Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism

Abstract

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue during the cold are not well understood. Here we demonstrate that the transcriptional coregulator transducin-like enhancer of split 3 (TLE3) inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes promotes mitochondrial oxidative metabolism and increases energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing, we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these binding sites are also enriched for early B-cell factor (EBF) transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 regulates thermogenic gene expression in beige adipocytes through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

“…Husemoen et al [ [94], Tang et al [95], Goodier et al [96], Petyuk et al [97], Roux et al [98], Castrogiovanni et al [99], Suleiman et al [100] [111], Ma et al [112], Chabbert et al [113], Abramsson et al [114], Aeby et al [115] and Roll et al [116] found that the expression of DCC (DCC netrin 1 receptor), PLP1, SNX19, SH3RF1, TNFRSF1A, NCSTN (nicastrin), DGCR2, NPAS2, CDNF (cerebral dopamine neurotrophic factor), SMCR8, HSPA2, STUB1, CHID1, ATP13A2, SQSTM1, LIG3, SP4, ACSL6, ERN1, ATF6B, LRFN2, NRG3, LRRTM3, GABRA2, ADAM30, GABRR2, TSHZ3, LOXL1, SCN1B and SRPX2 are associated with the prognosis of patients with cognitive impairment, but these genes might be novel target for T1DM. Recent studies found that KCP (kielin cysteine rich BMP regulator) [117], NOG (noggin) [118], COL6A3 [119], BTG2 [120], RPS6 [121], KLF15 [122], KLF3 [123], ZFP36 [124], ETV5 [125], TLE3 [126], NNMT (nicotinamide Nmethyltransferase) [127], WDTC1 [128], ZFHX3 [129], SIAH2 [130], MBOAT7 [131], RUNX1T1 [132], MAPK4 [133], KLF9 [134], SELENBP1 [135], HELZ2 [136], ELK1 [137], SERTAD2 [138], CRTC3 [139], ABCB11 [140], TACR1 [141], SLC22A11 [142], PER3 [143], P2RX5 [144], MF...…”

“…GABRR2, TSHZ3, LOXL1, SCN1B and SRPX2 are associated with the prognosis of patients with cognitive impairment, but these genes might be novel target for T1DM. Recent studies found that KCP (kielin cysteine rich BMP regulator) [117], NOG (noggin) [118], COL6A3 [119], BTG2 [120], RPS6 [121], KLF15 [122], KLF3 [123], ZFP36 [124], ETV5 [125], TLE3 [126], NNMT (nicotinamide N-methyltransferase) [127], WDTC1 [128], ZFHX3 [129], SIAH2 [130], MBOAT7 [131], RUNX1T1 [132], MAPK4 [133], KLF9 [134], SELENBP1 [135], HELZ2 [136], ELK1 [137], SERTAD2 [138], CRTC3 [139], ABCB11 [140], TACR1 [141], SLC22A11 [142], PER3 [143], P2RX5 [144], MFAP5 [145], FGL1 [146], OLFM4 [147], NTN1 [148], ESR1 [149], ABCB1 [150], VAV3 [151] and LAMB3 [152] plays an important role in the occurrence and development of obesity, but these genes might be novel target for T1DM. STAR (steroidogenic acute regulatory protein) [153], IL1RN [154], AQP5 [155], EGR1 [156], SFTPD (surfactant protein D) [157], KLF10 [158], PODXL (podocalyxin like) [159], FOXN3 [160], IL6R [161], PBX1 [162], APOD (apolipoprotein D) [163], ACVR2B [164], CD34 [165], INSR (insulin receptor) [166], APOA5 [167], STAR (steroidogenic acute regulatory protein) [168], PDK4 [169], GLS (glutaminase) [170], FKBP5 [171], SLC6A15 [172], MT2A [173], SLC38A4 [174], AQP7 [175], ABHD15 [176], ABCA1 [177], ZNRF1 [178], PPP1R3B [179], MAOA (monoamine oxidase A) [180], UBE2E2 [181], RNASEK (ribonuclease K) [182], PREX1 [183], DGKG (diacylglycerol kinase gamma) [184], POS...…”

Thermogenic Fat: Development, Physiological Function, and Therapeutic Potential

“…Several TFs and activating cofactors are shown to have negative effects on beige/brown fat formation and function including Hes1 [ 122 ], Irx3 [ 123 ], Irx5 [ 123 ], Rip140 [ 124 , 125 , 126 ], Tle3 [ 127 ], Zfp423 [ 128 , 129 ], Hoxc8 [ 130 ], Hoxc10 [ 131 ], Twist1 [ 132 ], Foxa3 [ 133 , 134 ], Foxo1 [ 135 , 136 ], Foxp1 [ 137 ], Rb [ 138 ], Src2 (Tif2), Smad3 [ 139 ], Usf1 [ 140 ], Mrtfa [ 141 ], Lxr [ 142 ], and P107 [ 143 , 144 , 145 ]. Transcriptional repressors such as Ctbp1 and Ctbp2 [ 90 , 146 ] suppress the WAT gene expression and promote the browning of WAT.…”

Thermogenic Fat: Development, Physiological Function, and Therapeutic Potential

“…Several TFs and activating cofactors are shown to have negative effects on beige/brown fat formation and function including Hes1 [122], Irx3 [123], Irx5 [123], Rip140 [124][125][126], Tle3 [127], Zfp423 [128,129], Hoxc8 [130], Hoxc10 [131], Twist1 [132], Foxa3 [133,134], Foxo1 [135,136], Foxp1 [137], Rb [138], Src2 (Tif2), Smad3 [139], Usf1 [140], Mrtfa [141], Lxr [142], and P107 [143][144][145]. Transcriptional repressors such as Ctbp1 and Ctbp2 [90,146] suppress the WAT gene expression and promote the browning of WAT.…”