“Multiple human adipocyte subtypes and mechanisms of their development”

2019 ◽  
Author(s):  
So Yun Min ◽  
Anand Desai ◽  
Zinger Yang ◽  
Agastya Sharma ◽  
Ryan M.J. Genga ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Adipose Tissue ◽  
Disease Risk ◽  
Human Adipose Tissue ◽  
Transcriptional Repressors ◽  
Mesenchymal Progenitor Cells ◽  
Human Adipocyte ◽  
Adipose Tissue Depots ◽  
Beige Adipocytes ◽  
Low Levels

SUMMARYHuman adipose tissue depots perform numerous diverse physiological functions, and are differentially linked to metabolic disease risk, yet only two major human adipocyte subtypes have been described, white and “brown/brite/beige.” The diversity and lineages of adipocyte classes have been studied in mice using genetic methods that cannot be applied in humans. Here we circumvent this problem by studying the fate of single mesenchymal progenitor cells obtained from human adipose tissue. We report that a minimum of four human adipocyte subtypes can be distinguished by transcriptomic analysis, specialized for functionally distinct processes such as adipokine secretion and thermogenesis. Evidence for the presence of these adipocytes subtypes in adult humans is evidenced by differential expression of key adipokines leptin and adiponectin in isolated mature adipocytes. The human adipocytes most similar to the mouse “brite/beige” adipocytes are enriched in mechanisms that promote iron accumulation and protect from oxidative stress, and are derived from progenitors that express high levels of cytokines such as IL1B, IL8, IL11 and the IL6 family cytokine LIF, and low levels of the transcriptional repressors ID1 and ID3. Our finding of this adipocyte repertoire and its developmental mechanisms provides a high-resolution framework to analyze human adipose tissue architecture and its role in systemic metabolism and metabolic disease.

scholarly journals A long-non-coding RNA, LINC00473, confers the human adipose tissue thermogenic phenotype through enhanced cAMP responsiveness

2018 ◽  
Author(s):  
Khanh-Van Tran ◽  
Cecilie Nandrup-Bus ◽  
Tiffany DeSouza ◽  
Ricardo Soares ◽  
Naja Zenius Jespersen ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Adipose Tissue ◽  
Disease Risk ◽  
Human Adipose Tissue ◽  
Non Coding Rna ◽  
Highly Correlated ◽  
Thermogenic Adipocytes ◽  
The Many ◽  
External Stimuli ◽  
Long Non Coding Rna

SummarySpecialized adipocytes localized in distinct depots mediate the many physiological functions of adipose tissue. In humans, paucity of thermogenic adipocytes correlates with high metabolic disease risk, raising much interest in the mechanisms by which these cells arise. Here we report molecular signatures associated with adipocyte development in different human depots and identify a long non-coding RNA, LINC00473, as the transcript most closely associated with enrichment of thermogenic adipocytes. LINC00473 expression is low in subjects with obesity or type-2 diabetes and is highly correlated with cAMP signaling and mitochondrial oxidative phosphorylation pathways. LINC00473 is localized in the nucleus and the cytoplasm, and its knockdown impairs induction of UCP1 and mitochondrial respiration. These results reveal that depot-enriched genes that modulate responsiveness to external stimuli, specifically LINC00473, are important determinants of the adipose tissue thermogenic phenotype, and potential targets for metabolic disease therapy.

scholarly journals Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cells

2019 ◽  
Vol 116 (36) ◽  
pp. 17970-17979 ◽  
Author(s):  
So Yun Min ◽  
Anand Desai ◽  
Zinger Yang ◽  
Agastya Sharma ◽  
Tiffany DeSouza ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Immune Cell ◽  
Human Adipose Tissue ◽  
Transcriptional Regulators ◽  
Mesenchymal Progenitor Cells ◽  
Human Adipocyte ◽  
Mesenchymal Progenitors ◽  
Sequencing Technologies ◽  
Tissue Browning

Single-cell sequencing technologies have revealed an unexpectedly broad repertoire of cells required to mediate complex functions in multicellular organisms. Despite the multiple roles of adipose tissue in maintaining systemic metabolic homeostasis, adipocytes are thought to be largely homogenous with only 2 major subtypes recognized in humans so far. Here we report the existence and characteristics of 4 distinct human adipocyte subtypes, and of their respective mesenchymal progenitors. The phenotypes of these distinct adipocyte subtypes are differentially associated with key adipose tissue functions, including thermogenesis, lipid storage, and adipokine secretion. The transcriptomic signature of “brite/beige” thermogenic adipocytes reveals mechanisms for iron accumulation and protection from oxidative stress, necessary for mitochondrial biogenesis and respiration upon activation. Importantly, this signature is enriched in human supraclavicular adipose tissue, confirming that these cells comprise thermogenic depots in vivo, and explain previous findings of a rate-limiting role of iron in adipose tissue browning. The mesenchymal progenitors that give rise to beige/brite adipocytes express a unique set of cytokines and transcriptional regulators involved in immune cell modulation of adipose tissue browning. Unexpectedly, we also find adipocyte subtypes specialized for high-level expression of the adipokines adiponectin or leptin, associated with distinct transcription factors previously implicated in adipocyte differentiation. The finding of a broad adipocyte repertoire derived from a distinct set of mesenchymal progenitors, and of the transcriptional regulators that can control their development, provides a framework for understanding human adipose tissue function and role in metabolic disease.

scholarly journals Ubc9 deletion in adipocytes causes lipoatrophy in mice

2020 ◽  
Author(s):  
Aaron R. Cox ◽  
Natasha Chernis ◽  
Kang Ho Kim ◽  
Peter M. Masschelin ◽  
Pradip K. Saha ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Balance ◽  
Hepatic Steatosis ◽  
Postnatal Growth ◽  
Endocrine Control ◽  
Brown Adipocytes ◽  
Human Adipocyte ◽  
White Adipocyte ◽  
Adipose Tissue Depots

ABSTRACTObjectiveWhite adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. WAT absence or loss occurring through lipodystrophy and lipoatrophy contributes to the development of dyslipidemia, hepatic steatosis, and insulin resistance. We previously demonstrated the sole small ubiquitin-like modifier (SUMO) E2-conjuguating enzyme Ubc9 represses human adipocyte differentiation. Germline and other tissue-specific deletions of Ubc9 frequently cause lethality in mice. As a result, the role of Ubc9 during WAT development remains unknown.MethodsTo determine how Ubc9 impacts body composition and energy balance, we generated adipocyte-specific Ubc9 knockout mice (Ubc9a-KO). CRISPR/Cas9 gene editing inserted loxP sites flanking exons 3 and 4 at the Ubc9 locus. Subsequent genetic crosses to AdipoQ-Cre transgenic mice allowed deletion of Ubc9 in white and brown adipocytes. We measured multiple metabolic endpoints that describe energy balance and carbohydrate metabolism in Ubc9a-KO and littermate controls during postnatal growth.ResultsTo our surprise, Ubc9a-KO mice developed hyperinsulinemia and hepatic steatosis. Global energy balance defects emerged from dysfunctional WAT marked by pronounced local inflammation, loss of serum adipokines, hepatomegaly, and near absence of major adipose tissue depots. We observed progressive lipoatrophy that commences in the early adolescent period.ConclusionsOur results demonstrate that Ubc9 expression in mature adipocytes is essential for maintaining WAT expansion. Deletion of Ubc9 in fat cells compromised and diminished adipocyte function that provoked WAT inflammation and ectopic lipid accumulation in the liver. Our findings reveal an indispensable role for Ubc9 during white adipocyte expansion and endocrine control of energy balance.

scholarly journals Adipose tissue: from amorphous filler to metabolic mastermind

2021 ◽  
Author(s):  
Silvia Corvera
Keyword(s):  
Adipose Tissue ◽  
Metabolic Diseases ◽  
Disease Risk ◽  
Appetite Control ◽  
Fat Storage ◽  
Fuel Distribution ◽  
Adipose Tissue Depots ◽  
Increased Risk ◽  
Adipocyte Hypertrophy ◽  
Adipocyte Hyperplasia

Adipose tissue plays a central role in the control of systemic glucose homeostasis through two major mechanisms: fat storage and secretion of specific cytokines known as adipokines. Fat storage in adipose tissue is critically important, as it prevents lipid deposition in liver and muscle, which in turn results in insulin resistance and increased risk of type 2 diabetes. Secretion of adipokines, such as leptin, protects from fuel depletion through appetite control, and other adipokines control fuel distribution and utilization. Fat storage capacity of adipose tissue increases through two mechanisms, adipocyte hypertrophy and adipocyte hyperplasia. Adipose tissue depots expand differently in diverse individuals and confer varying degrees of metabolic disease risk. There are multiple adipocyte subtypes that together mediate the functions of adipose tissue. They do so through specialized functions such as thermogenesis, which burns fuel to maintain core temperature, and through selective secretion of different adipokines. Much progress has been made in understanding the mechanisms by which adipose tissue controls systemic metabolism, increasing our hope of developing new, effective therapies for metabolic diseases.

Pattern of expression of adiponectin receptors in human adipose tissue depots and its relation to the metabolic state

2007 ◽  
Vol 31 (12) ◽  
pp. 1843-1848 ◽  
Author(s):  
M Nannipieri ◽  
A Bonotti ◽  
M Anselmino ◽  
F Cecchetti ◽  
S Madec ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Human Adipose Tissue ◽  
Adiponectin Receptors ◽  
Metabolic State ◽  
Adipose Tissue Depots

scholarly journals Multifaceted Roles of Beige Fat in Energy Homeostasis Beyond UCP1

Endocrinology ◽  
2018 ◽  
Vol 159 (7) ◽  
pp. 2545-2553 ◽  
Author(s):  
Carlos Henrique Sponton ◽  
Shingo Kajimura
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Uncoupling Protein ◽  
Developmental Regulation ◽  
Brown Adipocytes ◽  
Adipose Tissue Depots ◽  
Brown Adipose ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
Adipose Cells

Abstract Beige adipocytes are an inducible form of thermogenic adipose cells that emerge within the white adipose tissue in response to a variety of environmental stimuli, such as chronic cold acclimation. Similar to brown adipocytes that reside in brown adipose tissue depots, beige adipocytes are also thermogenic; however, beige adipocytes possess unique, distinguishing characteristics in their developmental regulation and biological function. This review highlights recent advances in our understanding of beige adipocytes, focusing on the diverse roles of beige fat in the regulation of energy homeostasis that are independent of the canonical thermogenic pathway via uncoupling protein 1.

scholarly journals Deciphering White Adipose Tissue Heterogeneity

Biology ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 23 ◽  
Author(s):  
Quyen Luong ◽  
Jun Huang ◽  
Kevin Y. Lee
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Lineage Tracing ◽  
The Body ◽  
Functional Heterogeneity ◽  
Tissue Heterogeneity ◽  
Adipose Tissue Depots ◽  
White Adipocytes ◽  
Increased Risk ◽  
Beige Adipocytes

Adipose tissue not only stores energy, but also controls metabolism through secretion of hormones, cytokines, proteins, and microRNAs that affect the function of cells and tissues throughout the body. Adipose tissue is organized into discrete depots throughout the body, and these depots are differentially associated with insulin resistance and increased risk of metabolic disease. In addition to energy-dissipating brown and beige adipocytes, recent lineage tracing studies have demonstrated that individual adipose depots are composed of white adipocytes that are derived from distinct precursor populations, giving rise to distinct subpopulations of energy-storing white adipocytes. In this review, we discuss this developmental and functional heterogeneity of white adipocytes both between and within adipose depots. In particular, we will highlight findings from our recent manuscript in which we find and characterize three major subtypes of white adipocytes. We will discuss these data relating to the differences between subcutaneous and visceral white adipose tissue and in relationship to previous work deciphering adipocyte heterogeneity within adipose tissue depots. Finally, we will discuss the possible implications of adipocyte heterogeneity may have for the understanding of lipodystrophies.

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