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Nature Metabolism Sep 2023In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the...
In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism. Mutations in human MECR cause pediatric-onset neurodegeneration, and we show that human-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis. In summary, this study identifies a role of mecr/MECR in ceramide and iron metabolism, providing a mechanistic link between mtFAS and neurodegeneration.
Topics: Child; Animals; Humans; Adipogenesis; Mitochondria; Ceramides; Drosophila; Iron; Fatty Acids
PubMed: 37653044
DOI: 10.1038/s42255-023-00873-0 -
Advances in Food and Nutrition Research 2024An inverse association between vitamin D status and obesity has been reported across diverse populations and age groups in humans. In animal model of diet-induced... (Review)
Review
An inverse association between vitamin D status and obesity has been reported across diverse populations and age groups in humans. In animal model of diet-induced obesity, dysregulation of vitamin D metabolism has been observed. However, the causal relationship between vitamin D status and obesity is not conclusive. Several explanations, such as volumetric dilution, sequestration of vitamin D into adipose tissue, and limited sunlight exposure, have been suggested as the underlying mechanisms linking poor vitamin D status and obesity. Vitamin D can modulate adipose tissue biology, spanning from adipocyte differentiation to adipocyte apoptosis and energy metabolism, indicating its potential impact on adiposity. In this chapter, we will review the prevalence of vitamin D deficiency and determinants of vitamin D deficiency among different populations, as well as changes in vitamin D metabolism associated with obesity. Additionally, we will review vitamin D's regulation of adipogenesis and lipogenesis at the cellular level in order to gain a deeper understanding of the underlying mechanisms linking vitamin D levels and obesity.
Topics: Humans; Vitamin D; Obesity; Vitamin D Deficiency; Animals; Adipogenesis; Adipose Tissue; Adipocytes
PubMed: 38777414
DOI: 10.1016/bs.afnr.2023.12.006 -
Dermatologie (Heidelberg, Germany) Aug 2023Obesity causes all types of lymphedema to deteriorate. Obesity-associated lymphedema is by now the most frequent secondary lymphedema and constitutes an entity in its... (Review)
Review
Obesity causes all types of lymphedema to deteriorate. Obesity-associated lymphedema is by now the most frequent secondary lymphedema and constitutes an entity in its own right. Obesity and its comorbidities, due to mechanical and inflammatory effects, decrease lymphatic transport and create a vicious circle of lymph stasis, local adipogenesis, and fibrosis. The therapeutic strategy must therefore address both lymphedema and obesity and its comorbidities.
Topics: Humans; Lymphedema; Obesity; Lymph; Lymphatic Vessels; Fibrosis; Chronic Disease
PubMed: 37382603
DOI: 10.1007/s00105-023-05180-z -
Frontiers in Endocrinology 2023Genistein (GN) has been highly recommended for its medicinal properties like anticancer, antidiabetic, antihyperlipidemic, antiviral, and antioxidant activities among... (Review)
Review
Genistein (GN) has been highly recommended for its medicinal properties like anticancer, antidiabetic, antihyperlipidemic, antiviral, and antioxidant activities among others. Recently, scientists realized that Genistein is an endocrine disruptor. It is an obesogen that interferes with the endocrine system causing obesity through many mechanisms like inducing adipocyte differentiation, lipid accumulation, and transformation of some stem cells into adipocytes (bone marrow mesenchymal stem cells for example) . Animal studies show that GN upregulates genes associated with adipogenesis like CCAAT/enhancer binding protein alpha (Cebpα), CCAAT/enhancer binding protein beta (Cebpβ), and PPARγ. studies reveal a strong binding affinity for estrogen receptors. All these findings were contingent on concentration and tissues. It is beyond dispute that obesity is one of the most frustrating medical conditions under the sun. The pathophysiology of this disease was first attributed to a high-calorie diet and lack of physical activity. However, studies proved that these two factors are not enough to account for obesity in both children and adults. This mini review highlights how Genistein interaction with the peroxisome proliferator-activated receptor gamma protein can cause obesity.
Topics: Animals; Child; Humans; Genistein; Cell Differentiation; Adipogenesis; Obesity
PubMed: 38098865
DOI: 10.3389/fendo.2023.1308341 -
Cell Death & Disease Nov 2023Dysregulation of the ubiquitin-proteasome system has been implicated in the pathogenesis of several metabolic disorders, including obesity, diabetes, and non-alcoholic...
Dysregulation of the ubiquitin-proteasome system has been implicated in the pathogenesis of several metabolic disorders, including obesity, diabetes, and non-alcoholic fatty liver disease; however, the mechanisms controlling pathogenic metabolic disorders remain unclear. Transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) regulates adipogenic genes. The study showed that the expression level of C/EBPβ is post-translationally regulated by the deubiquitinase ubiquitin-specific protease 1 (USP1) and that USP1 expression is remarkably upregulated during adipocyte differentiation and in the adipose tissue of mice fed a high-fat diet (HFD). We found that USP1 directly interacts with C/EBPβ. Knock-down of USP1 decreased C/EBPβ protein stability and increased its ubiquitination. Overexpression of USP1 regulates its protein stability and ubiquitination, whereas catalytic mutant of USP1 had no effect on them. It suggests that USP1 directly deubiquitinases C/EBPβ and increases the protein expression, leading to adipogenesis and lipid accumulation. Notably, the USP1-specific inhibitor ML323-originally developed to sensitize cancer cells to DNA-damaging agents-decreased adipocyte differentiation and lipid accumulation in 3T3-L1 cells without cytotoxicity. Oral gavage of ML323 was administered to HFD-fed mice, which showed weight loss and improvement in insulin and glucose sensitivity. Both fat mass and adipocyte size in white adipose tissues were significantly reduced by ML323 treatment, which also reduced the expression of genes involved in adipogenesis and inflammatory responses. ML323 also reduced lipid accumulation, hepatic triglycerides, free fatty acids, and macrophage infiltration in the livers of HFD-fed mice. Taken together, we suggest that USP1 plays an important role in adipogenesis by regulating C/EBPβ ubiquitination, and USP1-specific inhibitor ML323 is a potential treatment option and further study by ML323 is needed for clinical application for metabolic disorders.
Topics: Animals; Mice; 3T3-L1 Cells; Adipogenesis; CCAAT-Enhancer-Binding Protein-beta; Deubiquitinating Enzymes; Diet, High-Fat; Metabolic Diseases; PPAR gamma; Triglycerides; Ubiquitin-Specific Proteases
PubMed: 38012162
DOI: 10.1038/s41419-023-06317-7 -
Nature Metabolism May 2024White adipocytes function as major energy reservoirs in humans by storing substantial amounts of triglycerides, and their dysfunction is associated with metabolic...
White adipocytes function as major energy reservoirs in humans by storing substantial amounts of triglycerides, and their dysfunction is associated with metabolic disorders; however, the mechanisms underlying cellular specialization during adipogenesis remain unknown. Here, we generate a spatiotemporal proteomic atlas of human adipogenesis, which elucidates cellular remodelling as well as the spatial reorganization of metabolic pathways to optimize cells for lipid accumulation and highlights the coordinated regulation of protein localization and abundance during adipocyte formation. We identify compartment-specific regulation of protein levels and localization changes of metabolic enzymes to reprogramme branched-chain amino acids and one-carbon metabolism to provide building blocks and reduction equivalents. Additionally, we identify C19orf12 as a differentiation-induced adipocyte lipid droplet protein that interacts with the translocase of the outer membrane complex of lipid droplet-associated mitochondria and regulates adipocyte lipid storage by determining the capacity of mitochondria to metabolize fatty acids. Overall, our study provides a comprehensive resource for understanding human adipogenesis and for future discoveries in the field.
Topics: Humans; Adipogenesis; Proteomics; Lipid Metabolism; Mitochondria; Lipid Droplets; Proteome; Adipocytes; Cell Differentiation
PubMed: 38565923
DOI: 10.1038/s42255-024-01025-8 -
Developmental Cell Nov 2023Brown adipose tissue (BAT) is a thermogenic organ that protects animals against hypothermia and obesity. BAT derives from the multipotent paraxial mesoderm; however, the...
Brown adipose tissue (BAT) is a thermogenic organ that protects animals against hypothermia and obesity. BAT derives from the multipotent paraxial mesoderm; however, the identity of embryonic brown fat progenitor cells and regulators of adipogenic commitment are unclear. Here, we performed single-cell gene expression analyses of mesenchymal cells during mouse embryogenesis with a focus on BAT development. We identified cell populations associated with the development of BAT, including Dpp4+ cells that emerge at the onset of adipogenic commitment. Immunostaining and lineage-tracing studies show that Dpp4+ cells constitute the BAT fascia and contribute minorly as adipocyte progenitors. Additionally, we identified the transcription factor GATA6 as a marker of brown adipogenic progenitor cells. Deletion of Gata6 in the brown fat lineage resulted in a striking loss of BAT. Together, these results identify progenitor and transitional cells in the brown adipose lineage and define a crucial role for GATA6 in BAT development.
Topics: Animals; Mice; Adipocytes, Brown; Adipogenesis; Adipose Tissue, Brown; Dipeptidyl Peptidase 4; Obesity; Thermogenesis
PubMed: 37647897
DOI: 10.1016/j.devcel.2023.08.003 -
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 -
American Journal of Physiology. Cell... Sep 2023CROP-Seq combines gene silencing using CRISPR interference with single-cell RNA sequencing. Here, we applied CROP-Seq to study adipogenesis and adipocyte biology. Human...
CROP-Seq combines gene silencing using CRISPR interference with single-cell RNA sequencing. Here, we applied CROP-Seq to study adipogenesis and adipocyte biology. Human preadipocyte SGBS cell line expressing KRAB-dCas9 was transduced with a sgRNA library. Following selection, individual cells were captured using microfluidics at different timepoints during adipogenesis. Bioinformatic analysis of transcriptomic data was used to determine the knockdown effects, the dysregulated pathways, and to predict cellular phenotypes. Single-cell transcriptomes recapitulated adipogenesis states. For all targets, over 400 differentially expressed genes were identified at least at one timepoint. As a validation of our approach, the knockdown of and (which encode key proadipogenic transcription factors) resulted in the inhibition of adipogenesis. Gene set enrichment analysis generated hypotheses regarding the molecular function of novel genes. knockdown led to downregulation of transcriptional response to proinflammatory cytokine TNF-α in preadipocytes and to decreased CXCL-16 and IL-6 secretion. knockdown resulted in increased expression of adipogenesis markers. In summary, this powerful, hypothesis-free tool can identify novel regulators of adipogenesis, preadipocyte, and adipocyte function associated with metabolic disease. Genomics efforts led to the identification of many genomic loci that are associated with metabolic traits, many of which are tied to adipose tissue function. However, determination of the causal genes, and their mechanism of action in metabolism, is a time-consuming process. Here, we use an approach to determine the transcriptional outcome of candidate gene knockdown for multiple genes at the same time in a human cell model of adipogenesis.
Topics: Humans; RNA, Guide, CRISPR-Cas Systems; Adipogenesis; Adipocytes; Cell Line; Metabolic Diseases; Cell Differentiation
PubMed: 37486064
DOI: 10.1152/ajpcell.00148.2023 -
Molecular Metabolism Aug 2023Adipogenesis is key to maintaining organism-wide energy balance and healthy metabolic phenotype, making it critical to thoroughly comprehend its molecular regulation in...
Adipogenesis is key to maintaining organism-wide energy balance and healthy metabolic phenotype, making it critical to thoroughly comprehend its molecular regulation in humans. By single-nuclei RNA-sequencing (snRNA-seq) of over 20,000 differentiating white and brown preadipocytes, we constructed a high-resolution temporal transcriptional landscape of human white and brown adipogenesis. White and brown preadipocytes were isolated from a single individual's neck region, thereby eliminating inter-subject variability across two distinct lineages. These preadipocytes were also immortalized to allow for controlled, in vitro differentiation, allowing sampling of distinct cellular states across the spectrum of adipogenic progression. Pseudotemporal cellular ordering revealed the dynamics of ECM remodeling during early adipogenesis, and lipogenic/thermogenic response during late white/brown adipogenesis. Comparison with adipogenic regulation in murine models Identified several novel transcription factors as potential targets for adipogenic/thermogenic drivers in humans. Among these novel candidates, we explored the role of TRPS1 in adipocyte differentiation and showed that its knockdown impairs white adipogenesis in vitro. Key adipogenic and lipogenic markers revealed in our analysis were applied to analyze publicly available scRNA-seq datasets; these confirmed unique cell maturation features in recently discovered murine preadipocytes, and revealed inhibition of adipogenic expansion in humans with obesity. Overall, our study presents a comprehensive molecular description of both white and brown adipogenesis in humans and provides an important resource for future studies of adipose tissue development and function in both health and metabolic disease state.
Topics: Humans; Animals; Mice; Adipogenesis; RNA-Seq; Adipose Tissue, Brown; Adipose Tissue, White; Cell Differentiation; Repressor Proteins
PubMed: 37286033
DOI: 10.1016/j.molmet.2023.101746