Limits...
miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit.

Chen Y, Siegel F, Kipschull S, Haas B, Fröhlich H, Meister G, Pfeifer A - Nat Commun (2013)

Bottom Line: Brown adipocytes are a primary site of energy expenditure and reside not only in classical brown adipose tissue but can also be found in white adipose tissue.In contrast, transgenic overexpression of microRNA 155 in mice causes a reduction of brown adipose tissue mass and impairment of brown adipose tissue function.These data demonstrate that the bistable loop involving microRNA 155 and CCAAT/enhancer-binding protein β regulates brown lineage commitment, thereby, controlling the development of brown and beige fat cells.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology and Toxicology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.

ABSTRACT
Brown adipocytes are a primary site of energy expenditure and reside not only in classical brown adipose tissue but can also be found in white adipose tissue. Here we show that microRNA 155 is enriched in brown adipose tissue and is highly expressed in proliferating brown preadipocytes but declines after induction of differentiation. Interestingly, microRNA 155 and its target, the adipogenic transcription factor CCAAT/enhancer-binding protein β, form a bistable feedback loop integrating hormonal signals that regulate proliferation or differentiation. Inhibition of microRNA 155 enhances brown adipocyte differentiation and induces a brown adipocyte-like phenotype ('browning') in white adipocytes. Consequently, microRNA 155-deficient mice exhibit increased brown adipose tissue function and 'browning' of white fat tissue. In contrast, transgenic overexpression of microRNA 155 in mice causes a reduction of brown adipose tissue mass and impairment of brown adipose tissue function. These data demonstrate that the bistable loop involving microRNA 155 and CCAAT/enhancer-binding protein β regulates brown lineage commitment, thereby, controlling the development of brown and beige fat cells.

Show MeSH

Related in: MedlinePlus

Schematic model of miR-155-regulated brown adipogenesis.miR-155 and C/EBPβ form a self-inhibitory feedback loop that tightly regulates brown adipogenesis. miR-155 expression is induced by TGFβ1 signalling and mediates translational repression of C/EBPβ by binding to its 3′ UTR. In turn, C/EBPβ is induced by adipogenic hormones and inhibits transcription of miR-155. Thereby, miR-155 and C/EBPβ constitute a bistable system for the regulation of adipogenesis and thermogenesis by either maintaining preadipocytes in an undifferentiated precursor state (mitotic clonal expansion) or initiating the brown adipogenic program.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3644088&req=5

f7: Schematic model of miR-155-regulated brown adipogenesis.miR-155 and C/EBPβ form a self-inhibitory feedback loop that tightly regulates brown adipogenesis. miR-155 expression is induced by TGFβ1 signalling and mediates translational repression of C/EBPβ by binding to its 3′ UTR. In turn, C/EBPβ is induced by adipogenic hormones and inhibits transcription of miR-155. Thereby, miR-155 and C/EBPβ constitute a bistable system for the regulation of adipogenesis and thermogenesis by either maintaining preadipocytes in an undifferentiated precursor state (mitotic clonal expansion) or initiating the brown adipogenic program.

Mentions: Overall, miR-155 can be classified as a miRNA inhibitor of brown fat adipogenesis. Similar to the situation in cancer, where tumour promoting, oncogenic miRNAs and tumour-suppressive, anti-oncogenic miRNAs have been identified7, we propose that an interplay of ‘pro-adipogenic’ miRNAs—such as miR-193b-365 and miR-196a1253—and ‘anti-adipogenic’ miRNAs like miR-155 orchestrate adipogenic differentiation. Importantly, we found a reciprocal negative regulation (Fig. 7) between miR-155 and C/EBPβ that integrates pro- and anti-adipogenic cues. One such anti-adipogenic cue is TGFβ1, which is secreted by proliferating preadipocytes and induces miR-155 expression. High levels of miR-155 inhibit C/EBPβ expression, thereby suppressing premature differentiation and keeping preadipocytes in an undifferentiated state. Pro-adipogenic hormones induce expression of C/EBPβ, which in turn inhibits transcription of BIC/miR-155. Thereby, this double-negative feedback mechanism leads to robust commitment to one of the two possible states establishing a bistable system36. A similar bistable system has been described for miR-7 and the transcription factor Yan in the developing Drosophila eye54. The miR-155/C/EBPβ bistable loop might have evolved to convert weak or only transiently available external signals to a strong response, ensuring a uniform response of precursor cells to signals that either prohibit or induce adipogenesis.


miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit.

Chen Y, Siegel F, Kipschull S, Haas B, Fröhlich H, Meister G, Pfeifer A - Nat Commun (2013)

Schematic model of miR-155-regulated brown adipogenesis.miR-155 and C/EBPβ form a self-inhibitory feedback loop that tightly regulates brown adipogenesis. miR-155 expression is induced by TGFβ1 signalling and mediates translational repression of C/EBPβ by binding to its 3′ UTR. In turn, C/EBPβ is induced by adipogenic hormones and inhibits transcription of miR-155. Thereby, miR-155 and C/EBPβ constitute a bistable system for the regulation of adipogenesis and thermogenesis by either maintaining preadipocytes in an undifferentiated precursor state (mitotic clonal expansion) or initiating the brown adipogenic program.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3644088&req=5

f7: Schematic model of miR-155-regulated brown adipogenesis.miR-155 and C/EBPβ form a self-inhibitory feedback loop that tightly regulates brown adipogenesis. miR-155 expression is induced by TGFβ1 signalling and mediates translational repression of C/EBPβ by binding to its 3′ UTR. In turn, C/EBPβ is induced by adipogenic hormones and inhibits transcription of miR-155. Thereby, miR-155 and C/EBPβ constitute a bistable system for the regulation of adipogenesis and thermogenesis by either maintaining preadipocytes in an undifferentiated precursor state (mitotic clonal expansion) or initiating the brown adipogenic program.
Mentions: Overall, miR-155 can be classified as a miRNA inhibitor of brown fat adipogenesis. Similar to the situation in cancer, where tumour promoting, oncogenic miRNAs and tumour-suppressive, anti-oncogenic miRNAs have been identified7, we propose that an interplay of ‘pro-adipogenic’ miRNAs—such as miR-193b-365 and miR-196a1253—and ‘anti-adipogenic’ miRNAs like miR-155 orchestrate adipogenic differentiation. Importantly, we found a reciprocal negative regulation (Fig. 7) between miR-155 and C/EBPβ that integrates pro- and anti-adipogenic cues. One such anti-adipogenic cue is TGFβ1, which is secreted by proliferating preadipocytes and induces miR-155 expression. High levels of miR-155 inhibit C/EBPβ expression, thereby suppressing premature differentiation and keeping preadipocytes in an undifferentiated state. Pro-adipogenic hormones induce expression of C/EBPβ, which in turn inhibits transcription of BIC/miR-155. Thereby, this double-negative feedback mechanism leads to robust commitment to one of the two possible states establishing a bistable system36. A similar bistable system has been described for miR-7 and the transcription factor Yan in the developing Drosophila eye54. The miR-155/C/EBPβ bistable loop might have evolved to convert weak or only transiently available external signals to a strong response, ensuring a uniform response of precursor cells to signals that either prohibit or induce adipogenesis.

Bottom Line: Brown adipocytes are a primary site of energy expenditure and reside not only in classical brown adipose tissue but can also be found in white adipose tissue.In contrast, transgenic overexpression of microRNA 155 in mice causes a reduction of brown adipose tissue mass and impairment of brown adipose tissue function.These data demonstrate that the bistable loop involving microRNA 155 and CCAAT/enhancer-binding protein β regulates brown lineage commitment, thereby, controlling the development of brown and beige fat cells.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology and Toxicology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.

ABSTRACT
Brown adipocytes are a primary site of energy expenditure and reside not only in classical brown adipose tissue but can also be found in white adipose tissue. Here we show that microRNA 155 is enriched in brown adipose tissue and is highly expressed in proliferating brown preadipocytes but declines after induction of differentiation. Interestingly, microRNA 155 and its target, the adipogenic transcription factor CCAAT/enhancer-binding protein β, form a bistable feedback loop integrating hormonal signals that regulate proliferation or differentiation. Inhibition of microRNA 155 enhances brown adipocyte differentiation and induces a brown adipocyte-like phenotype ('browning') in white adipocytes. Consequently, microRNA 155-deficient mice exhibit increased brown adipose tissue function and 'browning' of white fat tissue. In contrast, transgenic overexpression of microRNA 155 in mice causes a reduction of brown adipose tissue mass and impairment of brown adipose tissue function. These data demonstrate that the bistable loop involving microRNA 155 and CCAAT/enhancer-binding protein β regulates brown lineage commitment, thereby, controlling the development of brown and beige fat cells.

Show MeSH
Related in: MedlinePlus