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1.
Cell Stem Cell ; 25(6): 830-845.e8, 2019 12 05.
Article in English | MEDLINE | ID: mdl-31564549

ABSTRACT

Metabolic pathways dynamically regulate tissue development and maintenance. However, the mechanisms that govern the metabolic adaptation of stem or progenitor cells to their local niche are poorly understood. Here, we define the transcription factor PRDM16 as a region-specific regulator of intestinal metabolism and epithelial renewal. PRDM16 is selectively expressed in the upper intestine, with enrichment in crypt-resident progenitor cells. Acute Prdm16 deletion in mice triggered progenitor apoptosis, leading to diminished epithelial differentiation and severe intestinal atrophy. Genomic and metabolic analyses showed that PRDM16 transcriptionally controls fatty acid oxidation (FAO) in crypts. Expression of this PRDM16-driven FAO program was highest in the upper small intestine and declined distally. Accordingly, deletion of Prdm16 or inhibition of FAO selectively impaired the development and maintenance of upper intestinal enteroids, and these effects were rescued by acetate treatment. Collectively, these data reveal that regionally specified metabolic programs regulate intestinal maintenance.


Subject(s)
DNA-Binding Proteins/metabolism , Intestinal Mucosa/metabolism , Stem Cells/cytology , Stem Cells/metabolism , Transcription Factors/metabolism , Animals , Blotting, Western , Cell Differentiation/genetics , Cell Differentiation/physiology , Chromatin Immunoprecipitation , DNA-Binding Proteins/genetics , Female , Flow Cytometry , Fluorescent Antibody Technique , Homeostasis/genetics , Homeostasis/physiology , Male , Mass Spectrometry , Mice , Transcription Factors/genetics
2.
EMBO J ; 36(11): 1528-1542, 2017 06 01.
Article in English | MEDLINE | ID: mdl-28408438

ABSTRACT

Brown adipose has the potential to counteract obesity, and thus, identifying signaling pathways that regulate the activity of this tissue is of great clinical interest. PRDM16 is a transcription factor that activates brown fat-specific genes while repressing white fat and muscle-specific genes in adipocytes. Whether PRDM16 also controls other gene programs to regulate adipocyte function was unclear. Here, we identify a novel role for PRDM16 in suppressing type I interferon (IFN)-stimulated genes (ISGs), including Stat1, in adipocytes in vitro and in vivo Ectopic activation of type I IFN signaling in brown adipocytes induces mitochondrial dysfunction and reduces uncoupling protein 1 (UCP1) expression. Prdm16-deficient adipose displays an exaggerated response to type I IFN, including higher STAT1 levels and reduced mitochondrial gene expression. Mechanistically, PRDM16 represses ISGs through binding to promoter regions of these genes and blocking the activating function of IFN regulatory factor 1 (IRF1). Together, these data indicate that PRDM16 diminishes responsiveness to type I IFN in adipose cells to promote thermogenic and mitochondrial function.


Subject(s)
Adipocytes/physiology , DNA-Binding Proteins/metabolism , Gene Expression Regulation , Interferon Regulatory Factor-1/antagonists & inhibitors , Interferon Type I/metabolism , Mitochondria/metabolism , Thermogenesis , Transcription Factors/metabolism , Animals , Mice , STAT1 Transcription Factor/antagonists & inhibitors , Uncoupling Protein 1/metabolism
3.
J Clin Invest ; 127(4): 1451-1462, 2017 Apr 03.
Article in English | MEDLINE | ID: mdl-28240605

ABSTRACT

Obesity causes insulin resistance, and PPARγ ligands such as rosiglitazone are insulin sensitizing, yet the mechanisms remain unclear. In C57BL/6 (B6) mice, obesity induced by a high-fat diet (HFD) has major effects on visceral epididymal adipose tissue (eWAT). Here, we report that HFD-induced obesity in B6 mice also altered the activity of gene regulatory elements and genome-wide occupancy of PPARγ. Rosiglitazone treatment restored insulin sensitivity in obese B6 mice, yet, surprisingly, had little effect on gene expression in eWAT. However, in subcutaneous inguinal fat (iWAT), rosiglitazone markedly induced molecular signatures of brown fat, including the key thermogenic gene Ucp1. Obesity-resistant 129S1/SvImJ mice (129 mice) displayed iWAT browning, even in the absence of rosiglitazone. The 129 Ucp1 locus had increased PPARγ binding and gene expression that were preserved in the iWAT of B6x129 F1-intercrossed mice, with an imbalance favoring the 129-derived alleles, demonstrating a cis-acting genetic difference. Thus, B6 mice have genetically defective Ucp1 expression in iWAT. However, when Ucp1 was activated by rosiglitazone, or by iWAT browning in cold-exposed or young mice, expression of the B6 version of Ucp1 was no longer defective relative to the 129 version, indicating epigenomic rescue. These results provide a framework for understanding how environmental influences like drugs can affect the epigenome and potentially rescue genetically determined disease phenotypes.


Subject(s)
Epigenesis, Genetic , Obesity/metabolism , PPAR gamma/physiology , Animals , Diet, High-Fat/adverse effects , Hypoglycemic Agents/pharmacology , Intra-Abdominal Fat/metabolism , Male , Mice, 129 Strain , Mice, Inbred C57BL , Protein Binding , Regulatory Elements, Transcriptional , Rosiglitazone , Subcutaneous Fat, Abdominal/metabolism , Thiazolidinediones/pharmacology , Transcriptional Activation , Transcriptome , Uncoupling Protein 1/genetics , Uncoupling Protein 1/metabolism
4.
Cell ; 166(1): 258-258.e1, 2016 Jun 30.
Article in English | MEDLINE | ID: mdl-27368105

ABSTRACT

Brown and beige adipose tissues have been identified as potential therapeutic targets for combating diet-induced obesity and metabolic disease. Here, we present transcriptional and developmental regulation of brown and beige adipose tissue, as well as critical physiological and pharmaceutical activators of thermogenesis in both tissues.


Subject(s)
Adipose Tissue, Brown/metabolism , Adipose Tissue/metabolism , Thermogenesis , Gene Expression Regulation , Humans , Immunity, Innate
5.
Diabetes ; 65(4): 927-41, 2016 04.
Article in English | MEDLINE | ID: mdl-26858361

ABSTRACT

Rapamycin extends life span in mice, yet paradoxically causes lipid dysregulation and glucose intolerance through mechanisms that remain incompletely understood. Whole-body energy balance can be influenced by beige/brite adipocytes, which are inducible by cold and other stimuli via ß-adrenergic signaling in white adipose depots. Induction of beige adipocytes is considered a promising strategy to combat obesity because of their ability to metabolize glucose and lipids, dissipating the resulting energy as heat through uncoupling protein 1. Here, we report that rapamycin blocks the ability of ß-adrenergic signaling to induce beige adipocytes and expression of thermogenic genes in white adipose depots. Rapamycin enhanced transcriptional negative feedback on the ß3-adrenergic receptor. However, thermogenic gene expression remained impaired even when the receptor was bypassed with a cell-permeable cAMP analog, revealing the existence of a second inhibitory mechanism. Accordingly, rapamycin-treated mice are cold intolerant, failing to maintain body temperature and weight when shifted to 4°C. Adipocyte-specific deletion of the mTORC1 subunit Raptor recapitulated the block in ß-adrenergic signaling. Our findings demonstrate a positive role for mTORC1 in the recruitment of beige adipocytes and suggest that inhibition of ß-adrenergic signaling by rapamycin may contribute to its physiological effects.


Subject(s)
Adipose Tissue, White/drug effects , Sirolimus/pharmacology , Thermogenesis/drug effects , Adipocytes/drug effects , Adipocytes/physiology , Adipose Tissue, White/metabolism , Animals , Dioxoles/pharmacology , Energy Metabolism/drug effects , Energy Metabolism/genetics , Female , Gene Expression Regulation/drug effects , Male , Mice , Mice, Inbred C57BL , Thermogenesis/genetics
6.
Proc Natl Acad Sci U S A ; 111(40): 14466-71, 2014 Oct 07.
Article in English | MEDLINE | ID: mdl-25197048

ABSTRACT

Brown adipocytes and muscle and dorsal dermis descend from precursor cells in the dermomyotome, but the factors that regulate commitment to the brown adipose lineage are unknown. Here, we prospectively isolated and determined the molecular profile of embryonic brown preadipose cells. Brown adipogenic precursor activity in embryos was confined to platelet-derived growth factor α(+), myogenic factor 5(Cre)-lineage-marked cells. RNA-sequence analysis identified early B-cell factor 2 (Ebf2) as one of the most selectively expressed genes in this cell fraction. Importantly, Ebf2-expressing cells purified from Ebf2(GFP) embryos or brown fat tissue did not express myoblast or dermal cell markers and uniformly differentiated into brown adipocytes. Interestingly, Ebf2-expressing cells from white fat tissue in adult animals differentiated into brown-like (or beige) adipocytes. Loss of Ebf2 in brown preadipose cells reduced the expression levels of brown preadipose-signature genes, whereas ectopic Ebf2 expression in myoblasts activated brown preadipose-specific genes. Altogether, these results indicate that Ebf2 specifically marks and regulates the molecular profile of brown preadipose cells.


Subject(s)
Adipocytes/metabolism , Adipose Tissue, Brown/metabolism , Adipose Tissue/metabolism , Basic Helix-Loop-Helix Transcription Factors/genetics , Adipocytes/cytology , Adipogenesis/genetics , Adipose Tissue/cytology , Adipose Tissue/embryology , Adipose Tissue, Brown/cytology , Adipose Tissue, Brown/embryology , Adipose Tissue, White/cytology , Adipose Tissue, White/embryology , Adipose Tissue, White/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Biomarkers/metabolism , Cell Lineage/genetics , Cells, Cultured , Embryo, Mammalian/cytology , Embryo, Mammalian/embryology , Embryo, Mammalian/metabolism , Flow Cytometry , Gene Expression Profiling , Gene Expression Regulation, Developmental , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Immunohistochemistry , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Microscopy, Confocal , Myogenic Regulatory Factor 5/genetics , Myogenic Regulatory Factor 5/metabolism , Oligonucleotide Array Sequence Analysis , Reverse Transcriptase Polymerase Chain Reaction
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