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Nature Communications Nov 2023White adipose tissue browning can promote lipid burning to increase energy expenditure and improve adiposity. Here, we show that Slc35d3 expression is significantly...
White adipose tissue browning can promote lipid burning to increase energy expenditure and improve adiposity. Here, we show that Slc35d3 expression is significantly lower in adipose tissues of obese mice. While adipocyte-specific Slc35d3 knockin is protected against diet-induced obesity, adipocyte-specific Slc35d3 knockout inhibits white adipose tissue browning and causes decreased energy expenditure and impaired insulin sensitivity in mice. Mechanistically, we confirm that SLC35D3 interacts with the NOTCH1 extracellular domain, which leads to the accumulation of NOTCH1 in the endoplasmic reticulum and thus inhibits the NOTCH1 signaling pathway. In addition, knockdown of Notch1 in mouse inguinal white adipose tissue mediated by orthotopic injection of AAV8-adiponectin-shNotch1 shows considerable improvement in obesity and glucolipid metabolism, which is more pronounced in adipocyte-specific Slc35d3 knockout mice than in knockin mice. Overall, in this study, we reveal that SLC35D3 is involved in obesity via NOTCH1 signaling, and low adipose SLC35D3 expression in obesity might be a therapeutic target for obesity and associated metabolic disorders.
Topics: Animals; Mice; Adipocytes; Adipose Tissue, Brown; Adipose Tissue, White; Diet, High-Fat; Energy Metabolism; Mice, Inbred C57BL; Mice, Knockout; Obesity; Signal Transduction; Receptors, Notch
PubMed: 37996411
DOI: 10.1038/s41467-023-43418-5 -
International Journal of Biological... 2023Adipocytes are adipose tissues that supply energy to the body through lipids. The two main types of adipocytes comprise white adipocytes (WAT) that store energy, and... (Review)
Review
Adipocytes are adipose tissues that supply energy to the body through lipids. The two main types of adipocytes comprise white adipocytes (WAT) that store energy, and brown adipocytes (BAT), which generate heat by burning stored fat (thermogenesis). Emerging evidence indicates that dysregulated adipocyte senescence may disrupt metabolic homeostasis, leading to various diseases and aging. Adipocytes undergo senescence via irreversible cell-cycle arrest in response to DNA damage, oxidative stress, telomere dysfunction, or adipocyte over-expansion upon chronic lipid accumulation. The amount of detectable BAT decreases with age. Activation of cell cycle regulators and dysregulation of adipogenesis-regulating factors may constitute a molecular mechanism that accelerates adipocyte senescence. To better understand the regulation of adipocyte senescence, the effects of post-translational modifications (PTMs), is essential for clarifying the activity and stability of these proteins. PTMs are covalent enzymatic protein modifications introduced following protein biosynthesis, such as phosphorylation, acetylation, ubiquitination, or glycosylation. Determining the contribution of PTMs to adipocyte senescence may identify new therapeutic targets for the regulation of adipocyte senescence. In this review, we discuss a conceptual case in which PTMs regulate adipocyte senescence and explain the mechanisms underlying protein regulation, which may lead to the development of effective strategies to combat metabolic diseases.
Topics: Adipose Tissue, Brown; Adipocytes, Brown; Adipogenesis; Protein Processing, Post-Translational; Cell Cycle Checkpoints
PubMed: 37928271
DOI: 10.7150/ijbs.86404 -
Nutrients Sep 2023Brown and beige adipocytes are renowned for their unique ability to generate heat through a mechanism known as thermogenesis. This process can be induced by exposure to... (Review)
Review
Brown and beige adipocytes are renowned for their unique ability to generate heat through a mechanism known as thermogenesis. This process can be induced by exposure to cold, hormonal signals, drugs, and dietary factors. The activation of these thermogenic adipocytes holds promise for improving glucose metabolism, reducing fat accumulation, and enhancing insulin sensitivity. However, the translation of preclinical findings into effective clinical therapies poses challenges, warranting further research to identify the molecular mechanisms underlying the differentiation and function of brown and beige adipocytes. Consequently, research has focused on the development of drugs, such as mirabegron, ephedrine, and thyroid hormone, that mimic the effects of cold exposure to activate brown fat activity. Additionally, nutritional interventions have been explored as an alternative approach to minimize potential side effects. Brown fat and beige fat have emerged as promising targets for addressing nutritional imbalances, with the potential to develop strategies for mitigating the impact of metabolic diseases. Understanding the influence of nutritional factors on brown fat activity can facilitate the development of strategies to promote its activation and mitigate metabolic disorders.
Topics: Adipose Tissue, Brown; Nutritional Status; Adipocytes; Adipocytes, Beige; Adipose Tissue, Beige
PubMed: 37764855
DOI: 10.3390/nu15184072 -
Stem Cell Research & Therapy Aug 2023Stem cell therapy is the most promising treatment option for regenerative medicine. Therapeutic effect of different stem cells has been verified in various disease... (Review)
Review
Stem cell therapy is the most promising treatment option for regenerative medicine. Therapeutic effect of different stem cells has been verified in various disease model. Dedifferentiated fat (DFAT) cells, derived from mature adipocytes, are induced pluripotent stem cells. Compared with ASCs and other stem cells, the DFAT cells have unique advantageous characteristics in their abundant sources, high homogeneity, easily harvest and low immunogenicity. The DFAT cells have shown great potential in tissue engineering and regenerative medicine for the treatment of clinical problems such as cardiac and kidney diseases, autoimmune disease, soft and hard tissue defect. In this review, we summarize the current understanding of DFAT cell properties and focus on the relevant practical applications of DFAT cells in cell therapy in recent years.
Topics: Regenerative Medicine; Tissue Engineering; Cell- and Tissue-Based Therapy; Adipocytes; Induced Pluripotent Stem Cells
PubMed: 37605289
DOI: 10.1186/s13287-023-03399-0 -
Communications Biology Jul 2023Brown adipose tissue (BAT) is responsible for regulating body temperature through adaptive thermogenesis. The ability of thermogenic adipocytes to dissipate chemical...
Brown adipose tissue (BAT) is responsible for regulating body temperature through adaptive thermogenesis. The ability of thermogenic adipocytes to dissipate chemical energy as heat counteracts weight gain and has gained considerable attention as a strategy against obesity. BAT undergoes major remodeling in a cold environment. This remodeling results from changes in the number and function of brown adipocytes, expanding the network of blood vessels and sympathetic nerves, and changes in the composition and function of immune cells. Such synergistic adaptation requires extensive crosstalk between individual cells in the tissue to coordinate their responses. To understand the mechanisms of intercellular communication in BAT, we apply the CellChat algorithm to single-cell transcriptomic data of mouse BAT. We construct an integrative network of the ligand-receptor interactome in BAT and identify the major signaling inputs and outputs of each cell type. By comparing the ligand-receptor interactions in BAT of mice housed at different environmental temperatures, we show that cold exposure enhances the intercellular interactions among the major cell types in BAT, including adipocytes, adipocyte progenitors, lymphatic and vascular endothelial cells, myelinated and non-myelinated Schwann cells, and immune cells. These interactions are predicted to regulate the remodeling of the extracellular matrix, the inflammatory response, angiogenesis, and neurite growth. Together, our integrative analysis of intercellular communications in BAT and their dynamic regulation in response to housing temperatures provides a new understanding of the mechanisms underlying BAT thermogenesis. The resources presented in this study offer a valuable platform for future investigations of BAT development and thermogenesis.
Topics: Animals; Mice; Endothelial Cells; Ligands; Obesity; Cell Communication; Adipocytes, Brown
PubMed: 37479789
DOI: 10.1038/s42003-023-05140-2 -
Experimental & Molecular Medicine Sep 2023Adipose tissue is a dynamic and metabolically active organ that plays a crucial role in energy homeostasis and endocrine function. Recent advancements in lipidomics... (Review)
Review
Adipose tissue is a dynamic and metabolically active organ that plays a crucial role in energy homeostasis and endocrine function. Recent advancements in lipidomics techniques have enabled the study of the complex lipid composition of adipose tissue and its role in metabolic disorders such as obesity, diabetes, and cardiovascular disease. In addition, adipose tissue lipidomics has emerged as a powerful tool for understanding the molecular mechanisms underlying these disorders and identifying bioactive lipid mediators and potential therapeutic targets. This review aims to summarize recent lipidomics studies that investigated the dynamic remodeling of adipose tissue lipids in response to specific physiological changes, pharmacological interventions, and pathological conditions. We discuss the molecular mechanisms of lipid remodeling in adipose tissue and explore the recent identification of bioactive lipid mediators generated in adipose tissue that regulate adipocytes and systemic metabolism. We propose that manipulating lipid-mediator metabolism could serve as a therapeutic approach for preventing or treating obesity-related metabolic diseases.
Topics: Humans; Adipose Tissue; Adipocytes; Obesity; Diabetes Mellitus; Metabolic Diseases; Lipid Metabolism; Lipids
PubMed: 37653032
DOI: 10.1038/s12276-023-01071-4 -
Nature Reviews. Endocrinology Dec 2023Adipose tissue is an endocrine organ and a crucial regulator of energy storage and systemic metabolic homeostasis. Additionally, adipose tissue is a pivotal regulator of... (Review)
Review
Adipose tissue is an endocrine organ and a crucial regulator of energy storage and systemic metabolic homeostasis. Additionally, adipose tissue is a pivotal regulator of cardiovascular health and disease, mediated in part by the endocrine and paracrine secretion of several bioactive products, such as adipokines. Adipose vasculature has an instrumental role in the modulation of adipose tissue expansion, homeostasis and metabolism. The role of the adipose vasculature has been extensively explored in the context of obesity, which is recognized as a global health problem. Obesity-induced accumulation of fat, in combination with vascular rarefaction, promotes adipocyte dysfunction and induces oxidative stress, hypoxia and inflammation. It is now recognized that obesity-associated endothelial dysfunction often precedes the development of cardiovascular diseases. Investigations have revealed heterogeneity within the vascular niche and dynamic reciprocity between vascular and adipose cells, which can become dysregulated in obesity. Here we provide a comprehensive overview of the evolving functions of the vasculature in regulating adipose tissue biology in health and obesity.
Topics: Humans; Adipose Tissue; Obesity; Adipocytes; Adipokines; Biology
PubMed: 37749386
DOI: 10.1038/s41574-023-00893-6 -
Journal of Biomedical Science Jan 2024Excessive lipid accumulation in the adipose tissue in obesity alters the endocrine and energy storage functions of adipocytes. Adipocyte lipid droplets represent key...
BACKGROUND
Excessive lipid accumulation in the adipose tissue in obesity alters the endocrine and energy storage functions of adipocytes. Adipocyte lipid droplets represent key organelles coordinating lipid storage and mobilization in these cells. Recently, we identified the small GTPase, Rab34, in the lipid droplet proteome of adipocytes. Herein, we have characterized the distribution, intracellular transport, and potential contribution of this GTPase to adipocyte physiology and its regulation in obesity.
METHODS
3T3-L1 and human primary preadipocytes were differentiated in vitro and Rab34 distribution and trafficking were analyzed using markers of cellular compartments. 3T3-L1 adipocytes were transfected with expression vectors and/or Rab34 siRNA and assessed for secretory activity, lipid accumulation and expression of proteins regulating lipid metabolism. Proteomic and protein interaction analyses were employed for the identification of the Rab34 interactome. These studies were combined with functional analysis to unveil the role played by the GTPase in adipocytes, with a focus on the actions conveyed by Rab34 interacting proteins. Finally, Rab34 regulation in response to obesity was also evaluated.
RESULTS
Our results show that Rab34 localizes at the Golgi apparatus in preadipocytes. During lipid droplet biogenesis, Rab34 translocates from the Golgi to endoplasmic reticulum-related compartments and then reaches the surface of adipocyte lipid droplets. Rab34 exerts distinct functions related to its intracellular location. Thus, at the Golgi, Rab34 regulates cisternae integrity as well as adiponectin trafficking and oligomerization. At the lipid droplets, this GTPase controls lipid accumulation and lipolysis through its interaction with the E1-ubiquitin ligase, UBA1, which induces the ubiquitination and proteasomal degradation of the fatty acid transporter and member of Rab34 interactome, FABP5. Finally, Rab34 levels in the adipose tissue and adipocytes are regulated in response to obesity and related pathogenic insults (i.e., fibrosis).
CONCLUSIONS
Rab34 plays relevant roles during adipocyte differentiation, including from the regulation of the oligomerization (i.e., biological activity) and secretion of a major adipokine with insulin-sensitizing actions, adiponectin, to lipid storage and mobilization from lipid droplets. Rab34 dysregulation in obesity may contribute to the altered adipokine secretion and lipid metabolism that characterize adipocyte dysfunction in conditions of excess adiposity.
Topics: Humans; Adiponectin; Proteomics; Adipocytes; Adipokines; GTP Phosphohydrolases; Obesity; Lipids; Fatty Acid-Binding Proteins
PubMed: 38183057
DOI: 10.1186/s12929-023-00990-8 -
International Journal of Biological... Dec 2023Adipogenesis is a complex biological process. However, the regulatory mechanism of circRNAs in adipogenesis is still unclear. In this study, we identified a novel...
Adipogenesis is a complex biological process. However, the regulatory mechanism of circRNAs in adipogenesis is still unclear. In this study, we identified a novel circRNA, circBTBD7, which was highly expressed in adipose tissue and peaked at two days after differentiation in bovine primary adipocytes. When circBTBD7 was knocked down in bovine primary adipocytes, the lipid droplets accumulation was significantly increased. Furthermore, the expression of adipocyte differentiation markers (PPARγ and C/EBPα) and lipogenic genes (FABP4, FASN and ACCα) were significantly upregulated. Moreover, circBTBD7 was mainly located in the cytoplasm, which indicated it was probably to act as competitive endogenous RNAs (ceRNAs). Subsequently, the dual luciferase reporter assay showed that circBTBD7 could bind to miR-183. Further, miR-183 promoted adipogenesis by inhibiting SMAD4. What's more, the rescue assays showed that circBTBD7 attenuated the inhibition of SMAD4 expression by sponging miR-183. In summary, these results suggested that circBTBD7 inhibited adipogenesis via the miR-183/SMAD4 axis.
Topics: Animals; Cattle; Adipogenesis; MicroRNAs; Adipocytes; Adipose Tissue; CCAAT-Enhancer-Binding Protein-alpha; Cell Differentiation
PubMed: 37689299
DOI: 10.1016/j.ijbiomac.2023.126740 -
International Journal of Biological... Dec 2023Excessive expansion of adipocytes can have unhealthy consequences as excess free fatty acids enter other tissues and cause ectopic fat deposition by resynthesizing... (Review)
Review
Excessive expansion of adipocytes can have unhealthy consequences as excess free fatty acids enter other tissues and cause ectopic fat deposition by resynthesizing triglycerides. This lipid accumulation in various tissues is harmful and can increase the risk of related metabolic diseases such as type II diabetes, cardiovascular disease, and insulin resistance. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that play a key role in energy metabolism as fatty acid metabolism sensors, and peroxisome proliferator-activated receptor γ (PPARγ) is the main subtype responsible for fat cell differentiation and adipogenesis. In this paper, we introduce the main structure and function of PPARγ and its regulatory role in the process of lipogenesis in the liver, kidney, skeletal muscle, and pancreas. This information can serve as a reference for further understanding the regulatory mechanisms and measures of the PPAR family in the process of ectopic fat deposition.
Topics: Humans; PPAR gamma; Diabetes Mellitus, Type 2; Lipid Metabolism; Adipocytes; Adipogenesis
PubMed: 37742894
DOI: 10.1016/j.ijbiomac.2023.127042