Systems biology reveals uncoupling beyond UCP1 in human white fat-derived beige adipocytes

Remodeling of energy-storing white fat into energy-consuming beige fat has led to a promising new approach to alleviate adiposity. Several studies have shown adipokines can induce white adipose tissue (WAT) beiging through autocrine or paracrine actions. Betatrophin, a novel adipokine, has been linked to energy expenditure and lipolysis but not clearly clarified. Here, we using high-fat diet-induced obesity to determine how betatrophin modulate beiging and adiposity. We found that betatrophin-knockdown mice displayed less white fat mass and decreased plasma TG and NEFA levels. Consistently, inhibition of betatrophin leads to the phenotype change of adipocytes characterized by increased mitochondria contents, beige adipocytes and mitochondria biogenesis-specific markers both in vivo and in vitro. Of note, blocking AMP-activated protein kinase (AMPK) signaling pathway is able to abolish enhanced beige-like characteristics in betatrophin-knockdown adipocytes. Collectively, downregulation of betatrophin induces beiging in white adipocytes through activation of AMPK signaling pathway. These processes suggest betatrophin as a latent therapeutic target for obesity.

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Cell biology of fat storage

Molecular Biology of the Cell ◽

10.1091/mbc.e15-10-0749 ◽

2016 ◽

Vol 27 (16) ◽

pp. 2523-2527 ◽

Cited By ~ 63

Author(s):

Paul Cohen ◽

Bruce M. Spiegelman

Keyword(s):

Immune Cells ◽

Cell Biology ◽

Critical Role ◽

Cell Types ◽

Fat Cells ◽

Obesity And Diabetes ◽

Beige Adipocytes ◽

Therapeutic Development ◽

White Fat

The worldwide epidemic of obesity and type 2 diabetes has greatly increased interest in the biology and physiology of adipose tissues. Adipose (fat) cells are specialized for the storage of energy in the form of triglycerides, but research in the last few decades has shown that fat cells also play a critical role in sensing and responding to changes in systemic energy balance. White fat cells secrete important hormone-like molecules such as leptin, adiponectin, and adipsin to influence processes such as food intake, insulin sensitivity, and insulin secretion. Brown fat, on the other hand, dissipates chemical energy in the form of heat, thereby defending against hypothermia, obesity, and diabetes. It is now appreciated that there are two distinct types of thermogenic fat cells, termed brown and beige adipocytes. In addition to these distinct properties of fat cells, adipocytes exist within adipose tissue, where they are in dynamic communication with immune cells and closely influenced by innervation and blood supply. This review is intended to serve as an introduction to adipose cell biology and to familiarize the reader with how these cell types play a role in metabolic disease and, perhaps, as targets for therapeutic development.

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miR17-92 cluster drives white adipose tissue browning

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0032 ◽

2020 ◽

Vol 65 (3) ◽

pp. 97-107

Author(s):

Yuanyuan Huang ◽

Hanlin Zhang ◽

Meng Dong ◽

Lei Zhang ◽

Jun Lin ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Critical Role ◽

Beneficial Effects ◽

Brown Adipose ◽

Beige Adipocytes ◽

Beige Fat ◽

And Function ◽

White Fat

White adipose tissue (WAT) browning may have beneficial effects for treating metabolic syndrome. miRNA are important regulators of the differentiation, development, and function of brown and beige adipocytes. Here, we found that the cold-inducible miRNA17-92 cluster is enriched in brown adipose tissue (BAT) compared with WAT. Overexpression of the miR17-92 cluster in C3H10T1/2 cells, a mouse mesenchymal stem cell line, enhanced the thermogenic capacity of adipocytes. Furthermore, we observed a significant reduction in adiposity in adipose tissue-specific miR17-92 cluster transgenic (TG) mice. This finding is partly explained by dramatic increases in white fat browning and energy expenditure. Interestingly, the miR17-92 cluster stimulated WAT browning without altering BAT activity in mice. In addition, when we removed the intrascapular BAT (iBAT), the TG mice could maintain their body temperature well under cold exposure. At the molecular level, we found that the miR17-92 cluster targets Rb1, a beige cell repressor in WAT. The present study reveals a critical role for the miR17-92 cluster in regulating WAT browning. These results may be helpful for better understanding the function of beige fat, which could compensate for the lack of BAT in humans, and may open new avenues for combatting metabolic syndrome.

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Comparative Transcriptome Profiling of Cold Exposure and β3-AR Agonist CL316,243-Induced Browning of White Fat

Frontiers in Physiology ◽

10.3389/fphys.2021.667698 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yu Li ◽

Xiaodan Ping ◽

Yankang Zhang ◽

Guoqiang Li ◽

Ting Zhang ◽

...

Keyword(s):

Cold Exposure ◽

Adrenergic Receptor ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Transcriptome Profiling ◽

Sequencing Analysis ◽

Qpcr Analysis ◽

Beige Adipocytes ◽

Beige Fat ◽

White Fat

Beige adipocytes are newly identified thermogenic-poised adipocytes that could be activated by cold or β3-adrenergic receptor (β3-AR) signaling and offer therapeutic potential for treating obesity and metabolic diseases. Here we applied RNA-sequencing analysis in the beige fat of mice under cold exposure or β3-AR agonist CL316,243 (CL) treatment to provide a comparative and comprehensive analysis for the similarity and heterogeneity of these two stimulants. Importantly, via KEGG analysis, we found that cold and CL commonly induced oxidative phosphorylation. Meanwhile, cold increased glycerolipid and amino acids metabolism while CL treatment triggered a broader spectrum of metabolic responses including carbohydrate metabolism. Besides, cold or CL treatment featured greater heterogeneity in downregulated gene programs. Of note, the top changed genes in each category were confirmed by qPCR analysis. Overall, our analysis provided a better understanding of the heterogeneity of differential models for beige adipocytes activation and a possible clue for optimizing β3-AR agonists in the future.

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Early postnatal interactions between beige adipocytes and sympathetic neurites regulate innervation of subcutaneous fat

eLife ◽

10.7554/elife.64693 ◽

2021 ◽

Vol 10 ◽

Author(s):

Jingyi Chi ◽

Zeran Lin ◽

William Barr ◽

Audrey Crane ◽

Xiphias Ge Zhu ◽

...

Keyword(s):

Early Development ◽

Sympathetic Innervation ◽

Subcutaneous Fat ◽

Postnatal Period ◽

Early Postnatal Period ◽

Tissue Imaging ◽

Beige Adipocyte ◽

Beige Adipocytes ◽

White Fat ◽

Knockout Model

While beige adipocytes have been found to associate with dense sympathetic neurites in mouse inguinal subcutaneous white fat (iWAT), little is known about when and how this patterning is established. Here, we applied whole-tissue imaging to examine the development of sympathetic innervation in iWAT. We found that parenchymal neurites actively grow between postnatal day 6 (P6) and P28, overlapping with early postnatal beige adipogenesis. Constitutive deletion of Prdm16 in adipocytes led to a significant reduction in early postnatal beige adipocytes and sympathetic density within this window. Using an inducible, adipocyte-specific Prdm16 knockout model, we found that Prdm16 is required for guiding sympathetic growth during early development. Deleting Prdm16 in adult animals, however, did not affect sympathetic structure in iWAT. Together, these findings highlight that beige adipocyte-sympathetic neurite communication is crucial to establish sympathetic structure during the early postnatal period but may be dispensable for its maintenance in mature animals.

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Unraveling the complexity of thermogenic remodeling of white fat reveals potential antiobesity therapies

Genes & Development ◽

10.1101/gad.349053.121 ◽

2021 ◽

Vol 35 (21-22) ◽

pp. 1395-1397

Author(s):

Nabil Rabhi ◽

Stephen R. Farmer

Keyword(s):

Molecular Mechanisms ◽

Cell Types ◽

Cellular Interaction ◽

Transcriptional Program ◽

Previous Issue ◽

Beige Adipocytes ◽

Dietary Cues ◽

Different Cell Types ◽

White Fat ◽

Complex Organ

Adipose tissue is a complex organ consisting of a mixture of mature adipocytes and stromal vascular cells. It displays a remarkable ability to adapt to environmental and dietary cues by changing its morphology and metabolic capacity. This plasticity is demonstrated by the emergence of interspersed thermogenic beige adipocytes within white depots in response to catecholamines secretion. Coordinated cellular interaction between different cell types within the tissue and a fine-tuned transcriptional program synergistically take place to promote beige remodeling. However, both cell–cell interactions and molecular mechanisms governing beige adipocyte appearance and maintenance are poorly understood. In this and the previous issue of Genes & Development, Shao and colleagues (pp. 1461–1474) and Shan and colleagues (pp. 1333–1338) advance our understanding of these issues and, in doing so, highlight potential therapeutic strategies to combat obesity-associated diseases.

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Transcription Regulators and Hormones Involved in the Development of Brown Fat and White Fat Browning: Transcriptional and Hormonal Control of Brown/Beige Fat Development

Physiological Research ◽

10.33549/physiolres.933650 ◽

2018 ◽

pp. 347-362 ◽

Cited By ~ 7

Author(s):

J. ZHANG ◽

H. WU ◽

S. MA ◽

F. JING ◽

C. YU ◽

...

Keyword(s):

Adipose Tissue ◽

Hormonal Control ◽

Brown Fat ◽

Metabolic Complications ◽

Adipose Tissues ◽

Brown Adipose ◽

Beige Adipocytes ◽

New Strategy ◽

Beige Fat ◽

White Fat

The high prevalence of obesity and related metabolic complications has inspired research on adipose tissues. Three kinds of adipose tissues are identified in mammals: brown adipose tissue (BAT), beige or brite adipose tissue and white adipose tissue (WAT). Beige adipocytes share some characteristics with brown adipocytes such as the expression of UCP1. Beige adipocytes can be activated by environmental stimuli or pharmacological treatment, and this change is accompanied by an increase in energy consumption. This process is called white browning, and it facilitates the maintenance of a lean and healthy phenotype. Thus, promoting beige adipocyte development in WAT shows promise as a new strategy in treating obesity and related metabolic consequences. In this review, we summarized the current understanding of the regulators and hormones that participate in the development of brown fat and white fat browning.

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Thermogenic Activity of UCP1 in Human White Fat-Derived Beige Adipocytes

Molecular Endocrinology ◽

10.1210/me.2014-1295 ◽

2015 ◽

Vol 29 (1) ◽

pp. 130-139 ◽

Cited By ~ 59

Author(s):

Stefano Bartesaghi ◽

Stefan Hallen ◽

Li Huang ◽

Per-Arne Svensson ◽

Remi A. Momo ◽

...

Keyword(s):

Beige Adipocytes ◽

White Fat

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Combining integrated systems-biology approaches with intervention-based experimental design provides a higher-resolution path forward for microbiome research

Behavioral and Brain Sciences ◽

10.1017/s0140525x18002911 ◽

2019 ◽

Vol 42 ◽

Author(s):

J. Alfredo Blakeley-Ruiz ◽

Carlee S. McClintock ◽

Ralph Lydic ◽

Helen A. Baghdoyan ◽

James J. Choo ◽

...

Keyword(s):

Systems Biology ◽

High Resolution ◽

Experimental Design ◽

Integrated Systems ◽

Microbiome Research ◽

Constructive Criticism

Abstract The Hooks et al. review of microbiota-gut-brain (MGB) literature provides a constructive criticism of the general approaches encompassing MGB research. This commentary extends their review by: (a) highlighting capabilities of advanced systems-biology “-omics” techniques for microbiome research and (b) recommending that combining these high-resolution techniques with intervention-based experimental design may be the path forward for future MGB research.

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