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Nature Reviews. Molecular Cell Biology Apr 2019Obesity is characterized by increased adipose tissue mass and has been associated with a strong predisposition towards metabolic diseases and cancer. Thus, it... (Review)
Review
Obesity is characterized by increased adipose tissue mass and has been associated with a strong predisposition towards metabolic diseases and cancer. Thus, it constitutes a public health issue of major proportion. The expansion of adipose depots can be driven either by the increase in adipocyte size (hypertrophy) or by the formation of new adipocytes from precursor differentiation in the process of adipogenesis (hyperplasia). Notably, adipocyte expansion through adipogenesis can offset the negative metabolic effects of obesity, and the mechanisms and regulators of this adaptive process are now emerging. Over the past several years, we have learned a considerable amount about how adipocyte fate is determined and how adipogenesis is regulated by signalling and systemic factors. We have also gained appreciation that the adipogenic niche can influence tissue adipogenic capability. Approaches aimed at increasing adipogenesis over adipocyte hypertrophy can now be explored as a means to treat metabolic diseases.
Topics: Adipocytes; Adipogenesis; Animals; Cell Differentiation; Health; Humans; Obesity; Signal Transduction
PubMed: 30610207
DOI: 10.1038/s41580-018-0093-z -
The Journal of Clinical Investigation Jul 2019Development of novel and effective therapeutics for treating various cancers is probably the most congested and challenging enterprise of pharmaceutical companies.... (Review)
Review
Development of novel and effective therapeutics for treating various cancers is probably the most congested and challenging enterprise of pharmaceutical companies. Diverse drugs targeting malignant and nonmalignant cells receive clinical approval each year from the FDA. Targeting cancer cells and nonmalignant cells unavoidably changes the tumor microenvironment, and cellular and molecular components relentlessly alter in response to drugs. Cancer cells often reprogram their metabolic pathways to adapt to environmental challenges and facilitate survival, proliferation, and metastasis. While cancer cells' dependence on glycolysis for energy production is well studied, the roles of adipocytes and lipid metabolic reprogramming in supporting cancer growth, metastasis, and drug responses are less understood. This Review focuses on emerging mechanisms involving adipocytes and lipid metabolism in altering the response to cancer treatment. In particular, we discuss mechanisms underlying cancer-associated adipocytes and lipid metabolic reprogramming in cancer drug resistance.
Topics: Adipocytes; Animals; Drug Resistance, Neoplasm; Glycolysis; Humans; Lipid Metabolism; Neoplasms; Tumor Microenvironment
PubMed: 31264969
DOI: 10.1172/JCI127201 -
Cancer Metastasis Reviews Sep 2022Many epithelial tumors grow in the vicinity of or metastasize to adipose tissue. As tumors develop, crosstalk between adipose tissue and cancer cells leads to changes in... (Review)
Review
Many epithelial tumors grow in the vicinity of or metastasize to adipose tissue. As tumors develop, crosstalk between adipose tissue and cancer cells leads to changes in adipocyte function and paracrine signaling, promoting a microenvironment that supports tumor growth. Over the last decade, it became clear that tumor cells co-opt adipocytes in the tumor microenvironment, converting them into cancer-associated adipocytes (CAA). As adipocytes and cancer cells engage, a metabolic symbiosis ensues that is driven by bi-directional signaling. Many cancers (colon, breast, prostate, lung, ovarian cancer, and hematologic malignancies) stimulate lipolysis in adipocytes, followed by the uptake of fatty acids (FA) from the surrounding adipose tissue. The FA enters the cancer cell through specific fatty acid receptors and binding proteins (e.g., CD36, FATP1) and are used for membrane synthesis, energy metabolism (β-oxidation), or lipid-derived cell signaling molecules (derivatives of arachidonic and linolenic acid). Therefore, blocking adipocyte-derived lipid uptake or lipid-associated metabolic pathways in cancer cells, either with a single agent or in combination with standard of care chemotherapy, might prove to be an effective strategy against cancers that grow in lipid-rich tumor microenvironments.
Topics: Adipocytes; Adipose Tissue; Fatty Acids; Female; Humans; Ovarian Neoplasms; Tumor Microenvironment
PubMed: 35941408
DOI: 10.1007/s10555-022-10059-x -
Clinical Science (London, England :... Oct 2019Adipose tissues collectively as an endocrine organ and energy storage are crucial for systemic metabolic homeostasis. The major cell type in the adipose tissue, the... (Review)
Review
Adipose tissues collectively as an endocrine organ and energy storage are crucial for systemic metabolic homeostasis. The major cell type in the adipose tissue, the adipocytes or fat cells, are remarkably plastic and can increase or decrease their size and number to adapt to changes in systemic or local metabolism. Changes in adipocyte size occur through hypertrophy or atrophy, and changes in cell numbers mainly involve de novo generation of new cells or death of existing cells. Recently, dedifferentiation, whereby a mature adipocyte is reverted to an undifferentiated progenitor-like status, has been reported as a mechanism underlying adipocyte plasticity. Dedifferentiation of mature adipocytes has been observed under both physiological and pathological conditions. This review covers several aspects of adipocyte dedifferentiation, its relevance to adipose tissue function, molecular pathways that drive dedifferentiation, and the potential of therapeutic targeting adipocyte dedifferentiation in human health and metabolic diseases.
Topics: Adipocytes; Adipose Tissue; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Communication; Cell Dedifferentiation; Cell Plasticity; Cells, Cultured; Cellular Microenvironment; Humans; Lactation; Metabolic Diseases
PubMed: 31654064
DOI: 10.1042/CS20190128 -
Frontiers in Endocrinology 2020Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that plays vital roles in modulating metabolism, immunity, and oncogenesis. ATF3 acts... (Review)
Review
Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that plays vital roles in modulating metabolism, immunity, and oncogenesis. ATF3 acts as a hub of the cellular adaptive-response network. Multiple extracellular signals, such as endoplasmic reticulum (ER) stress, cytokines, chemokines, and LPS, are connected to ATF3 induction. The function of ATF3 as a regulator of metabolism and immunity has recently sparked intense attention. In this review, we describe how ATF3 can act as both a transcriptional activator and a repressor. We then focus on the role of ATF3 and ATF3-regulated signals in modulating metabolism, immunity, and oncogenesis. The roles of ATF3 in glucose metabolism and adipose tissue regulation are also explored. Next, we summarize how ATF3 regulates immunity and maintains normal host defense. In addition, we elaborate on the roles of ATF3 as a regulator of prostate, breast, colon, lung, and liver cancers. Further understanding of how ATF3 regulates signaling pathways involved in glucose metabolism, adipocyte metabolism, immuno-responsiveness, and oncogenesis in various cancers, including prostate, breast, colon, lung, and liver cancers, is then provided. Finally, we demonstrate that ATF3 acts as a master regulator of metabolic homeostasis and, therefore, may be an appealing target for the treatment of metabolic dyshomeostasis, immune disorders, and various cancers.
Topics: Activating Transcription Factor 3; Adipocytes; Animals; Endoplasmic Reticulum Stress; Energy Metabolism; Homeostasis; Humans; Neoplasms
PubMed: 32922364
DOI: 10.3389/fendo.2020.00556 -
Molecular Metabolism Apr 2020The diminished glucose lowering effect of insulin in obesity, called "insulin resistance," is associated with glucose intolerance, type 2 diabetes, and other serious... (Review)
Review
BACKGROUND
The diminished glucose lowering effect of insulin in obesity, called "insulin resistance," is associated with glucose intolerance, type 2 diabetes, and other serious maladies. Many publications on this topic have suggested numerous hypotheses on the molecular and cellular disruptions that contribute to the syndrome. However, significant uncertainty remains on the mechanisms of its initiation and long-term maintenance.
SCOPE OF REVIEW
To simplify insulin resistance analysis, this review focuses on the unifying concept that adipose tissue is a central regulator of systemic glucose homeostasis by controlling liver and skeletal muscle metabolism. Key aspects of adipose function related to insulin resistance reviewed are: 1) the modes by which specific adipose tissues control hepatic glucose output and systemic glucose disposal, 2) recently acquired understanding of the underlying mechanisms of these modes of regulation, and 3) the steps in these pathways adversely affected by obesity that cause insulin resistance.
MAJOR CONCLUSIONS
Adipocyte heterogeneity is required to mediate the multiple pathways that control systemic glucose tolerance. White adipocytes specialize in sequestering triglycerides away from the liver, muscle, and other tissues to limit toxicity. In contrast, brown/beige adipocytes are very active in directly taking up glucose in response to β adrenergic signaling and insulin and enhancing energy expenditure. Nonetheless, white, beige, and brown adipocytes all share the common feature of secreting factors and possibly exosomes that act on distant tissues to control glucose homeostasis. Obesity exerts deleterious effects on each of these adipocyte functions to cause insulin resistance.
Topics: Adipocytes, Beige; Adipocytes, Brown; Adipocytes, White; Animals; Humans; Insulin Resistance
PubMed: 32180558
DOI: 10.1016/j.molmet.2019.12.014 -
The Journal of Experimental Biology Mar 2018White adipose tissue (AT) is the main lipid storage depot in vertebrates. Initially considered to be a simple lipid store, AT has recently been recognized as playing a... (Review)
Review
White adipose tissue (AT) is the main lipid storage depot in vertebrates. Initially considered to be a simple lipid store, AT has recently been recognized as playing a role as an endocrine organ that is implicated in processes such as energy homeostasis and as a rich source of stem cells. Interest in adipogenesis has increased not only because of the prevalence of obesity, metabolic syndrome and type 2 diabetes in humans, but also in aquaculture because of the excessive fat deposition experienced in some cultured fish species, which may compromise both their welfare and their final product quality. Adipocyte development is well conserved among vertebrates, and this conservation has facilitated the rapid characterization of several adipogenesis models in fish. This Review presents the main findings of adipogenesis research based in primary cultures of the preadipocytes of farmed fish species. Zebrafish has emerged as an excellent model for studying the early stages of adipocyte fish development Nevertheless, larger fish species are more suitable for the isolation of preadipocytes from visceral AT and for studies in which preadipocytes are differentiated to form mature adipocytes. Differentiated adipocytes contain lipid droplets and express adipocyte marker genes such as those encoding the peroxisome proliferator activated receptor γ (), CCAAT-enhancer-binding protein α (), lipoprotein lipase (), fatty acid synthase (), fatty acid binding protein 11 (), fatty acid transporter protein1 (), adiponectin and leptin. Differentiated adipocytes also have elevated glycerol 3-phosphate (G3P) dehydrogenase (GPDH) activity. To better understand fish adipocyte development and regulation, different adipokines, fatty acids, growth factors and PPAR agonists have been studied, providing relevant insights into which factors affect these processes and counterbalance AT dysregulation.
Topics: Adipocytes; Adipogenesis; Animals; Aquaculture; Cell Differentiation; Fishes
PubMed: 29514876
DOI: 10.1242/jeb.161588 -
Advances in Experimental Medicine and... 2017In obesity, the process of adipogenesis largely determines the number of adipocytes in body fat depots. Adipogenesis is regulated by several adipocyte-selective... (Review)
Review
In obesity, the process of adipogenesis largely determines the number of adipocytes in body fat depots. Adipogenesis is regulated by several adipocyte-selective microRNAs (miRNAs) and transcription factors that modulate adipocyte proliferation and differentiation. However, some miRNAs block expression of master regulators of adipogenesis. Additionally, specific miRNAs have been implicated in adipocyte differentiation and mature adipocyte functions. While, each miRNA targets multiple mRNAs, which may coordinate or antagonize each other's functions, several miRNAs are dysregulated in other tissues during obesity-related comorbidities. In this respect, development of lipid droplets, macrophage accumulation, macrophage polarization, tumor necrosis factor receptor-associated factor 6 activity, lipolysis, lipotoxicity and insulin resistance are effectively controlled by miRNAs.
Topics: Adipocytes; Adipogenesis; Animals; Cell Differentiation; Cell Proliferation; Humans; Lipolysis; MicroRNAs; Obesity; RNA, Messenger
PubMed: 28585213
DOI: 10.1007/978-3-319-48382-5_21 -
Cell Stem Cell Jun 2017Aging and obesity induce ectopic adipocyte accumulation in bone marrow cavities. This process is thought to impair osteogenic and hematopoietic regeneration. Here we...
Aging and obesity induce ectopic adipocyte accumulation in bone marrow cavities. This process is thought to impair osteogenic and hematopoietic regeneration. Here we specify the cellular identities of the adipogenic and osteogenic lineages of the bone. While aging impairs the osteogenic lineage, high-fat diet feeding activates expansion of the adipogenic lineage, an effect that is significantly enhanced in aged animals. We further describe a mesenchymal sub-population with stem cell-like characteristics that gives rise to both lineages and, at the same time, acts as a principal component of the hematopoietic niche by promoting competitive repopulation following lethal irradiation. Conversely, bone-resident cells committed to the adipocytic lineage inhibit hematopoiesis and bone healing, potentially by producing excessive amounts of Dipeptidyl peptidase-4, a protease that is a target of diabetes therapies. These studies delineate the molecular identity of the bone-resident adipocytic lineage, and they establish its involvement in age-dependent dysfunction of bone and hematopoietic regeneration.
Topics: Adipocytes; Aging; Animals; Bone Marrow; Bone Regeneration; Dipeptidyl Peptidase 4; Hematopoiesis; Mice; Mice, Transgenic; Obesity
PubMed: 28330582
DOI: 10.1016/j.stem.2017.02.009 -
Blood Feb 2022Adipocytes occupy 70% of the cellular volume within the bone marrow (BM) wherein multiple myeloma (MM) originates and resides. However, the nature of the interaction...
Adipocytes occupy 70% of the cellular volume within the bone marrow (BM) wherein multiple myeloma (MM) originates and resides. However, the nature of the interaction between MM cells and adipocytes remains unclear. Cancer-associated adipocytes support tumor cells through various mechanisms, including metabolic reprogramming of cancer cells. We hypothesized that metabolic interactions mediate the dependence of MM cells on BM adipocytes. Here we show that BM aspirates from precursor states of MM, including monoclonal gammopathy of undetermined significance and smoldering MM, exhibit significant upregulation of adipogenic commitment compared with healthy donors. In vitro coculture assays revealed an adipocyte-induced increase in MM cell proliferation in monoclonal gammopathy of undetermined significance/smoldering MM compared with newly diagnosed MM. Using murine MM cell/BM adipocyte coculture assays, we describe MM-induced lipolysis in adipocytes via activation of the lipolysis pathway. Upregulation of fatty acid transporters 1 and 4 on MM cells mediated the uptake of secreted free fatty acids (FFAs) by adjacent MM cells. The effect of FFAs on MM cells was dose dependent and revealed increased proliferation at lower concentrations vs induction of lipotoxicity at higher concentrations. Lipotoxicity occurred via the ferroptosis pathway. Exogenous treatment with arachidonic acid, a very-long-chain FFA, in a murine plasmacytoma model displayed a reduction in tumor burden. Taken together, our data reveal a novel pathway involving MM cell-induced lipolysis in BM adipocytes and suggest prevention of FFA uptake by MM cells as a potential target for myeloma therapeutics.
Topics: Adipocytes; Animals; Cell Line; Coculture Techniques; Fatty Acid Transport Proteins; Fatty Acids; Humans; Lipolysis; Male; Mice, SCID; Multiple Myeloma; Tumor Cells, Cultured; Mice
PubMed: 34662370
DOI: 10.1182/blood.2021013832