KSRP ablation enhances brown fat gene program in white adipose tissue through reduced miR-150 expression.
Brown adipose tissue oxidizes chemical energy for heat generation and energy expenditure. Promoting brown-like transformation in white adipose tissue (WAT) is a promising strategy for combating obesity. Here, we find that targeted deletion of KH-type splicing regulatory protein (KSRP), an RNA-binding protein that regulates gene expression at multiple levels, causes a reduction in body adiposity. The expression of brown fat-selective genes is increased in subcutaneous/inguinal WAT (iWAT) of Ksrp(-/-) mice because of the elevated expression of PR domain containing 16 and peroxisome proliferator-activated receptor gamma coactivator 1α, which are key regulators promoting the brown fat gene program. The expression of microRNA (miR)-150 in iWAT is decreased due to impaired primary miR-150 processing in the absence of KSRP. We show that miR-150 directly targets and represses Prdm16 and Ppargc1a, and that forced expression of miR-150 attenuates the elevated expression of brown fat genes caused by KSRP deletion. This study reveals the in vivo function of KSRP in controlling brown-like transformation of iWAT through post-transcriptional regulation of miR-150 expression.
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL.
Chu-Fang
CF
Chou
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL.
Yi-Yu
YY
Lin
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL.
Hsu-Kun
HK
Wang
Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL.
Xiaolin
X
Zhu
Gene Expression Regulation Laboratory, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Matteo
M
Giovarelli
Gene Expression Regulation Laboratory, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Paola
P
Briata
Gene Expression Regulation Laboratory, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Roberto
R
Gherzi
Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL garveyt@uab.edu cchen@uab.edu.
W Timothy
WT
Garvey
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL garveyt@uab.edu cchen@uab.edu.
Ching-Yi
CY
Chen
D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D050154:Adiposity / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D059305:Diet, High-Fat; D015536:Down-Regulation; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000502:physiology; D015534:Trans-Activators / Q000172:deficiency* / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C507913:Khsrp protein, mouse; D035683:MicroRNAs; C529101:Mirn150 microRNA, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C521133:Prdm16 protein, mouse; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors