title: 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.
authors.affiliation: Department of Immunology, Kyoto Prefectural University of Medicine, Kamikyo, Kyoto 602-8566, Japan.
authors.forename: Tsunao
authors.initials: T
authors.lastname: Kishida
authors.affiliation: Department of Immunology, Kyoto Prefectural University of Medicine, Kamikyo, Kyoto 602-8566, Japan.
authors.forename: Akika
authors.initials: A
authors.lastname: Ejima
authors.affiliation: Department of Immunology, Kyoto Prefectural University of Medicine, Kamikyo, Kyoto 602-8566, Japan; Department of Dental Medicine, Kyoto Prefectural University of Medicine, Kamikyo, Kyoto 602-8566, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Immunology, Kyoto Prefectural University of Medicine, Kamikyo, Kyoto 602-8566, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Dental Medicine, Kyoto Prefectural University of Medicine, Kamikyo, Kyoto 602-8566, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Immunology, Kyoto Prefectural University of Medicine, Kamikyo, Kyoto 602-8566, Japan. Electronic address: mazda@koto.kpu-m.ac.jp.
authors.forename: Osam
authors.initials: O
authors.lastname: Mazda
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation*; D000818:Animals; D002460:Cell Line; D065150:Cellular Reprogramming; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000628:therapy*; D059305:Diet, High-Fat / Q000009:adverse effects; D050171:Dyslipidemias / Q000628:therapy*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000628:therapy*; D014157:Transcription Factors / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: D004268:DNA-Binding Proteins; C416371:PRDM16 protein, human; D014157:Transcription Factors