. Proinflammatory scores based on diet and lifestyle factors were associated with an increased prevalence of dyslipidemia and insulin resistance. Further, epidemiological studies on the relationship between dietary acculturation and chronic disease are warranted.

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Reprogrammed Functional Brown Adipocytes Ameliorate Insulin Resistance and Dyslipidemia in Diet-Induced Obesity and Type 2 Diabetes.

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