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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 -
Physiological Reviews Jul 1998The adipocyte plays a critical role in energy balance. Adipose tissue growth involves an increase in adipocyte size and the formation of new adipocytes from precursor... (Review)
Review
The adipocyte plays a critical role in energy balance. Adipose tissue growth involves an increase in adipocyte size and the formation of new adipocytes from precursor cells. For the last 20 years, the cellular and molecular mechanisms of adipocyte differentiation have been extensively studied using preadipocyte culture systems. Committed preadipocytes undergo growth arrest and subsequent terminal differentiation into adipocytes. This is accompanied by a dramatic increase in expression of adipocyte genes including adipocyte fatty acid binding protein and lipid-metabolizing enzymes. Characterization of regulatory regions of adipose-specific genes has led to the identification of the transcription factors peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and CCAAT/enhancer binding protein (C/EBP), which play a key role in the complex transcriptional cascade during adipocyte differentiation. Growth and differentiation of preadipocytes is controlled by communication between individual cells or between cells and the extracellular environment. Various hormones and growth factors that affect adipocyte differentiation in a positive or negative manner have been identified. In addition, components involved in cell-cell or cell-matrix interactions such as preadipocyte factor-1 and extracellular matrix proteins are also pivotal in regulating the differentiation process. Identification of these molecules has yielded clues to the biochemical pathways that ultimately result in transcriptional activation via PPAR-gamma and C/EBP. Studies on the regulation of the these transcription factors and the mode of action of various agents that influence adipocyte differentiation will reveal the physiological and pathophysiological mechanisms underlying adipose tissue development.
Topics: Adipocytes; Adipose Tissue; Animals; Cell Differentiation; Humans
PubMed: 9674695
DOI: 10.1152/physrev.1998.78.3.783 -
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 -
Cold Spring Harbor Perspectives in... Sep 2012Adipose tissue is an important site for lipid storage, energy homeostasis, and whole-body insulin sensitivity. It is important to understand the mechanisms involved in... (Review)
Review
Adipose tissue is an important site for lipid storage, energy homeostasis, and whole-body insulin sensitivity. It is important to understand the mechanisms involved in adipose tissue development and function, which can be regulated by the endocrine actions of various peptide and steroid hormones. Recent studies have revealed that white and brown adipocytes can be derived from distinct precursor cells. This review will focus on transcriptional control of adipogenesis and its regulation by several endocrine hormones. The general functions and cellular origins of adipose tissue and how the modulation of adipocyte development pertains to metabolic disease states will also be considered.
Topics: Adipocytes, Brown; Adipocytes, White; Adipogenesis; Adipose Tissue; Animals; Gene Regulatory Networks; Humans; Metabolic Diseases; Models, Biological; Signal Transduction
PubMed: 22952395
DOI: 10.1101/cshperspect.a008417 -
Annual Review of Nutrition 2007Lipolysis of white adipose tissue triacylglycerol stores results in the liberation of glycerol and nonesterified fatty acids that are released into the vasculature for... (Review)
Review
Lipolysis of white adipose tissue triacylglycerol stores results in the liberation of glycerol and nonesterified fatty acids that are released into the vasculature for use by other organs as energy substrates. In response to changes in nutritional state, lipolysis rates are precisely regulated through hormonal and biochemical signals. These signals modulate the activity of lipolytic enzymes and accessory proteins, allowing for maximal responsiveness of adipose tissue to changes in energy requirements and availability. Recently, a number of novel adipocyte triacylglyceride lipases have been identified, including desnutrin/ATGL, greatly expanding our understanding of adipocyte lipolysis. We have also begun to better appreciate the role of a number of nonenzymatic proteins that are critical to triacylglyceride breakdown. This review provides an overview of key mediators of lipolysis and the regulation of this process by changes in nutritional status and nutrient intakes.
Topics: Adipocytes; Animals; Hormones; Humans; Lipase; Lipolysis; Nutritional Status; Signal Transduction; Triglycerides
PubMed: 17313320
DOI: 10.1146/annurev.nutr.27.061406.093734 -
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 -
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 -
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 -
Frontiers in Endocrinology 2020Maintenance of adipocyte precursors is critical for regulating metabolism and preventing obesity related disease. These precursors have been immortalized and studied in... (Review)
Review
Maintenance of adipocyte precursors is critical for regulating metabolism and preventing obesity related disease. These precursors have been immortalized and studied in cellular models as well as-more recently-in animal models. However, little is known about adipocyte precursors from animals of different ages. Most research has focused on adipocyte precursors during obesity. This review goes over the most recent reports of adipocyte precursors during development and in adulthood. Some of these new analyses are due to new techniques such as single cell-RNA sequencing and temporally controlled lineage tracing. With these tools, we have been able to further our understanding of adipocyte precursor lineages and their different regulatory mechanisms. As we learn more about adipocyte precursor plasticity and regulation, we can hope to use this knowledge for future clinical applications.
Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Cell Differentiation; Humans; Obesity; Single-Cell Analysis
PubMed: 33679601
DOI: 10.3389/fendo.2020.613606 -
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