Critical review of beige adipocyte thermogenic activation and contribution to whole-body energy expenditure

2017 ◽  
Vol 31 (2) ◽  
Author(s):  
Érique Castro ◽  
Tiago E. Oliveira Silva ◽  
William T. Festuccia
Keyword(s):  
Energy Expenditure ◽  
Metabolic Diseases ◽  
Uncoupling Protein ◽  
Whole Body ◽  
Beige Adipocyte ◽  
White Adipocytes ◽  
Beige Adipocytes ◽  
Whole Body Metabolism ◽  
Beige Cells ◽  
Body Energy

AbstractBeige (or brite, “brown in white”) adipocytes are uncoupling protein 1 (UCP1)-positive cells residing in white adipose depots that, depending on the conditions, behave either as classic white adipocytes, storing energy as lipids, or as brown adipocytes, dissipating energy from oxidative metabolism as heat through non-shivering thermogenesis. Because of their thermogenic potential and, therefore, possible usage to treat metabolic diseases such as obesity and type 2 diabetes, beige cells have attracted the attention of many scientists worldwide aiming to develop strategies to safely recruit and activate their thermogenic activity. Indeed, in recent years, a large variety of conditions, molecules (including nutrients) and signaling pathways were reported to promote the recruitment of beige adipocytes. Despite of those advances, the true contribution of beige adipocyte thermogenesis to whole-body energy expenditure is still not completely defined. Herein, we discuss some important aspects that should be considered when studying beige adipocyte biology and the contribution to energy balance and whole-body metabolism.

scholarly journals Breaking BAT: can browning create a better white?

2015 ◽  
Vol 228 (1) ◽  
pp. R19-R29 ◽  
Author(s):  
Amy Warner ◽  
Jens Mittag
Keyword(s):  
Energy Expenditure ◽  
Metabolic Diseases ◽  
Uncoupling Protein ◽  
Whole Body ◽  
Direct Stimulation ◽  
White Adipocytes ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
Underlying Mechanisms ◽  
Body Energy

Obesity and its comorbidities are a growing problem worldwide. In consequence, several new strategies have been proposed to promote weight loss and improve insulin sensitivity. Recently, it has been demonstrated that certain populations of white adipocytes can be ‘browned’, i.e., recruited to a more brown-like adipocyte, capable of thermogenesis through increased expression of uncoupling protein 1. The list of browning agents that induce these so-called beige adipocytes is growing constantly. However, the underlying mechanisms are often poorly understood, with the possibility that some of these agents cause browning as a secondary effect. Moreover, it remains unclear whether beige adipocytes can contribute sufficiently to affect whole-body energy expenditure in a functionally significant manner. This review presents an overview of the different molecular pathways leading to the induction of beige fat, including direct stimulation and indirect actions on the CNS or the immune system. We discuss the available evidence on the capacity of beige adipocytes to influence whole-body energy expenditure in rodents, and lastly outline the potential problems of translating browning capacity into the potential treatment of human metabolic diseases.

scholarly journals Macrophage infiltration into obese adipose tissues suppresses the induction of UCP1 level in mice

2016 ◽  
Vol 310 (8) ◽  
pp. E676-E687 ◽  
Author(s):  
Tomoya Sakamoto ◽  
Takahiro Nitta ◽  
Koji Maruno ◽  
Yu-Sheng Yeh ◽  
Hidetoshi Kuwata ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Cold Exposure ◽  
Uncoupling Protein ◽  
Mitochondrial Protein ◽  
Whole Body ◽  
Marker Genes ◽  
Adipose Tissues ◽  
Expression Levels ◽  
Beige Adipocytes ◽  
Thermogenic Adipocytes

Emergence of thermogenic adipocytes such as brown and beige adipocytes is critical for whole body energy metabolism. Promoting the emergence of these adipocytes, which increase energy expenditure, could be a viable strategy in treating obesity and its related diseases. However, little is known regarding the mechanisms that regulate the emergence of these adipocytes in obese adipose tissue. Here, we demonstrated that classically activated macrophages (M1 Mϕ) suppress the induction of thermogenic adipocytes in obese adipose tissues of mice. Cold exposure significantly induced the expression levels of uncoupling protein-1 (UCP1), which is a mitochondrial protein unique in thermogenic adipocytes, in C57BL/6 mice fed a normal diet. However, UCP1 induction was significantly suppressed in adipose tissues of C57BL/6 mice fed a high-fat diet, into which M1 Mϕ infiltrated. Depletion of M1 Mϕ using clodronate liposomes eliminated the suppressive effect and markedly reduced the mRNA level of tumor necrosis factor-α (TNFα) in the adipose tissues. Importantly, consistent with the observed changes in the expression levels of marker genes for thermogenic adipocytes, combination treatment of clodronate liposome and cold exposure resulted in metabolic benefits such as lowered body weight and blood glucose level in obese mice. Moreover, intraperitoneal injection of recombinant TNFα protein suppressed UCP1 induction in lean adipose tissues of mice. Collectively, our data indicate that infiltrated M1 Mϕ suppress the induction of thermogenic adipocytes in obese adipose tissues via TNFα. This report suggests that inflammation induced by infiltrated Mϕ could cause not only insulin resistance but also reduction of energy expenditure in adipose tissues.

scholarly journals Brown Adipose Tissue - role in metabolic disorders

2019 ◽  
Vol 13 (1) ◽  
pp. 002
Author(s):  
Tahniyah Haq ◽  
Frank Joseph Ong ◽  
Sarah Kanji
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Metabolic Diseases ◽  
Uncoupling Protein ◽  
Whole Body ◽  
Positron Emission ◽  
Brown Adipose ◽  
Magnetic Resonance Imaging Mri ◽  
Fdg Pet Ct ◽  
Body Energy

Brown adipose tissue, a thermogenic organ, previously thought to be present in only small mammals and children has recently been identified in adult humans. Located primarily in the supraclavicular and cervical area, it produces heat by uncoupling oxidative phosphorylation due to the unique presence of uncoupling protein 1 by a process called nonshivering thermogenesis. BAT activity depends on many factors including age, sex, adiposity and outdoor temperature. Positron-emission tomography using 18F-fluorodeoxyglucose and computed tomography (18F-FDG PET–CT), magnetic resonance imaging (MRI) and thermal imaging (IRT) are among several methods used to detect BAT in humans. The importance of BAT is due to its role in whole body energy expenditure and fuel metabolism. Thus it is postulated that it may be useful in the treatment of metabolic diseases. However, there are still many unanswered questions to the clinical usefulness of this novel tissue. IMC J Med Sci 2019; 13(1): 002

scholarly journals CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Emmanouela Tsagkaraki ◽  
Sarah M. Nicoloro ◽  
Tiffany DeSouza ◽  
Javier Solivan-Rivera ◽  
Anand Desai ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
High Efficiency ◽  
Ex Vivo ◽  
Uncoupling Protein ◽  
Whole Body ◽  
Small Samples ◽  
Genetic Enhancement ◽  
Human Adipocyte ◽  
Beige Adipocytes ◽  
Whole Body Metabolism

AbstractObesity and type 2 diabetes are associated with disturbances in insulin-regulated glucose and lipid fluxes and severe comorbidities including cardiovascular disease and steatohepatitis. Whole body metabolism is regulated by lipid-storing white adipocytes as well as “brown” and “brite/beige” adipocytes that express thermogenic uncoupling protein 1 (UCP1) and secrete factors favorable to metabolic health. Implantation of brown fat into obese mice improves glucose tolerance, but translation to humans has been stymied by low abundance of primary human beige adipocytes. Here we apply methods to greatly expand human adipocyte progenitors from small samples of human subcutaneous adipose tissue and then disrupt the thermogenic suppressor gene NRIP1 by CRISPR. Ribonucleoprotein consisting of Cas9 and sgRNA delivered ex vivo are fully degraded by the human cells following high efficiency NRIP1 depletion without detectable off-target editing. Implantation of such CRISPR-enhanced human or mouse brown-like adipocytes into high fat diet fed mice decreases adiposity and liver triglycerides while enhancing glucose tolerance compared to implantation with unmodified adipocytes. These findings advance a therapeutic strategy to improve metabolic homeostasis through CRISPR-based genetic enhancement of human adipocytes without exposing the recipient to immunogenic Cas9 or delivery vectors.

scholarly journals Isoliquiritigenin Enhances the Beige Adipocyte Potential of Adipose-Derived Stem Cells by JNK Inhibition

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5660
Author(s):  
Hanbyeol Moon ◽  
Jung-Won Choi ◽  
Byeong-Wook Song ◽  
Il-Kwon Kim ◽  
Soyeon Lim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Low Dose ◽  
Uncoupling Protein ◽  
Adipogenic Differentiation ◽  
Adipose Derived Stem Cells ◽  
Beige Adipocyte ◽  
White Adipocyte ◽  
White Adipocytes ◽  
Beige Adipocytes

Human adipose-derived stem cells (hASCs) can be isolated from fat tissue and have attracted interest for their potential therapeutic applications in metabolic disease. hASCs can be induced to undergo adipogenic differentiation in vitro by exposure to chemical agents or inductive growth factors. We investigated the effects and mechanism of differentiating hASC-derived white adipocytes into functional beige and brown adipocytes with isoliquiritigenin (ILG) treatment. Here, we showed that hASC-derived white adipocytes could promote brown adipogenesis by expressing both uncoupling protein 1 (UCP1) and PR/SET Domain 16 (PRDM16) following low-dose ILG treatments. ILG treatment of white adipocytes enhanced the expression of brown fat-specific markers, while the expression levels of c-Jun N-terminal kinase (JNK) signaling pathway proteins were downregulated. Furthermore, we showed that the inhibition of JNK phosphorylation contributed to white adipocyte differentiation into beige adipocytes, which was validated by the use of SP600125. We identified distinct regulatory effects of ILG dose responses and suggested that low-dose ILG induced the beige adipocyte potential of hASCs via JNK inhibition.

scholarly journals CRISPR-enhanced human adipocyte “browning” as cell therapy for metabolic disease

2020 ◽  
Author(s):  
Emmanouela Tsagkaraki ◽  
Sarah Nicoloro ◽  
Tiffany De Souza ◽  
Javier Solivan-Rivera ◽  
Anand Desai ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Ex Vivo ◽  
Uncoupling Protein ◽  
Suppressor Gene ◽  
Whole Body ◽  
Long Term Stability ◽  
Beige Adipocytes ◽  
Liver Triglycerides ◽  
Whole Body Metabolism ◽  
Mouse Adipocytes

AbstractObesity and type 2 diabetes (T2D) are associated with poor tissue responses to insulin1,2, disturbances in glucose and lipid fluxes3–5 and comorbidities including steatohepatitis6 and cardiovascular disease7,8. Despite extensive efforts at prevention and treatment9,10, diabetes afflicts over 400 million people worldwide11. Whole body metabolism is regulated by adipose tissue depots12–14, which include both lipid-storing white adipocytes and less abundant “brown” and “brite/beige” adipocytes that express thermogenic uncoupling protein UCP1 and secrete factors favorable to metabolic health15–18. Application of clustered regularly interspaced short palindromic repeats (CRISPR) gene editing19,20 to enhance “browning” of white adipose tissue is an attractive therapeutic approach to T2D. However, the problems of cell-selective delivery, immunogenicity of CRISPR reagents and long term stability of the modified adipocytes are formidable. To overcome these issues, we developed methods that deliver complexes of SpyCas9 protein and sgRNA ex vivo to disrupt the thermogenesis suppressor gene NRIP121,22 with near 100% efficiency in human or mouse adipocytes. NRIP1 gene disruption at discrete loci strongly ablated NRIP1 protein and upregulated expression of UCP1 and beneficial secreted factors, while residual Cas9 protein and sgRNA were rapidly degraded. Implantation of the CRISPR-enhanced human or mouse brown-like adipocytes into high fat diet fed mice decreased adiposity and liver triglycerides while enhancing glucose tolerance compared to mice implanted with unmodified adipocytes. These findings advance a therapeutic strategy to improve metabolic homeostasis through CRISPR-based genetic modification of human adipocytes without exposure of the recipient to immunogenic Cas9 or delivery vectors.

scholarly journals Role of toll-like receptors and their ligands in adipocyte secretion

2021 ◽  
Vol 5 (1) ◽  
pp. 001-007
Author(s):  
Mishra A ◽  
Shestopalov AV ◽  
Gaponov AM ◽  
Alexandrov IA ◽  
Roumiantsev SA
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Low Grade ◽  
White Adipocyte ◽  
White Adipocytes ◽  
Beige Adipocytes ◽  
Whole Body Metabolism ◽  
Significant Expression ◽  
Adipose Tissue Remodeling

Background: Adipose tissue is one of the main sites of energy homeostasis that regulates whole body metabolism with the help of adipokines. Disruption in its proper functioning results in adipose tissue remodeling (primarily hypertrophy and hyperplasia) which directly influences the secretion of said adipokines. Obesity characterized as chronic low-grade inflammation of the adipose tissue is one such condition that has far reaching effects on whole body metabolism. Inflammation in turn results in immune cells infiltrating into the tissue and further promoting adipocyte dysfunction. Purpose: In our study we explored this adipose tissue-innate immunity axis by differentiating adipose tissue derived stem cells (ADSCs) into white and beige adipocytes. We further stimulated our cultures with lipopolysaccharide (LPS), flagellin, or meteorin-like, glial cell differentiation regulator (METRNL) to trigger an inflammatory response. We then evaluated Toll-like receptor (TLR) mRNA expression and secretion of interleukin (IL-6), interleukin-8 (IL-8), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in these cultures. Results: We found that TLR2 is the highest expressed receptor in adipocytes. Further, LPS and METRNL are strong activators of TLR2 in white and beigeBMP7(-) adipocytes. TLR4 was not significantly expressed in any of our cultures despite LPS stimulation. TLR9 expression is upregulated in ADSCs upon LPS and METRNL stimulation. IL-6 and IL-8 secretion is increased upon LPS stimulation in white adipocytes. METRNL activates both IL-6 and IL-8 expression in adipocyte cultures. Lastly, BDNF and NGF is secreted by all adipocyte cultures with beigeBMP7(-) and beigeBMP7(+) secreting slightly higher amounts in comparison to white adipocytes. Conclusion: ADSCs and adipocytes alike are capable of expressing TLRs, but white adipocytes remain the highest expressing in both control and stimulated cultures. TLR2 is highly expressed in white and beige adipocytes whereas TLR4 showed no significant expression. LPS and METRNL trigger IL-6 and IL-8 secretion in adipocytes. Products of white adipocyte “browning” are capable of secreting higher amounts of BDNF and NGF in comparison to white adipocytes.

scholarly journals Liensinine Inhibits Beige Adipocytes Recovering to white Adipocytes through Blocking Mitophagy Flux In Vitro and In Vivo

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1640 ◽  
Author(s):  
Siyu Xie ◽  
Yuan Li ◽  
Wendi Teng ◽  
Min Du ◽  
Yixuan Li ◽  
...  
Keyword(s):  
Body Weight Gain ◽  
Uncoupling Protein ◽  
Molecular Characteristics ◽  
Potential Candidate ◽  
Beige Adipocyte ◽  
White Adipocyte ◽  
White Adipocytes ◽  
Beige Adipocytes

Promoting white-to-beige adipocyte transition is a promising approach for obesity treatment. Although Liensinine (Lie), a kind of isoquinoline alkaloid, has been reported to affect white-to-beige adipocyte transition, its effects on inhibiting beige adipocytes recovering to white adipocytes and maintaining the characteristics of beige adipocyte remain unclear. Therefore, we explored the effects and underlying mechanism of Lie on beige adipocyte maintenance in vitro and in vivo. Here, we first demonstrated that after white adipocytes turned to beige adipocytes by rosiglitazone (Rosi) stimuli, beige adipocytes gradually lost their characteristics and returned to white adipocytes again once Rosi was withdrawn. We found that Lie retained high levels of uncoupling protein 1 (UCP1) and mitochondrial oxidative phosphorylation complex I, II, III, IV and V (COX I–V), oxygen consumption rate (OCR) after Rosi withdrawal. In addition, after Rosi withdrawal, the beige-to-white adipocyte transition was coupled to mitophagy, while Lie inhibited mitophagy flux by promoting the accumulation of pro-cathepsin B (pro-CTSB), pro-cathepsin D (pro-CTSD) and pro-cathepsin L (pro-CTSL), ultimately maintaining the beige adipocytes characteristics in vitro. Moreover, through blocking mitophagy flux, Lie significantly retained the molecular characteristics of beige adipocyte, reduced body weight gain rate and enhanced energy expenditure after stimuli withdrawal in vivo. Together, our data showed that Lie inhibited lysosomal cathepsin activity by promoting the accumulation of pro-CTSB, pro-CTSD and pro-CTSL, which subsequently inhibited mitophagy flux, and ultimately inhibited the beige adipocytes recovering to white adipocytes and maintained the characteristics of beige adipocyte after stimuli withdrawal. In conclusion, by blocking lysosome-mediated mitophagy, Lie inhibits beige adipocytes recovering to white adipocytes and may be a potential candidate for preventing high fat diet induced obesity.

A compendium of G-protein–coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure

2020 ◽  
Vol 134 (5) ◽  
pp. 473-512 ◽  
Author(s):  
Ryan P. Ceddia ◽  
Sheila Collins
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Signaling Pathways ◽  
G Protein ◽  
Uncoupling Protein ◽  
Beige Adipocytes ◽  
Nucleotide Regulation ◽  
Ucp1 Expression ◽  
Thermogenic Adipocytes ◽  
G Protein Coupled

Abstract With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand–receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein–coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.

Adipokines as key players in β cell function and failure

2019 ◽  
Vol 133 (22) ◽  
pp. 2317-2327 ◽  
Author(s):  
Nicolás Gómez-Banoy ◽  
James C. Lo
Keyword(s):  
Metabolic Diseases ◽  
Cell Function ◽  
Whole Body ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Axis ◽  
Β Cell Function ◽  
Prevalence Of Obesity ◽  
Specific Factors ◽  
Whole Body Metabolism

Abstract The growing prevalence of obesity and its related metabolic diseases, mainly Type 2 diabetes (T2D), has increased the interest in adipose tissue (AT) and its role as a principal metabolic orchestrator. Two decades of research have now shown that ATs act as an endocrine organ, secreting soluble factors termed adipocytokines or adipokines. These adipokines play crucial roles in whole-body metabolism with different mechanisms of action largely dependent on the tissue or cell type they are acting on. The pancreatic β cell, a key regulator of glucose metabolism due to its ability to produce and secrete insulin, has been identified as a target for several adipokines. This review will focus on how adipokines affect pancreatic β cell function and their impact on pancreatic β cell survival in disease contexts such as diabetes. Initially, the “classic” adipokines will be discussed, followed by novel secreted adipocyte-specific factors that show therapeutic promise in regulating the adipose–pancreatic β cell axis.

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