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American Journal of Physiology. Cell... May 2021Adipocytes are specialized cells with pleiotropic roles in physiology and pathology. Several types of fat cells with distinct metabolic properties coexist in various... (Review)
Review
Adipocytes are specialized cells with pleiotropic roles in physiology and pathology. Several types of fat cells with distinct metabolic properties coexist in various anatomically defined fat depots in mammals. White, beige, and brown adipocytes differ in their handling of lipids and thermogenic capacity, promoting differences in size and morphology. Moreover, adipocytes release lipids and proteins with paracrine and endocrine functions. The intrinsic properties of adipocytes pose specific challenges in culture. Mature adipocytes float in suspension culture due to high triacylglycerol content and are fragile. Moreover, a fully differentiated state, notably acquirement of the unilocular lipid droplet of white adipocyte, has so far not been reached in two-dimensional culture. Cultures of mouse and human-differentiated preadipocyte cell lines and primary cells have been established to mimic white, beige, and brown adipocytes. Here, we survey various models of differentiated preadipocyte cells and primary mature adipocyte survival describing main characteristics, culture conditions, advantages, and limitations. An important development is the advent of three-dimensional culture, notably of adipose spheroids that recapitulate in vivo adipocyte function and morphology in fat depots. Challenges for the future include isolation and culture of adipose-derived stem cells from different anatomic location in animal models and humans differing in sex, age, fat mass, and pathophysiological conditions. Further understanding of fat cell physiology and dysfunction will be achieved through genetic manipulation, notably CRISPR-mediated gene editing. Capturing adipocyte heterogeneity at the single-cell level within a single fat depot will be key to understanding diversities in cardiometabolic parameters among lean and obese individuals.
Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Cell Communication; Cell Culture Techniques; Cell Line; Cell Survival; Humans; Phenotype; Species Specificity; Spheroids, Cellular; Tissue Culture Techniques
PubMed: 33439778
DOI: 10.1152/ajpcell.00519.2020 -
Genes & Development Mar 2021Obesity is the most common cause of insulin resistance, and the current obesity epidemic is driving a parallel rise in the incidence of T2DM. It is now widely recognized... (Review)
Review
Obesity is the most common cause of insulin resistance, and the current obesity epidemic is driving a parallel rise in the incidence of T2DM. It is now widely recognized that chronic, subacute tissue inflammation is a major etiologic component of the pathogenesis of insulin resistance and metabolic dysfunction in obesity. Here, we summarize recent advances in our understanding of immunometabolism. We discuss the characteristics of chronic inflammation in the major metabolic tissues and how obesity triggers these events, including a focus on the role of adipose tissue hypoxia and macrophage-derived exosomes. Last, we also review current and potential new therapeutic strategies based on immunomodulation.
Topics: Adipose Tissue; Cell Hypoxia; Chronic Disease; Exosomes; Humans; Immunomodulation; Inflammation; Metabolic Diseases
PubMed: 33649162
DOI: 10.1101/gad.346312.120 -
Trends in Cell Biology Apr 2022The important role of mitochondria in the regulation of white adipose tissue (WAT) remodeling and energy balance is increasingly appreciated. The remarkable... (Review)
Review
The important role of mitochondria in the regulation of white adipose tissue (WAT) remodeling and energy balance is increasingly appreciated. The remarkable heterogeneity of the adipose tissue stroma provides a cellular basis to enable adipose tissue plasticity in response to various metabolic stimuli. Regulating mitochondrial function at the cellular level in adipocytes, in adipose progenitor cells (APCs), and in adipose tissue macrophages (ATMs) has a profound impact on adipose homeostasis. Moreover, mitochondria facilitate the cell-to-cell communication within WAT, as well as the crosstalk with other organs, such as the liver, the heart, and the pancreas. A better understanding of mitochondrial regulation in the diverse adipose tissue cell types allows us to develop more specific and efficient approaches to improve adipose function and achieve improvements in overall metabolic health.
Topics: Adipocytes; Adipose Tissue; Adipose Tissue, White; Homeostasis; Humans; Mitochondria
PubMed: 34810062
DOI: 10.1016/j.tcb.2021.10.008 -
Journal of Lipid Research Oct 2019The breakthrough discoveries of leptin and adiponectin more than two decades ago led to a widespread recognition of adipose tissue as an endocrine organ. Many more... (Review)
Review
The breakthrough discoveries of leptin and adiponectin more than two decades ago led to a widespread recognition of adipose tissue as an endocrine organ. Many more adipose tissue-secreted signaling mediators (adipokines) have been identified since then, and much has been learned about how adipose tissue communicates with other organs of the body to maintain systemic homeostasis. Beyond proteins, additional factors, such as lipids, metabolites, noncoding RNAs, and extracellular vesicles (EVs), released by adipose tissue participate in this process. Here, we review the diverse signaling mediators and mechanisms adipose tissue utilizes to relay information to other organs. We discuss recently identified adipokines (proteins, lipids, and metabolites) and briefly outline the contributions of noncoding RNAs and EVs to the ever-increasing complexities of adipose tissue inter-organ communication. We conclude by reflecting on central aspects of adipokine biology, namely, the contribution of distinct adipose tissue depots and cell types to adipokine secretion, the phenomenon of adipokine resistance, and the capacity of adipose tissue to act both as a source and sink of signaling mediators.
Topics: Adiponectin; Adipose Tissue; Animals; Humans; Leptin; Lipid Metabolism; Signal Transduction
PubMed: 31209153
DOI: 10.1194/jlr.R094060 -
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 -
International Journal of Molecular... Apr 2020Thermogenesis is the production of heat that occurs in all warm-blooded animals. During cold exposure, there is obligatory thermogenesis derived from body metabolism as... (Review)
Review
Thermogenesis is the production of heat that occurs in all warm-blooded animals. During cold exposure, there is obligatory thermogenesis derived from body metabolism as well as adaptive thermogenesis through shivering and non-shivering mechanisms. The latter mainly occurs in brown adipose tissue (BAT) and muscle; however, white adipose tissue (WAT) also can undergo browning via adrenergic stimulation to acquire thermogenic potential. Thyroid hormone (TH) also exerts profound effects on thermoregulation, as decreased body temperature and increased body temperature occur during hypothyroidism and hyperthyroidism, respectively. We have termed the TH-mediated thermogenesis under thermoneutral conditions "activated" thermogenesis. TH acts on the brown and/or white adipose tissues to induce uncoupled respiration through the induction of the uncoupling protein (Ucp1) to generate heat. TH acts centrally to activate the BAT and browning through the sympathetic nervous system. However, recent studies also show that TH acts peripherally on the BAT to directly stimulate Ucp1 expression and thermogenesis through an autophagy-dependent mechanism. Additionally, THs can exert Ucp1-independent effects on thermogenesis, most likely through activation of exothermic metabolic pathways. This review summarizes thermogenic effects of THs on adipose tissues.
Topics: Adipose Tissue; Adipose Tissue, Beige; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Energy Metabolism; Glucose; Humans; Mitochondria; Oxidation-Reduction; Thermogenesis; Thyroid Hormones
PubMed: 32344721
DOI: 10.3390/ijms21083020 -
Nature Metabolism Jan 2020The complex relationship between metabolic disease risk and body fat distribution in humans involves cellular characteristics which are specific to body fat...
The complex relationship between metabolic disease risk and body fat distribution in humans involves cellular characteristics which are specific to body fat compartments. Here we show depot-specific differences in the stromal vascual fraction of visceral and subcutaneous adipose tissue by performing single-cell RNA sequencing of tissue specimen from obese individuals. We characterize multiple immune cells, endothelial cells, fibroblasts, adipose and hematopoietic stem cell progenitors. Subpopulations of adipose-resident immune cells are metabolically active and associated with metabolic disease status and those include a population of potential dysfunctional CD8+ T cells expressing metallothioneins. We identify multiple types of adipocyte progenitors that are common across depots, including a subtype enriched in individuals with type 2 diabetes. Depot-specific analysis reveals a class of adipocyte progenitors unique to visceral adipose tissue, which shares common features with beige preadipocytes. Our human single-cell transcriptome atlas across fat depots provides a resource to dissect functional genomics of metabolic disease.
Topics: Adipocytes; Adipose Tissue; Adult; Body Fat Distribution; Female; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Humans; Male; Metabolic Diseases; Middle Aged; Obesity; Single-Cell Analysis
PubMed: 32066997
DOI: 10.1038/s42255-019-0152-6 -
International Journal of Molecular... Oct 2021Lipedema is a painful fat disorder that affects ~11% of the female population. It is characterized by bilateral, disproportionate accumulation of subcutaneous adipose... (Review)
Review
Lipedema is a painful fat disorder that affects ~11% of the female population. It is characterized by bilateral, disproportionate accumulation of subcutaneous adipose tissue predominantly in the lower body. The onset of lipedema pathophysiology is thought to occur during periods of hormonal fluctuation, such as puberty, pregnancy, or menopause. Although the identification and characterization of lipedema have improved, the underlying disease etiology remains to be elucidated. Estrogen, a key regulator of adipocyte lipid and glucose metabolism, and female-associated body fat distribution are postulated to play a contributory role in the pathophysiology of lipedema. Dysregulation of adipose tissue accumulation via estrogen signaling likely occurs by two mechanisms: (1). altered adipocyte estrogen receptor distribution (ERα/ERß ratio) and subsequent metabolic signaling and/or (2). increased release of adipocyte-produced steroidogenic enzymes leading to increased paracrine estrogen release. These alterations could result in increased activation of peroxisome proliferator-activated receptor γ (PPARγ), free fatty acid entry into adipocytes, glucose uptake, and angiogenesis while decreasing lipolysis, mitochondriogenesis, and mitochondrial function. Together, these metabolic alterations would lead to increased adipogenesis and adipocyte lipid deposition, resulting in increased adipose depot mass. This review summarizes research characterizing estrogen-mediated adipose tissue metabolism and its possible relation to excessive adipose tissue accumulation associated with lipedema.
Topics: Adipose Tissue; Animals; Estrogens; Humans; Lipedema; Receptors, Estrogen; Signal Transduction
PubMed: 34769153
DOI: 10.3390/ijms222111720 -
Biochimica Et Biophysica Acta.... Mar 2023Fasting and starvation were common occurrences during human evolution and accordingly have been an important environmental factor shaping human energy metabolism. Humans... (Review)
Review
Fasting and starvation were common occurrences during human evolution and accordingly have been an important environmental factor shaping human energy metabolism. Humans can tolerate fasting reasonably well through adaptative and well-orchestrated time-dependent changes in energy metabolism. Key features of the adaptive response to fasting are the breakdown of liver glycogen and muscle protein to produce glucose for the brain, as well as the gradual depletion of the fat stores, resulting in the release of glycerol and fatty acids into the bloodstream and the production of ketone bodies in the liver. In this paper, an overview is presented of our current understanding of the effects of fasting on adipose tissue metabolism. Fasting leads to reduced uptake of circulating triacylglycerols by adipocytes through inhibition of the activity of the rate-limiting enzyme lipoprotein lipase. In addition, fasting stimulates the degradation of stored triacylglycerols by activating the key enzyme adipose triglyceride lipase. The mechanisms underlying these events are discussed, with a special interest in insights gained from studies on humans. Furthermore, an overview is presented of the effects of fasting on other metabolic pathways in the adipose tissue, including fatty acid synthesis, glucose uptake, glyceroneogenesis, autophagy, and the endocrine function of adipose tissue.
Topics: Humans; Adipose Tissue; Fasting; Adipocytes; Lipolysis; Triglycerides
PubMed: 36521736
DOI: 10.1016/j.bbalip.2022.159262 -
Nature Sep 2022Adipose tissues communicate with the central nervous system to maintain whole-body energy homeostasis. The mainstream view is that circulating hormones secreted by the...
Adipose tissues communicate with the central nervous system to maintain whole-body energy homeostasis. The mainstream view is that circulating hormones secreted by the fat convey the metabolic state to the brain, which integrates peripheral information and regulates adipocyte function through noradrenergic sympathetic output. Moreover, somatosensory neurons of the dorsal root ganglia innervate adipose tissue. However, the lack of genetic tools to selectively target these neurons has limited understanding of their physiological importance. Here we developed viral, genetic and imaging strategies to manipulate sensory nerves in an organ-specific manner in mice. This enabled us to visualize the entire axonal projection of dorsal root ganglia from the soma to subcutaneous adipocytes, establishing the anatomical underpinnings of adipose sensory innervation. Functionally, selective sensory ablation in adipose tissue enhanced the lipogenic and thermogenetic transcriptional programs, resulting in an enlarged fat pad, enrichment of beige adipocytes and elevated body temperature under thermoneutral conditions. The sensory-ablation-induced phenotypes required intact sympathetic function. We postulate that beige-fat-innervating sensory neurons modulate adipocyte function by acting as a brake on the sympathetic system. These results reveal an important role of the innervation by dorsal root ganglia of adipose tissues, and could enable future studies to examine the role of sensory innervation of disparate interoceptive systems.
Topics: Adipose Tissue; Adipose Tissue, Beige; Animals; Axons; Energy Metabolism; Ganglia, Spinal; Homeostasis; Hormones; Mice; Organ Specificity; Sensory Receptor Cells; Subcutaneous Fat; Sympathetic Nervous System; Thermogenesis
PubMed: 36045288
DOI: 10.1038/s41586-022-05137-7