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Journal of Interferon & Cytokine... Aug 2019Comprehension of adipocyte function has evolved beyond a long-held belief of their inert nature, as simple energy storing and releasing cells. Adipocytes, including... (Review)
Review
Comprehension of adipocyte function has evolved beyond a long-held belief of their inert nature, as simple energy storing and releasing cells. Adipocytes, including white, brown, and beige, are capable mediators of global metabolic health, but their intersection with inflammation is a budding field of exploration. Evidence hints at a reciprocal relationship adipocytes share with immune cells. Adipocyte's capacity to behave in an "immune-like" manner and ability to sense inflammatory cues that subsequently alter core adipocyte function might play an important role in shaping immune responses. Clarifying this intricate relationship could uncover previously underappreciated contribution of adipocytes to inflammation-driven human health and disease. In this review, we highlight the potential of largely underappreciated adipocyte "immune-like" function and how it may contribute to inflammation, immunity, and pathology of various diseases.
Topics: Adipocytes; Animals; Humans; Inflammation
PubMed: 30920343
DOI: 10.1089/jir.2019.0014 -
Frontiers in Endocrinology 2023The ability to generate thermogenic fat could be a targeted therapy to thwart obesity and improve metabolic health. Brown and beige adipocytes are two types of... (Review)
Review
The ability to generate thermogenic fat could be a targeted therapy to thwart obesity and improve metabolic health. Brown and beige adipocytes are two types of thermogenic fat cells that regulate energy balance. Both adipocytes share common morphological, biochemical, and thermogenic properties. Yet, recent evidence suggests unique features exist between brown and beige adipocytes, such as their cellular origin and thermogenic regulatory processes. Beige adipocytes also appear highly plastic, responding to environmental stimuli and interconverting between beige and white adipocyte states. Additionally, beige adipocytes appear to be metabolically heterogenic and have substrate specificity. Nevertheless, obese and aged individuals cannot develop beige adipocytes in response to thermogenic fat-inducers, creating a key clinical hurdle to their therapeutic promise. Thus, elucidating the underlying developmental, molecular, and functional mechanisms that govern thermogenic fat cells will improve our understanding of systemic energy regulation and strive for new targeted therapies to generate thermogenic fat. This review will examine the recent advances in thermogenic fat biogenesis, molecular regulation, and the potential mechanisms for their failure.
Topics: Humans; Aged; Adipocytes; Adipose Tissue, Brown; Adipocytes, Beige; Energy Metabolism; Obesity
PubMed: 37020585
DOI: 10.3389/fendo.2023.1150059 -
Trends in Biochemical Sciences Jun 2022Insulin stimulates glucose uptake into adipocytes via mTORC2/AKT signaling and GLUT4 translocation and directs glucose carbons into glycolysis, glycerol for TAG... (Review)
Review
Insulin stimulates glucose uptake into adipocytes via mTORC2/AKT signaling and GLUT4 translocation and directs glucose carbons into glycolysis, glycerol for TAG synthesis, and de novo lipogenesis. Adipocyte insulin resistance is an early indicator of type 2 diabetes in obesity, a worldwide health crisis. Thus, understanding the interplay between insulin signaling and central carbon metabolism pathways that maintains adipocyte function, blood glucose levels, and metabolic homeostasis is critical. While classically viewed through the lens of individual enzyme-substrate interactions, advances in mass spectrometry are beginning to illuminate adipocyte signaling and metabolic networks on an unprecedented scale, yet this is just the tip of the iceberg. Here, we review how 'omics approaches help to elucidate adipocyte insulin action in cellular time and space.
Topics: Adipocytes; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Signal Transduction
PubMed: 35304047
DOI: 10.1016/j.tibs.2022.02.009 -
Frontiers in Immunology 2021The role of adipose tissue (AT) inflammation in obesity and its multiple related-complications is a rapidly expanding area of scientific interest. Within the last 30... (Review)
Review
The role of adipose tissue (AT) inflammation in obesity and its multiple related-complications is a rapidly expanding area of scientific interest. Within the last 30 years, the role of the adipocyte as an endocrine and immunologic cell has been progressively established. Like the macrophage, the adipocyte is capable of linking the innate and adaptive immune system through the secretion of adipokines and cytokines; exosome release of lipids, hormones, and microRNAs; and contact interaction with other immune cells. Key innate immune cells in AT include adipocytes, macrophages, neutrophils, and innate lymphoid cells type 2 (ILC2s). The role of the innate immune system in promoting adipose tissue inflammation in obesity will be highlighted in this review. T cells and B cells also play important roles in contributing to AT inflammation and are discussed in this series in the chapter on adaptive immunity.
Topics: Adaptive Immunity; Adipocytes; Adipokines; Adipose Tissue; Cytokines; Humans; Immunity, Innate; Macrophages; Obesity; T-Lymphocytes
PubMed: 34248937
DOI: 10.3389/fimmu.2021.650768 -
Cells Sep 2023Innate immune signaling in adipocytes affects systemic metabolism. Cytosolic nucleic acid sensing has been recently shown to stimulate thermogenic adipocyte...
Innate immune signaling in adipocytes affects systemic metabolism. Cytosolic nucleic acid sensing has been recently shown to stimulate thermogenic adipocyte differentiation and protect from obesity; however, DNA efflux from adipocyte mitochondria is a potential proinflammatory signal that causes adipose tissue dysfunction and insulin resistance. Cytosolic DNA activates the stimulator of interferon response genes (STING), a key signal transducer which triggers type I interferon (IFN-I) expression; hence, STING activation is expected to induce IFN-I response and adipocyte dysfunction. However, we show herein that mouse adipocytes had a diminished IFN-I response to STING stimulation by 2'3'-cyclic-GMP-AMP (cGAMP). We also show that cGAMP triggered autophagy in murine and human adipocytes. In turn, STING inhibition reduced autophagosome number, compromised the mitochondrial network and caused inflammation and fat accumulation in adipocytes. STING hence stimulates a process that removes damaged mitochondria, thereby protecting adipocytes from an excessive IFN-I response to mitochondrial DNA efflux. In summary, STING appears to limit inflammation in adipocytes by promoting mitophagy under non-obesogenic conditions.
Topics: Animals; Humans; Mice; Adipocytes; Autophagy; DNA, Mitochondrial; Inflammation; Interferon Type I; Membrane Proteins
PubMed: 37830559
DOI: 10.3390/cells12192345 -
Oncology Reports Jul 2023Locally advanced and metastatic pancreatic cancer (PC) frequently grows in adipose tissue and has a poor prognosis. Although adipose tissue is largely composed of...
Locally advanced and metastatic pancreatic cancer (PC) frequently grows in adipose tissue and has a poor prognosis. Although adipose tissue is largely composed of adipocytes, the mechanisms by which adipocytes impact PC are poorly understood. Using an coculture model, it was shown that adipocytes promoted tumor progression, and an intricate metabolic network between PC cells and adipocytes was identified and elucidated. First, the proteome of Panc‑1 PC cells cultured with or without mature adipocytes was identified. This revealed activated hypoxia signaling in cocultured Panc‑1 cells, which was confirmed by the increased expression of factors downstream of hypoxia signaling, such as ANGPTL4 and glycolytic genes, as determined by reverse transcription‑quantitative PCR and western blot analysis. In addition, it was demonstrated that coculture with cancer cells activated STAT3 and induced an insulin‑resistant phenotype in adipocytes. Furthermore, enhanced fatty acid β‑oxidation and increased lipid droplets (LDs) were observed in the cocultured cancer cells. In contrast, downregulated lipid metabolism and a decrease in the size of LDs were found in cocultured adipocytes. Finally, it was shown that the increase in LDs contributed to the increased metastatic capacity of the cocultured PC cells. These data demonstrated that interrupting the mechanisms of lipid uptake from adipocytes in the microenvironment may offer a potential strategy for attenuating PC metastasis.
Topics: Humans; Fatty Acids; Pancreatic Neoplasms; Adipocytes; Signal Transduction; Tumor Microenvironment
PubMed: 37264956
DOI: 10.3892/or.2023.8578 -
The Biochemical Journal Jun 2020Metabolic inflexibility, defined as the inability to respond or adapt to metabolic demand, is now recognised as a driving factor behind many pathologies associated with... (Review)
Review
Metabolic inflexibility, defined as the inability to respond or adapt to metabolic demand, is now recognised as a driving factor behind many pathologies associated with obesity and the metabolic syndrome. Adipose tissue plays a pivotal role in the ability of an organism to sense, adapt to and counteract environmental changes. It provides a buffer in times of nutrient excess, a fuel reserve during starvation and the ability to resist cold-stress through non-shivering thermogenesis. Recent advances in single-cell RNA sequencing combined with lineage tracing, transcriptomic and proteomic analyses have identified novel adipocyte progenitors that give rise to specialised adipocytes with diverse functions, some of which have the potential to be exploited therapeutically. This review will highlight the common and distinct functions of well-known adipocyte populations with respect to their lineage and plasticity, as well as introducing the most recent members of the adipocyte family and their roles in whole organism energy homeostasis. Finally, this article will outline some of the more preliminary findings from large data sets generated by single-cell transcriptomics of mouse and human adipose tissue and their implications for the field, both for discovery and for therapy.
Topics: Adipocytes; Adipose Tissue, Brown; Animals; Humans; Mice; Thermogenesis
PubMed: 32539124
DOI: 10.1042/BCJ20200298 -
Cells Nov 2019Cellular plasticity is a transformation of a terminally differentiated cell into another cell type, which has been long known to occur in disease and regeneration.... (Review)
Review
Cellular plasticity is a transformation of a terminally differentiated cell into another cell type, which has been long known to occur in disease and regeneration. However, white adipocytes (fat cells) have only recently been observed to undergo different types of cellular plasticity. Adipocyte transdifferentiation into myofibroblasts and cancer-associated fibroblasts occurs in fibrosis and cancer, respectively. On the other hand, reversible adipocyte dedifferentiation into adipocyte progenitor cells (preadipocytes) has been demonstrated in mammary gland and in dermal adipose tissue. Here we discuss the research on adipocyte plasticity, including the experimental approaches that allowed to detect and study it, the current state of the knowledge, major research questions which remain to be addressed, and the advances required to stimulate adipocyte plasticity research. In the future, the knowledge of the molecular mechanisms of adipocyte plasticity can be utilized both to prevent adipocyte plasticity in disease and to stimulate it for use in regenerative medicine.
Topics: Adipocytes, White; Adipogenesis; Adipose Tissue, White; Cell Plasticity; Cellular Reprogramming; Humans
PubMed: 31775295
DOI: 10.3390/cells8121507 -
Cells May 2023Aging and obesity are the two prominent driving forces of metabolic dysfunction, yet the common underlying mechanisms remain elusive. PPARγ, a central metabolic...
Aging and obesity are the two prominent driving forces of metabolic dysfunction, yet the common underlying mechanisms remain elusive. PPARγ, a central metabolic regulator and primary drug target combatting insulin resistance, is hyperacetylated in both aging and obesity. By employing a unique adipocyte-specific PPARγ acetylation-mimetic mutant knock-in mouse model, namely aKQ, we demonstrate that these mice develop worsened obesity, insulin resistance, dyslipidemia, and glucose intolerance as they age, and these metabolic deregulations are resistant to intervention by intermittent fasting. Interestingly, aKQ mice show a whitening phenotype of brown adipose tissue (BAT) manifested in lipid filling and suppressed BAT markers. Diet-induced obese aKQ mice retain an expected response to thiazolidinedione (TZD) treatment, while BAT function remains impaired. This BAT whitening phenotype persists even with the activation of SirT1 through resveratrol treatment. Moreover, the adverse effect of TZDs on bone loss is exacerbated in aKQ mice and is potentially mediated by their increased Adipsin levels. Our results collectively suggest pathogenic implications of adipocyte PPARγ acetylation, contributing to metabolic dysfunction in aging and thus posing as a potential therapeutic target.
Topics: Animals; Mice; Acetylation; Adipocytes; Adipose Tissue, Brown; Insulin Resistance; Obesity; PPAR gamma
PubMed: 37408258
DOI: 10.3390/cells12101424 -
BMC Medicine Apr 2023Dysfunctional adipose tissue (AT) is known to contribute to the pathophysiology of metabolic disease, including type 2 diabetes mellitus (T2DM). This dysfunction may...
BACKGROUND
Dysfunctional adipose tissue (AT) is known to contribute to the pathophysiology of metabolic disease, including type 2 diabetes mellitus (T2DM). This dysfunction may occur, in part, as a consequence of gut-derived endotoxaemia inducing changes in adipocyte mitochondrial function and reducing the proportion of BRITE (brown-in-white) adipocytes. Therefore, the present study investigated whether endotoxin (lipopolysaccharide; LPS) directly contributes to impaired human adipocyte mitochondrial function and browning in human adipocytes, and the relevant impact of obesity status pre and post bariatric surgery.
METHODS
Human differentiated abdominal subcutaneous (AbdSc) adipocytes from participants with obesity and normal-weight participants were treated with endotoxin to assess in vitro changes in mitochondrial function and BRITE phenotype. Ex vivo human AbdSc AT from different groups of participants (normal-weight, obesity, pre- and 6 months post-bariatric surgery) were assessed for similar analyses including circulating endotoxin levels.
RESULTS
Ex vivo AT analysis (lean & obese, weight loss post-bariatric surgery) identified that systemic endotoxin negatively correlated with BAT gene expression (p < 0.05). In vitro endotoxin treatment of AbdSc adipocytes (lean & obese) reduced mitochondrial dynamics (74.6% reduction; p < 0.0001), biogenesis (81.2% reduction; p < 0.0001) and the BRITE phenotype (93.8% reduction; p < 0.0001). Lean AbdSc adipocytes were more responsive to adrenergic signalling than obese AbdSc adipocytes; although endotoxin mitigated this response (92.6% reduction; p < 0.0001).
CONCLUSIONS
Taken together, these data suggest that systemic gut-derived endotoxaemia contributes to both individual adipocyte dysfunction and reduced browning capacity of the adipocyte cell population, exacerbating metabolic consequences. As bariatric surgery reduces endotoxin levels and is associated with improving adipocyte functionality, this may provide further evidence regarding the metabolic benefits of such surgical interventions.
Topics: Humans; Diabetes Mellitus, Type 2; Endotoxemia; Adipocytes; Obesity; Lipopolysaccharides; Endotoxins
PubMed: 37076885
DOI: 10.1186/s12916-023-02857-z