Adrenergic-Independent Signaling via CHRNA2 Regulates Beige Fat Activation

Jun, Hee-Jin; Ma, Yingxu; Chen, Yong; Gong, Jianke; Liu, S.; Wang, Jine; Knights, Alexander J.; Qiao, Xuguang; Emont, Margo P.; Xu, X.Z. Shawn; Kajimura, Shingo; Wu, Jun

doi:10.1016/j.devcel.2020.05.017

Cited by 30 publications

(26 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, miR-182-5p deficiency had no effect on Ucp1 expression ( Supplemental Figure 6, B and C ) and macrophages’ polarization ( Supplemental Figure 6D ) in BAT of cold-exposed mice, indicating miR-182-5p plays a selective role in controlling thermogenic gene expression in beige fat but not in BAT. These results are consistent with the findings that both FGF21 ( 6 ) and the acetylcholine signaling pathway ( 25 ) have a major effect on beige but not BAT thermogenesis and that distinct mechanisms are present in WAT and BAT to regulate thermogenesis ( 23 , 26 , 27 ). How the tissue selectivity of miR-182-5p is established is unclear, but it is known that BAT has much lower numbers of macrophages compared with WAT ( 28 , 29 ).…”

Section: Discussionsupporting

confidence: 92%

The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis

Meng¹,

Xiao²,

Liang³

et al. 2021

JCI Insight

View full text Add to dashboard Cite

A dynamically regulated microenvironment, which is mediated by crosstalks between adipocytes and neighboring cells, is critical for adipose tissue homeostasis and function. However, information on key molecules and/or signaling pathways regulating the crosstalks remains limited. In this study, we identify adipocyte miR-182-5p as a crucial anti-obesity molecule that stimulates beige fat thermogenesis by promoting the crosstalk between adipocytes and macrophages. miR-182-5p is highly enriched in thermogenic adipocytes and its expression is markedly stimulated by cold exposure in mice. In contrast, miR-182-5p expression is significantly reduced in adipose tissues of obese humans and mice. Knockout of miR-185-5p decreased cold-induced beige fat thermogenesis whereas overexpression of miR-185-5p increased beiging and thermogenesis in mice. Mechanistically, miR-182-5p promotes FGF21 expression and secretion in adipocytes by suppressing Nr1d1 at 5'UTR, which in turn stimulates acetylcholine synthesis and release in macrophages. Increased acetylcholine expression activates the nicotine acetylcholine receptor in adipocytes, which stimulates PKA signaling and consequent thermogenic gene expression. Our study reveals a key role of the miR-182-5p/FGF21/acetylcholine/acetylcholine receptor axis that mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis. Activation of the miR-182-5p-induced signaling pathway in adipose tissue may be an effective approach to ameliorate obesity and associated metabolic diseases.

show abstract

Section: Discussionsupporting

confidence: 92%

The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis

Meng¹,

Xiao²,

Liang³

et al. 2021

JCI Insight

View full text Add to dashboard Cite

show abstract

“…Thus, we saw no evidence that browning of ingWAT was mediated by a reduction in proinflammatory macrophages or the associated cytokines (e.g., TNFα), as has been suggested ( 41 , 42 ). Similarly, we saw no compelling evidence for the involvement of anti-inflammatory macrophages in the browning process in ingWAT where these macrophages have been suggested to play a mediatory role ( 14 – 17 , 20 , 21 , 28 , 29 , 43 ).…”

Section: Discussioncontrasting

confidence: 56%

“…Certain macrophages have also been suggested to be needed to maintain sympathetic innervation as such ( 27 ). In addition (or alternatively), anti-inflammatory macrophages have been suggested to release acetylcholine that would interact with cholinergic receptors on the brite/beige adipocytes themselves ( 28 , 29 ) and in this way stimulate thermogenic recruitment.…”

Section: Introductionmentioning

confidence: 99%

Thermogenic recruitment of brown and brite/beige adipose tissues is not obligatorily associated with macrophage accretion or attrition

Boulet

Luijten

Cannon

et al. 2021

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

A regulatory or mediatory role—positive or negative—for macrophages in the recruitment of brown adipose tissue is presently discussed. As the recruited state in the tissue is a dynamic process, maintenance of the recruited state would need persistent alterations in macrophage complement. Contrary to this expectation, we demonstrate here an absence of alterations in macrophage complement in thermogenically recruited brown—or brite/beige—adipose tissues. Macrophage regulation of thermogenic capacity is thus less likely.

show abstract

“…Recently, a glycolytic beige population was identified that could be induced by chronic cold adaptation in the absence of -adrenergic receptor signaling (Chen et al, 2019). Excess calorie intake also can trigger the activation of CHRNA2-dependent beige adipocytes (Jun et al, 2020), which also are glycolytic and -adrenergic signaling independent. Interestingly, Foxp4-inactivated beige adipocytes appeared to only react to cold exposure, not to an adrenoceptor agonist (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

FOXP4 differentially controls cold-induced beige adipocyte differentiation and thermogenesis

Wang

Chen

et al. 2021

Preprint

View full text Add to dashboard Cite

Beige adipocytes possess a discrete developmental origin and notable plasticity in thermogenic capacity in response to various environmental cues. But the transcriptional machinery controlling beige adipocyte development and thermogenesis remains largely unknown. By analyzing beige adipocyte-specific knockout mice, we identified a transcription factor, Forkhead Box P4 (FOXP4) that differentially governs beige adipocyte differentiation and activation. Depletion of Foxp4 caused a decline in the frequency of beige preadipocytes by switching their cell fate towards fibroblastic cells at the expense of beige adipocytes. However, we observed that ablation of Foxp4 in differentiated adipocytes profoundly potentiated their thermogenesis upon cold exposure. Of note, the outcome of Foxp4-deficiency on UCP1-mediated thermogenesis was confined to beige adipocytes, rather than to brown adipocytes. Taken together, we submit that FOXP4 primes beige adipocyte cell fate commitment and differentiation by potent transcriptional repression of the thermogenic program.

show abstract

Adrenergic-Independent Signaling via CHRNA2 Regulates Beige Fat Activation

Cited by 30 publications

References 35 publications

The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis

The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis

Thermogenic recruitment of brown and brite/beige adipose tissues is not obligatorily associated with macrophage accretion or attrition

FOXP4 differentially controls cold-induced beige adipocyte differentiation and thermogenesis

Contact Info

Product

Resources

About