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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.

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Related in: MedlinePlus

miR-155 regulates cold-induced thermogenesis in BAT and ‘browning’ of WAT.(a) Representative infrared thermographic image of 12–16-week-old male wt and miR-155−/− littermates kept at 4 °C for 4 h. (b) Statistical analysis of body surface temperature as measured by infrared thermography. Data are represented as means±s.e.m. (***P<0.001; Student’s t-test; n.s., not significant; wt group n=7, miR-155−/− group n=5). (c) Hematoxylin and eosin staining of interscapular BAT sections from wt and miR-155−/− littermates kept at room tempertaure (RT) or post cold exposure (4 °C, 4 h). Scale bar, 50 μm. (d) Lipolysis assay of BAT from 12-week-old wt and miR-155−/− littermates kept in 4 °C for 4 h. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; n=4). (e) Ex vivo oxygraph measurement of cellular mitochondrial respiration in BAT 12–16-weeks-old wt or miR-155−/− littermates exposed to 4 °C. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; wt group n=6, miR-155−/− group n=5). (f) qRT–PCR analyses of UCP1 and PGC-1α expression in BAT of 12–16-week-old wt or miR-155−/− littermates after cold exposure. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; n=4). (g) Representative hematoxylin and eosin staining of igWAT sections from wt and miR-155−/− littermates at RT or post cold exposure (top). Immunohistochemical staining for UCP1 abundance in respective igWAT sections (bottom). Scale bar, 50 μm. (h) qRT–PCR analyses of UCP1 and PGC-1α in igWAT 12–16-week-old wt or miR-155−/− littermates exposed to 4 °C for 4 h. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; wt group n=4, miR-155−/− group n=4). (i) Oxygraph measurement of cellular mitochondrial respiration in igWAT of wt and miR-155−/− littermates at 12–16 weeks of age. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; wt group n=6, miR-155−/− group n=5).
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f6: miR-155 regulates cold-induced thermogenesis in BAT and ‘browning’ of WAT.(a) Representative infrared thermographic image of 12–16-week-old male wt and miR-155−/− littermates kept at 4 °C for 4 h. (b) Statistical analysis of body surface temperature as measured by infrared thermography. Data are represented as means±s.e.m. (***P<0.001; Student’s t-test; n.s., not significant; wt group n=7, miR-155−/− group n=5). (c) Hematoxylin and eosin staining of interscapular BAT sections from wt and miR-155−/− littermates kept at room tempertaure (RT) or post cold exposure (4 °C, 4 h). Scale bar, 50 μm. (d) Lipolysis assay of BAT from 12-week-old wt and miR-155−/− littermates kept in 4 °C for 4 h. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; n=4). (e) Ex vivo oxygraph measurement of cellular mitochondrial respiration in BAT 12–16-weeks-old wt or miR-155−/− littermates exposed to 4 °C. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; wt group n=6, miR-155−/− group n=5). (f) qRT–PCR analyses of UCP1 and PGC-1α expression in BAT of 12–16-week-old wt or miR-155−/− littermates after cold exposure. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; n=4). (g) Representative hematoxylin and eosin staining of igWAT sections from wt and miR-155−/− littermates at RT or post cold exposure (top). Immunohistochemical staining for UCP1 abundance in respective igWAT sections (bottom). Scale bar, 50 μm. (h) qRT–PCR analyses of UCP1 and PGC-1α in igWAT 12–16-week-old wt or miR-155−/− littermates exposed to 4 °C for 4 h. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; wt group n=4, miR-155−/− group n=4). (i) Oxygraph measurement of cellular mitochondrial respiration in igWAT of wt and miR-155−/− littermates at 12–16 weeks of age. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; wt group n=6, miR-155−/− group n=5).

Mentions: To analyse the effect of miR-155 suppression on WAT browning and BAT recruitment in vivo, we used BIC/miR-155-knockout (miR-155−/−) mice41. BAT activation was studied by exposing mice to cold (4 °C). Interscapular temperature of miR-155−/− mice was significantly higher (38.4±0.66 °C) as compared with the wt littermates (35±0.37 °C) after cold exposure, indicating that inducible thermogenesis of BAT is significantly increased in the absence of miR-155 (Fig. 6a). In addition, analysis of body core temperature revealed a significant difference between miR-155−/− and wt mice already at room temperature (RT). After 4 h cold exposure, core temperature dropped by 3±0.39 °C in wt but only 0.8±0.3 °C in miR-155−/− mice (Supplementary Fig. S8f).


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)

miR-155 regulates cold-induced thermogenesis in BAT and ‘browning’ of WAT.(a) Representative infrared thermographic image of 12–16-week-old male wt and miR-155−/− littermates kept at 4 °C for 4 h. (b) Statistical analysis of body surface temperature as measured by infrared thermography. Data are represented as means±s.e.m. (***P<0.001; Student’s t-test; n.s., not significant; wt group n=7, miR-155−/− group n=5). (c) Hematoxylin and eosin staining of interscapular BAT sections from wt and miR-155−/− littermates kept at room tempertaure (RT) or post cold exposure (4 °C, 4 h). Scale bar, 50 μm. (d) Lipolysis assay of BAT from 12-week-old wt and miR-155−/− littermates kept in 4 °C for 4 h. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; n=4). (e) Ex vivo oxygraph measurement of cellular mitochondrial respiration in BAT 12–16-weeks-old wt or miR-155−/− littermates exposed to 4 °C. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; wt group n=6, miR-155−/− group n=5). (f) qRT–PCR analyses of UCP1 and PGC-1α expression in BAT of 12–16-week-old wt or miR-155−/− littermates after cold exposure. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; n=4). (g) Representative hematoxylin and eosin staining of igWAT sections from wt and miR-155−/− littermates at RT or post cold exposure (top). Immunohistochemical staining for UCP1 abundance in respective igWAT sections (bottom). Scale bar, 50 μm. (h) qRT–PCR analyses of UCP1 and PGC-1α in igWAT 12–16-week-old wt or miR-155−/− littermates exposed to 4 °C for 4 h. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; wt group n=4, miR-155−/− group n=4). (i) Oxygraph measurement of cellular mitochondrial respiration in igWAT of wt and miR-155−/− littermates at 12–16 weeks of age. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; wt group n=6, miR-155−/− group n=5).
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f6: miR-155 regulates cold-induced thermogenesis in BAT and ‘browning’ of WAT.(a) Representative infrared thermographic image of 12–16-week-old male wt and miR-155−/− littermates kept at 4 °C for 4 h. (b) Statistical analysis of body surface temperature as measured by infrared thermography. Data are represented as means±s.e.m. (***P<0.001; Student’s t-test; n.s., not significant; wt group n=7, miR-155−/− group n=5). (c) Hematoxylin and eosin staining of interscapular BAT sections from wt and miR-155−/− littermates kept at room tempertaure (RT) or post cold exposure (4 °C, 4 h). Scale bar, 50 μm. (d) Lipolysis assay of BAT from 12-week-old wt and miR-155−/− littermates kept in 4 °C for 4 h. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; n=4). (e) Ex vivo oxygraph measurement of cellular mitochondrial respiration in BAT 12–16-weeks-old wt or miR-155−/− littermates exposed to 4 °C. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; wt group n=6, miR-155−/− group n=5). (f) qRT–PCR analyses of UCP1 and PGC-1α expression in BAT of 12–16-week-old wt or miR-155−/− littermates after cold exposure. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; n=4). (g) Representative hematoxylin and eosin staining of igWAT sections from wt and miR-155−/− littermates at RT or post cold exposure (top). Immunohistochemical staining for UCP1 abundance in respective igWAT sections (bottom). Scale bar, 50 μm. (h) qRT–PCR analyses of UCP1 and PGC-1α in igWAT 12–16-week-old wt or miR-155−/− littermates exposed to 4 °C for 4 h. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; wt group n=4, miR-155−/− group n=4). (i) Oxygraph measurement of cellular mitochondrial respiration in igWAT of wt and miR-155−/− littermates at 12–16 weeks of age. Data are represented as means±s.e.m. (*P<0.05; Student’s t-test; wt group n=6, miR-155−/− group n=5).
Mentions: To analyse the effect of miR-155 suppression on WAT browning and BAT recruitment in vivo, we used BIC/miR-155-knockout (miR-155−/−) mice41. BAT activation was studied by exposing mice to cold (4 °C). Interscapular temperature of miR-155−/− mice was significantly higher (38.4±0.66 °C) as compared with the wt littermates (35±0.37 °C) after cold exposure, indicating that inducible thermogenesis of BAT is significantly increased in the absence of miR-155 (Fig. 6a). In addition, analysis of body core temperature revealed a significant difference between miR-155−/− and wt mice already at room temperature (RT). After 4 h cold exposure, core temperature dropped by 3±0.39 °C in wt but only 0.8±0.3 °C in miR-155−/− mice (Supplementary Fig. S8f).

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