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ELife May 2024The energy-burning capability of beige adipose tissue is a potential therapeutic tool for reducing obesity and metabolic disease, but this capacity is decreased by...
The energy-burning capability of beige adipose tissue is a potential therapeutic tool for reducing obesity and metabolic disease, but this capacity is decreased by aging. Here, we evaluate the impact of aging on the profile and activity of adipocyte stem and progenitor cells (ASPCs) and adipocytes during the beiging process in mice. We found that aging increases the expression of and other fibro-inflammatory genes in fibroblastic ASPCs and blocks their differentiation into beige adipocytes. Fibroblastic ASPC populations from young and aged mice were equally competent for beige differentiation in vitro, suggesting that environmental factors suppress adipogenesis in vivo. Examination of adipocytes by single nucleus RNA-sequencing identified compositional and transcriptional differences in adipocyte populations with aging and cold exposure. Notably, cold exposure induced an adipocyte population expressing high levels of de novo lipogenesis (DNL) genes, and this response was severely blunted in aged animals. We further identified , which encodes the natriuretic peptide clearance receptor, as a marker gene for a subset of white adipocytes and an aging-upregulated gene in adipocytes. In summary, this study indicates that aging blocks beige adipogenesis and dysregulates adipocyte responses to cold exposure and provides a resource for identifying cold and aging-regulated pathways in adipose tissue.
Topics: Animals; Adipogenesis; Aging; Mice; Cold Temperature; Adipocytes, Beige; Mice, Inbred C57BL; Male; Adipocytes; Cell Differentiation; Cellular Reprogramming; Metabolic Reprogramming
PubMed: 38775132
DOI: 10.7554/eLife.87756 -
FEBS Open Bio Oct 2020Dysregulation of adipocyte differentiation and dysfunction play key roles in the pathogenesis of obesity and associated disorders such as diabetes and metabolic...
Dysregulation of adipocyte differentiation and dysfunction play key roles in the pathogenesis of obesity and associated disorders such as diabetes and metabolic syndrome, and as such, a better understanding of the molecular mechanism of adipogenesis may help to elucidate the pathological condition of obesity and its associated disorders. Regucalcin (RGN) plays multiple regulatory roles in intracellular Ca signaling pathways in mammalian cells. Here, we report that overexpression of RGN enhances lipid accumulation in 3T3-L1 adipocyte cells after adipogenic stimulation, accompanied by upregulation of adipocyte differentiation marker proteins. In contrast, genetic disruption of RGN inhibited adipogenic stimulation-induced differentiation of 3T3-L1 cells. Furthermore, RGN overexpression in differentiated 3T3-L1 adipocytes blocked inflammatory crosstalk between 3T3-L1 adipocytes and RAW264.7 macrophages in a transwell coculture system. Knockdown of RGN expression in cocultured 3T3-L1 adipocytes enhanced their susceptibility to RAW264.7 macrophage-mediated inflammation. These results suggest that RGN is required for 3T3-L1 adipocyte differentiation and that it exerts anti-inflammatory activity against 3T3-L1 adipocyte inflammation after coculture with RAW264.7 macrophages. Thus, RGN may be a novel regulator of adipocyte differentiation and act as a suppressor of inflammation in macrophage-infiltrated adipocyte tissue.
Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Calcium-Binding Proteins; Cell Differentiation; Cell Line; Coculture Techniques; Inflammation; Intracellular Signaling Peptides and Proteins; Macrophages; Mice; Obesity; RAW 264.7 Cells; Signal Transduction
PubMed: 32783343
DOI: 10.1002/2211-5463.12947 -
Trends in Endocrinology and Metabolism:... Feb 2019Hair follicles (HFs) strongly interact with adipocytes within the dermal white adipose tissue (dWAT), suggesting a strong physiological dependence on the content of... (Review)
Review
Hair follicles (HFs) strongly interact with adipocytes within the dermal white adipose tissue (dWAT), suggesting a strong physiological dependence on the content of immature and mature adipocytes in this layer. This content is regulated by the proliferation and differentiation of adipocyte precursors, as well as by dedifferentiation of mature existing adipocytes. Spatially, long-range interactions between HFs and dWAT involve the exchange of extracellular vesicles which are differentially released by precursors, preadipocytes, and mature adipocytes. Different exogenous factors, including light irradiation, are likely to modify the release of adipocyte-derived exosomes in dWAT, which can lead to aberrations of the HF cycle. Consequently, dWAT should be considered as a potential target for the modulation of hair growth.
Topics: Adipocytes; Adipose Tissue, White; Animals; Cell Differentiation; Cell Proliferation; Hair Follicle; Humans
PubMed: 30558832
DOI: 10.1016/j.tem.2018.11.004 -
Current Opinion in Cell Biology Aug 2017Intracellular lipid droplets (LDs) are remarkably dynamic and complex organelles that enact regulated storage and release of lipids to fulfil their fundamental roles in... (Review)
Review
Intracellular lipid droplets (LDs) are remarkably dynamic and complex organelles that enact regulated storage and release of lipids to fulfil their fundamental roles in energy metabolism, membrane synthesis and provision of lipid-derived signaling molecules. Although small LDs are observed in all types of eukaryotic cells, it is adipocytes that present the widest range of sizes up to the massive unilocular droplet of a white adipocyte. Our knowledge of the proteins and associated processes that control LD dynamics is improving. The dynamic expression of LD-associated proteins is vital for controlling LD biology and is most apparent during adipocyte differentiation. Recent findings on the molecular mechanisms of lipid droplet enlargement reveal the importance of distinct functional groups of proteins and phospholipids.
Topics: Adipocytes; Animals; Cell Differentiation; Endoplasmic Reticulum; Lipid Droplets; Lipid Metabolism; Lipids; Phospholipids; Proteins
PubMed: 28231490
DOI: 10.1016/j.ceb.2017.02.002 -
Nature Reviews. Molecular Cell Biology Aug 2016White adipocytes store excess energy in the form of triglycerides, whereas brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function... (Review)
Review
White adipocytes store excess energy in the form of triglycerides, whereas brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function relies on the activation of brown and beige adipocyte-specific gene programmes that are coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators. A number of transcriptional and epigenetic regulators are also required for promoting beige adipocyte biogenesis in response to various environmental stimuli. A better understanding of the molecular mechanisms governing the generation and function of brown and beige adipocytes is necessary to allow us to control adipose cell fate and stimulate thermogenesis. This may provide a therapeutic approach for the treatment of obesity and obesity-associated diseases, such as type 2 diabetes.
Topics: Adipocytes, Beige; Adipocytes, Brown; Animals; Cell Lineage; Epigenesis, Genetic; Humans; Transcription, Genetic
PubMed: 27251423
DOI: 10.1038/nrm.2016.62 -
European Journal of Cell Biology Sep 2023Although phenotypically different, brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) are able to produce heat through non-shivering thermogenesis due...
Although phenotypically different, brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) are able to produce heat through non-shivering thermogenesis due to the presence of mitochondrial uncoupling protein 1 (UCP1). The appearance of thermogenically active beige adipocytes in iWAT is known as browning. Both brown and beige cells originate from mesenchymal stem cells (MSCs), and in culture conditions a browning response can be induced with hypothermia (i.e. 32 °C) during which nuclear leptin immunodetection was observed. The central role of leptin in regulating food intake and energy consumption is well recognised, but its importance in the browning process at the cellular level is unclear. Here, immunocytochemical analysis of MSC-derived adipocytes established nuclear localization of both leptin and leptin receptor suggesting an involvement of the leptin pathway in the browning response. In order to elucidate whether leptin modulates the expression of brown and beige adipocyte markers, BAT and iWAT samples from leptin-deficient (ob/ob) mice were analysed and exhibited reduced brown/beige marker expression compared to wild-type controls. When MSCs were isolated and differentiated into adipocytes, leptin deficiency was observed to induce a white phenotype, especially when incubated at 32 °C. These adaptations were accompanied with morphological signs of impaired adipogenic differentiation. Overall, our results indicate that leptin supports adipocyte browning and suggest a potential role for leptin in adipogenesis and browning.
Topics: Animals; Mice; Adipocytes; Adipocytes, Brown; Adipogenesis; Cell Differentiation; Leptin; Signal Transduction
PubMed: 37467572
DOI: 10.1016/j.ejcb.2023.151342 -
FEBS Letters Aug 2010Adipocyte differentiation is controlled by a tightly regulated transcriptional cascade in which PPARgamma and members of the C/EBP family are key players. Here we review... (Review)
Review
Adipocyte differentiation is controlled by a tightly regulated transcriptional cascade in which PPARgamma and members of the C/EBP family are key players. Here we review the roles of PPARgamma and C/EBPs in adipocyte differentiation with emphasis on the recently published genome-wide binding profiles for PPARgamma and C/EBPalpha. Interestingly, these analyses show that PPARgamma and C/EBPalpha binding sites are associated with most genes that are induced during adipogenesis suggesting direct activation of many more adipocyte genes than previously anticipated. Furthermore, an extensive overlap between the C/EBPalpha and PPARgamma cistromes indicate a hitherto unrecognized direct crosstalk between these transcription factors. As more genome-wide data emerge in the future, this crosstalk will likely be found to include several other adipogenic transcription factors.
Topics: Adipocytes; Adipogenesis; Animals; CCAAT-Enhancer-Binding Proteins; Cell Differentiation; Genome-Wide Association Study; Humans; PPAR gamma
PubMed: 20542036
DOI: 10.1016/j.febslet.2010.06.010 -
Life Sciences Dec 2019Lansoprazole (LPZ) is one of the most commonly prescribed drugs for treatment of acid-related diseases, and it is increasingly recognized for its potential application...
AIMS
Lansoprazole (LPZ) is one of the most commonly prescribed drugs for treatment of acid-related diseases, and it is increasingly recognized for its potential application as an anti-diabetic therapy. Although LPZ target tissues remain poorly understood, possible sites of action include adipose tissue. In this study, we assessed effects of LPZ on adipocyte differentiation and function by using 3T3-L1 preadipocytes and HFD-induced obesity mice as an in vitro and in vivo model, respectively.
MAIN METHODS
Oil red O staining and intracellular triacylglycerol content were used to determine lipid accumulation. Glucose uptake was performed to measure mature adipocyte function. Expression of adipocyte genes was determined by qRT-PCR and immunoblotting.
KEY FINDINGS
LPZ has dual effects on differentiation of 3T3-L1 cells. At low concentrations, LPZ enhanced adipocyte differentiation via induction of PPARγ and C/EBPα, two master adipogenic transcription factors, as well as lipogenic proteins, ACC1 and FASN. Increasing of adipocyte number subsequently increased basal and insulin-stimulated glucose uptake, and expression of Glut4 mRNA. Conversely, high concentrations of LPZ strongly inhibited differentiation and expression of PPARγ and C/EBPα, and maintained expression of preadipocytes markers, β-catenin and Pref-1. Inhibition of adipogenesis by LPZ reduced mature adipocyte number, Glut4 mRNA expression and insulin-stimulated glucose uptake. In addition, treatment with LPZ at 200 mg/kg significantly reduced body weight gain and total fat mass in HFD-induced obese mice.
SIGNIFICANCE
These results indicate that effects of LPZ on adipocyte differentiation are dependent on concentration and are correlated with PPARγ and C/EBPα.
Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; CCAAT-Enhancer-Binding Protein-alpha; Cell Differentiation; Diet, High-Fat; Glucose Transporter Type 4; Insulin; Lansoprazole; Lipid Metabolism; Lipogenesis; Male; Mice; Mice, Inbred C57BL; Obesity; PPAR gamma; Triglycerides
PubMed: 31644894
DOI: 10.1016/j.lfs.2019.116897 -
Experimental Biology and Medicine... Mar 2016Adipose (AD) tissue development and function relies on the ability of adipocytes to proliferate and differentiate into lipid-containing cells that also have endocrine... (Review)
Review
Adipose (AD) tissue development and function relies on the ability of adipocytes to proliferate and differentiate into lipid-containing cells that also have endocrine function. Research suggests that certain conditions can induce AD tissue stem cells to differentiate into various cell types and that the microenvironment of the cell, including the extracellular matrix (ECM), is essential in maintaining cell and tissue function. This review provides an overview of factors involved in the proliferation and differentiation of adipocytes. A brief review of the numerous factors that influence PPARγ, the transcription factor thought to be the master regulator of adipocyte differentiation, provides context of established pathways that regulate adipogenesis. Thought provoking findings from research with hypoxia that is supported by earlier research that vascular development is related to adipogenesis are reviewed. Finally, our understanding of the critical role of the ECM and environment in adipogenesis is discussed and compared with studies that suggest that adipocytes may dedifferentiate and can convert into other cell types.
Topics: Adipocytes; Animals; Cell Differentiation; Environmental Exposure; Extracellular Matrix; Humans; PPAR gamma
PubMed: 26645953
DOI: 10.1177/1535370215619041 -
Oxidative Medicine and Cellular... 2013Metabolic diseases, such as type 2 diabetes and obesity, are increasing globally, and much work has been performed to elucidate the regulatory mechanisms of these... (Review)
Review
Metabolic diseases, such as type 2 diabetes and obesity, are increasing globally, and much work has been performed to elucidate the regulatory mechanisms of these diseases. Nuclear factor E2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor that serves as a primary cellular defense against the cytotoxic effects of oxidative stress. Recent studies have proposed a close relationship between oxidative stress and energy metabolism-associated disease. The Nrf2 pathway, as a master regulator of cellular defense against oxidative stress, has emerged as a critical target of energy metabolism; however, its effects are controversial. This review examines the current state of research on the role of Nrf2 on energy metabolism, specifically with respect to its participation in adipocyte differentiation, obesity, and insulin resistance, and discusses the possibility of using Nrf2 as a therapeutic target in the clinic.
Topics: Adipocytes; Animals; Cell Differentiation; Humans; Insulin Resistance; NF-E2-Related Factor 2; Obesity
PubMed: 24194976
DOI: 10.1155/2013/184598