Regulatory microRNAs in Brown, Brite and White Adipose Tissue

MicroRNAs (miRNAs) constitute a class of short noncoding RNAs which regulate gene expression by targeting messenger RNA, inducing translational repression and messenger RNA degradation. This regulation of gene expression by miRNAs in adipose tissue (AT) can impact on the regulation of metabolism and energy homeostasis, particularly considering the different types of adipocytes which exist in mammals, i.e., white adipocytes (white AT; WAT), brown adipocytes (brown AT; BAT), and inducible brown adipocytes in WAT (beige or brite or brown-in-white adipocytes). Indeed, an increasing number of miRNAs has been identified to regulate key signaling pathways of adipogenesis in BAT, brite AT, and WAT by acting on transcription factors that promote or inhibit adipocyte differentiation. For example, MiR-328, MiR-378, MiR-30b/c, MiR-455, MiR-32, and MiR-193b-365 activate brown adipogenesis, whereas MiR-34a, MiR-133, MiR-155, and MiR-27b are brown adipogenesis inhibitors. Given that WAT mainly stores energy as lipids, whilst BAT mainly dissipates energy as heat, clarifying the effects of miRNAs in different types of AT has recently attracted significant research interest, aiming to also develop novel miRNA-based therapies against obesity, diabetes, and other obesity-related diseases. Therefore, this review presents an up-to-date comprehensive overview of the role of key regulatory miRNAs in BAT, brite AT, and WAT.

Download Full-text

Peroxisome Proliferator-Activated Receptors-α and -γ, and cAMP-Mediated Pathways, Control Retinol-Binding Protein-4 Gene Expression in Brown Adipose Tissue

Endocrinology ◽

10.1210/en.2011-1367 ◽

2012 ◽

Vol 153 (3) ◽

pp. 1162-1173 ◽

Cited By ~ 33

Author(s):

Meritxell Rosell ◽

Elayne Hondares ◽

Sadahiko Iwamoto ◽

Frank J. Gonzalez ◽

Martin Wabitsch ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Retinol Binding Protein ◽

Peroxisome Proliferator ◽

Brown Adipocytes ◽

Retinol Binding Protein 4 ◽

White Adipocytes ◽

Brown Adipose ◽

Rbp4 Gene

Retinol binding protein-4 (RBP4) is a serum protein involved in the transport of vitamin A. It is known to be produced by the liver and white adipose tissue. RBP4 release by white fat has been proposed to induce insulin resistance. We analyzed the regulation and production of RBP4 in brown adipose tissue. RBP4 gene expression is induced in brown fat from mice exposed to cold or treated with peroxisome proliferator-activated receptor (PPAR) agonists. In brown adipocytes in culture, norepinephrine, cAMP, and activators of PPARγ and PPARα induced RBP4 gene expression and RBP4 protein release. The induction of RBP4 gene expression by norepinephrine required intact PPAR-dependent pathways, as evidenced by impaired response of the RBP4 gene expression to norepinephrine in PPARα-null brown adipocytes or in the presence of inhibitors of PPARγ and PPARα. PPARγ and norepinephrine can also induce the RBP4 gene in white adipocytes, and overexpression of PPARα confers regulation by this PPAR subtype to white adipocytes. The RBP4 gene promoter transcription is activated by cAMP, PPARα, and PPARγ. This is mediated by a PPAR-responsive element capable of binding PPARα and PPARγ and required also for activation by cAMP. The induction of the RBP4 gene expression by norepinephrine in brown adipocytes is protein synthesis dependent and requires PPARγ-coactivator-1-α, which acts as a norepinephine-induced coactivator of PPAR on the RBP4 gene. We conclude that PPARγ- and PPARα-mediated signaling controls RBP4 gene expression and releases in brown adipose tissue, and thermogenic activation induces RBP4 gene expression in brown fat through mechanisms involving PPARγ-coactivator-1-α coactivation of PPAR signaling.

Download Full-text

Life without RNAi: noncoding RNAs and their functions in Saccharomyces cerevisiaeThis paper is one of a selection of papers published in this Special Issue, entitled 30th Annual International Asilomar Chromatin and Chromosomes Conference, and has undergone the Journal’s usual peer review process.

Biochemistry and Cell Biology ◽

10.1139/o09-043 ◽

2009 ◽

Vol 87 (5) ◽

pp. 767-779 ◽

Cited By ~ 24

Author(s):

Benjamin R. Harrison ◽

Oya Yazgan ◽

Jocelyn E. Krebs

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Chromatin Structure ◽

Messenger Rna ◽

Peer Review Process ◽

Regulation Of Gene Expression ◽

Noncoding Rnas ◽

Rna Degradation ◽

Small Interfering Rnas ◽

Ideal System

There are a number of well-characterized and fundamental roles for noncoding RNAs (ncRNAs) in gene regulation in all kingdoms of life. ncRNAs, such as ribosomal RNAs, transfer RNAs, small nuclear RNAs, small nucleolar RNAs, and small interfering RNAs, can serve catalytic and scaffolding functions in transcription, messenger RNA processing, translation, and RNA degradation. Recently, our understanding of gene expression has been dramatically challenged by the identification of large and diverse populations of novel ncRNAs in the eukaryotic genomes surveyed thus far. Studies carried out using the budding yeast Saccharomyces cerevisiae indicate that at least some coding genes are regulated by these novel ncRNAs. S. cerevisiae lacks RNA interference (RNAi) and, thus, provides an ideal system for studying the RNAi-independent mechanisms of ncRNA-based gene regulation. The current picture of gene regulation is one of great unknowns, in which the transcriptional environment surrounding a given locus may have as much to do with its regulation as its DNA sequence or local chromatin structure. Drawing on the recent research in S. cerevisiae and other organisms, this review will discuss the identification of ncRNAs, their origins and processing, and several models that incorporate ncRNAs into the regulation of gene expression and chromatin structure.

Download Full-text

Adipocytes and Stromal Cells Regulate Brown Adipogenesis Through Secretory Factors During the Postnatal White-to-Brown Conversion of Adipose Tissue in Syrian Hamsters

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.698692 ◽

2021 ◽

Vol 9 ◽

Author(s):

Junnosuke Mae ◽

Kazuki Nagaya ◽

Yuko Okamatsu-Ogura ◽

Ayumi Tsubota ◽

Shinya Matsuoka ◽

...

Keyword(s):

Adipose Tissue ◽

Signaling Pathways ◽

Mapk Signaling ◽

Brown Adipocyte ◽

Brown Adipocytes ◽

Syrian Hamsters ◽

White Adipocytes ◽

Adipocyte Progenitors ◽

Mapk Signaling Pathways ◽

Brown Adipogenesis

Brown adipose tissue (BAT) is a specialized tissue that regulates non-shivering thermogenesis. In Syrian hamsters, interscapular adipose tissue is composed primarily of white adipocytes at birth, which is converted to BAT through the proliferation and differentiation of brown adipocyte progenitors and the simultaneous disappearance of white adipocytes. In this study, we investigated the regulatory mechanism of brown adipogenesis during postnatal BAT formation in hamsters. Interscapular adipose tissue of a 10-day-old hamster, which primarily consists of brown adipocyte progenitors and white adipocytes, was digested with collagenase and fractioned into stromal–vascular (SV) cells and white adipocytes. SV cells spontaneously differentiated into brown adipocytes that contained multilocular lipid droplets and expressed uncoupling protein 1 (Ucp1), a marker of brown adipocytes, without treatment of adipogenic cocktail such as dexamethasone and insulin. The spontaneous differentiation of SV cells was suppressed by co-culture with adipocytes or by the addition of white adipocyte-conditioned medium. Conversely, the addition of SV cell-conditioned medium increased the expression of Ucp1. These results indicate that adipocytes secrete factors that suppress brown adipogenesis, whereas SV cells secrete factors that promote brown adipogenesis. Transcriptome analysis was conducted; however, no candidate suppressing factors secreted from adipocytes were identified. In contrast, 19 genes that encode secretory factors, including bone morphogenetic protein (BMP) family members, BMP3B, BMP5, and BMP7, were highly expressed in SV cells compared with adipocytes. Furthermore, the SMAD and MAPK signaling pathways, which represent the major BMP signaling pathways, were activated in SV cells, suggesting that BMPs secreted from SV cells induce brown adipogenesis in an autocrine manner through the SMAD/MAPK signaling pathways. Treatment of 5-day-old hamsters with type I BMP receptor inhibitor, LDN-193189, for 5 days reduced p38 MAPK phosphorylation and drastically suppressed BAT formation of interscapular adipose tissue. In conclusion, adipocytes and stromal cells regulate brown adipogenesis through secretory factors during the postnatal white-to-brown conversion of adipose tissue in Syrian hamsters.

Download Full-text

Regulation of gene expression by FSP27 in white and brown adipose tissue

BMC Genomics ◽

10.1186/1471-2164-11-446 ◽

2010 ◽

Vol 11 (1) ◽

pp. 446 ◽

Cited By ~ 25

Author(s):

De Li ◽

Yinxin Zhang ◽

Li Xu ◽

Linkang Zhou ◽

Yue Wang ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Regulation Of Gene Expression ◽

Brown Adipose

Download Full-text

Intron and Its Splicing Mechanism and Their Connection with Human Disease

Bangladesh Journal of Medical Science ◽

10.3329/bjms.v15i3.24527 ◽

2016 ◽

Vol 15 (3) ◽

pp. 307-312

Author(s):

Mine Dosay-Akbulut

Keyword(s):

Human Genome ◽

Human Disease ◽

Rna Splicing ◽

Messenger Rna ◽

Developmental Disorders ◽

Regulation Of Gene Expression ◽

Medical Science ◽

Intronless Genes ◽

Different Types ◽

Extra Difficulty

In the maturation mechanism of a messenger RNA, splicing play an important role with removing the noncoding introns and ligating the coding exons. Alternative splicing (AS) gives an extra difficulty to this mechanism and to the regulation of gene expression. The possible disturbing in the alternative RNA splicing mechanism can be a reason to several diseases like cancers and neurodegenerative disorders. Intronless genes (IGs) are seen in almost 3% of the human genome. Functionality of IGs has an important role in signal transduction genes and related regulatory proteins. This diversity can be reason to IG-associated diseases, especially neuropathies, developmental disorders, and cancer. The retroelements can be seen in almost half of the human genome. The known informations indicate that insertion of retroelement into exons and introns of genes promote different types of genetic disease, including cancer. The retroelement connected mutagenesis cause to fifty different types of human disease. The molecular informations and bioinformatic analyses can be used to explain the connection with splicing mutations and genetic mechanisms of several different human disease and understanding of this mechanism play an important role in the formation of treatment programme against to these diseases.Bangladesh Journal of Medical Science Vol.15(3) 2016 p.307-312

Download Full-text

Effect of hypothyroidism on adenylyl cyclase activity and subtype gene expression in brown adipose tissue

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.2.r762 ◽

1997 ◽

Vol 273 (2) ◽

pp. R762-R767 ◽

Cited By ~ 2

Author(s):

A. Chaudhry ◽

J. G. Granneman

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Adenylyl Cyclase ◽

Regulation Of Gene Expression ◽

Mrna Levels ◽

Adrenergic Stimulation ◽

Functional Responses ◽

Synergistic Interactions ◽

Brown Adipose

Brown adipose tissue (BAT) expresses several adenylyl cyclase (AC) subtypes, and adrenergic stimulation selectively upregulates AC-III gene expression. Previous studies have described synergistic interactions between the sympathetic nervous system (SNS) and 3,5,3'-triiodothyronine (T3) on the regulation of gene expression in BAT. Because adrenergic stimulation also increases the activity of BAT type II thyroxine 5'-deiodinase (DII) and local T3 generation is important for many functional responses in BAT, we examined the effects of thyroid hormone status on the expression of various AC subtypes. Hypothyroidism selectively increased AC-III mRNA levels in BAT but not in white adipose tissue. Of the other subtypes examined, hypothyroidism did not alter AC-VI mRNA levels and slightly reduced AC-IX mRNA levels in BAT. The increase in AC-III expression was paralleled by an increase in forskolin-stimulated AC activity in BAT membranes. Sympathetic denervation of BAT abolished the increase in both AC activity and AC-III mRNA expression produced by hypothyroidism, but did not affect the expression of other subtypes. Surgical denervation also prevented the induction of AC-III in the cold-stressed euthyroid rat, but injections of T3 failed to alter AC-III expression in intact or denervated BAT. Our results indicate that T3 does not directly affect expression of AC-III. Rather, hypothyroidism increases BAT AC-III expression indirectly via an increase in sympathetic stimulation. Furthermore, our results strongly indicate that the increase in AC activity in hypothyroid BAT is due to increased expression of AC-III.

Download Full-text

Brown adipocytes postnatally arise through both differentiation from progenitors and conversion from white adipocytes in Syrian hamster

Journal of Applied Physiology ◽

10.1152/japplphysiol.00622.2017 ◽

2018 ◽

Vol 124 (1) ◽

pp. 99-108 ◽

Cited By ~ 4

Author(s):

Yuko Okamatsu-Ogura ◽

Junko Nio-Kobayashi ◽

Kazuki Nagaya ◽

Ayumi Tsubota ◽

Kazuhiro Kimura

Keyword(s):

Adipose Tissue ◽

Lipid Droplets ◽

Brown Adipocyte ◽

Fat Tissue ◽

Brown Adipocytes ◽

Syrian Hamsters ◽

Monocarboxylate Transporter 1 ◽

White Adipocytes ◽

Proliferation And Differentiation ◽

Adipocyte Progenitors

To investigate the postnatal development of brown adipose tissue (BAT) in Syrian hamsters, we histologically examined interscapular fat tissue from 5–16-day-old pups, focusing on how brown adipocytes arise. Interscapular fat of 5-day-old hamsters mainly consisted of white adipocytes containing large unilocular lipid droplets, as observed in typical white adipose tissue (WAT). On day 7, clusters of small, proliferative nonadipocytes with a strong immunoreactivity for Ki67 appeared near the edge of the interscapular fat tissue. The area of the Ki67-positive regions expanded to ~50% of the total tissue area by day 10. The interscapular fat showed the typical BAT feature by day 16. A brown adipocyte-specific marker, uncoupling protein-1, was clearly detected on day 10 and thereafter, while not detected on day 7. During conversion of interscapular fat from WAT to BAT, unilocular adipocytes completely and rapidly disappeared without obvious apoptosis. Dual immunofluorescence staining for Ki67 and monocarboxylate transporter 1 (MCT1), another selective marker for brown adipocytes, revealed that most of the proliferating cells were of the brown adipocyte lineage. Electron microscopic examination showed that some of the white adipocytes contained small lipid droplets in addition to the large droplet and expressed MCT1 as do progenitor and mature brown adipocytes, implying a direct conversion from white to brown adipocytes. These results suggest that BAT of Syrian hamsters develops postnatally through two different pathways: the proliferation and differentiation of brown adipocyte progenitors and the conversion of unilocular adipocytes to multilocular brown adipocytes. NEW & NOTEWORTHY Brown and white adipose tissues (BAT and WAT, respectively) are quite different in morphological features and function; however, the boundary between these tissues is obscure. In this study, we histologically evaluated the process of BAT development in Syrian hamsters, which shows postnatal conversion of WAT to BAT. Our results suggest that brown adipocytes arise through two different pathways: the proliferation and differentiation of brown adipocyte progenitors and the conversion from white adipocytes.

Download Full-text

Monocyte Chemoattractant Protein-1 in Subcutaneous Abdominal Adipose Tissue: Characterization of Interstitial Concentration and Regulation of Gene Expression by Insulin

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-2814 ◽

2007 ◽

Vol 92 (7) ◽

pp. 2688-2695 ◽

Cited By ~ 38

Author(s):

Giuseppe Murdolo ◽

Ann Hammarstedt ◽

Madeléne Sandqvist ◽

Martin Schmelz ◽

Christian Herder ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Regulation Of Gene Expression ◽

Whole Body ◽

Mrna Levels ◽

Abdominal Adipose Tissue ◽

Monocyte Chemoattractant Protein 1 ◽

Monocyte Chemoattractant ◽

Monocyte Chemoattractant Protein ◽

Adipose Organ

Abstract Context: The chemokine monocyte chemoattractant protein-1 (MCP-1) is implicated in obesity-associated chronic inflammation, insulin resistance, and atherosclerosis. Objectives: The objectives of this study were to: 1) characterize the interstitial levels and the gene expression of MCP-1 in the sc abdominal adipose tissue (SCAAT), 2) elucidate the response of MCP-1 to acute hyperinsulinemia, and 3) determine the relationship between MCP-1 and arterial stiffness. Design: Nine lean (L) and nine uncomplicated obese (OB) males were studied in the fasting state and during a euglycemic-hyperinsulinemic clamp combined with the microdialysis technique. Interstitial and serum MCP-1 (iMCP-1 and sMCP-1, respectively) levels, pulse wave analysis, and SCAAT biopsies were characterized at baseline and after hyperinsulinemia. Results: OB showed elevated sMCP-1 (P < 0.01) but similar iMCP-1 levels as compared with L. Basal iMCP-1 concentrations were considerably higher than sMCP-1 (P < 0.0001), and a gradient between iMCP-1 and sMCP-1 levels was maintained throughout the hyperinsulinemia. At baseline, SCAAT gene expression profile revealed a “co-upregulation” of MCP-1, MCP-2, macrophage inflammatory protein-1α, and CD68 in OB, and whole-body glucose disposal inversely correlated with the MCP-1 gene expression. After hyperinsulinemia, MCP-1 and MCP-2 mRNA levels significantly increased in L, but not in OB. Finally, sMCP-1 excess in the OB positively correlated with the stiffer vasculature. Conclusions: These observations demonstrate similar interstitial concentrations and a differential gene response to hyperinsulinemia of MCP-1 in the SCAAT from L and OB individuals. In human obesity, we suggest the SCAAT MCP-1 gene overexpression as a biomarker of an “inflamed” adipose organ and impaired glucose metabolism.

Download Full-text

Expression of GPR43 in Brown Adipogenesis Is Enhanced by Rosiglitazone and Controlled by PPARγ/RXR Heterodimerization

PPAR Research ◽

10.1155/2018/1051074 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Jiamiao Hu ◽

Arong Zhou ◽

Peter C. K. Cheung ◽

Baodong Zheng ◽

Shaoxiao Zeng ◽

...

Keyword(s):

Adipocyte Differentiation ◽

Late Phase ◽

Short Chain Fatty Acids ◽

Brown Adipocyte ◽

Biological Functions ◽

Brown Adipocytes ◽

White Adipocytes ◽

G Protein Coupled ◽

Brown Adipogenesis

GPR43, a G-protein coupled receptor recognizing short-chain fatty acids, has been reported to participate in many biological functions of white adipocytes, such as adipogenesis and lipolysis. However, the functional role of GPR43 in brown adipocytes is still not clear. In this study, we investigated the effects of the PPARγ agonist rosiglitazone on GPR43 expression in brown adipogenesis. The results demonstrated that GPR43 was expressed during the late phase of brown adipocyte differentiation, which could be further augmented by adipogenic agent rosiglitazone treatment. The PPARγ/RXR heterodimerization was found to be the key transcription factor for this enhancing effect of rosiglitazone on GPR43 expression. Taken together, these results suggested GPR43 levels might be regulated by PPARγ-activated events during brown adipocytes differentiation and reflect the adipogenesis status of brown adipocytes.

Download Full-text

Seeing the trees in the forest: selective electroporation of adipocytes within adipose tissue

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00567.2003 ◽

2004 ◽

Vol 287 (3) ◽

pp. E574-E582 ◽

Cited By ~ 29

Author(s):

James G. Granneman ◽

Pipeng Li ◽

Yuyan Lu ◽

Jacqueline Tilak

Keyword(s):

Adipose Tissue ◽

Adrenergic Receptor ◽

Fat Cells ◽

Subcellular Targeting ◽

In Vivo Electroporation ◽

Brown Adipocytes ◽

Adrenergic Signaling ◽

Large Size ◽

White Adipocytes

Electroporation has been recently adapted for the transfer of macromolecules into cells of tissues in vivo. Although mature adipocytes constitute <20% of cells residing in adipose tissue, we hypothesized that fat cells might be susceptible to selective electrotransfer of plasmid DNA owing to their large size relative to other cells in the tissue. Results demonstrate the feasibility of electroporating DNA into mature fat cells with >99% selectivity over other cells in the tissue. Further experiments used the “adiporation” technique to image the subcellular targeting of fluorescent bioreporter molecules to the nucleus, mitochondria, and lipid droplets of adipocytes within intact adipose tissue. Finally, we utilized fluorescent bioreporters to examine the effects of constitutive activation of the β-adrenergic signaling pathway in adipocytes. These results demonstrate that overexpression of rat β1-adrenergic receptors alters the cellular morphology of white adipocytes in a fashion that mimics the effects of systemic infusion of β3-adrenergic receptor agonists. Hallmarks of the altered morphology include pronounced fragmentation of the single lipid droplet, repositioning of the nucleus, and induction of mitochondrial biogenesis. These results indicate that activation of β-adrenergic signaling within adipocytes is sufficient to induce a phenotype that resembles typical brown adipocytes and suggest that in vivo electroporation will allow molecular dissection of the mechanisms involved.

Download Full-text