An increasing number of studies have characterized the bone as an endocrine organ, and that bone secreted factors may not only regulate local bone remodeling, but also other tissues and whole-body metabolic functions. The precise nature of these regulatory factors and their roles at bridging the bone, bone marrow adipose tissue, extramedullary body fat and whole-body energy homeostasis are being explored. In this study, we report that KIAA1199, a secreted factor produced from bone and bone marrow, previously described as an inhibitor of bone formation, also plays a role at promoting adipogenesis. KIAA1199-deficient mice exhibit reduced bone marrow adipose tissue, subcutaneous and visceral fat tissue mass, blood cholesterol, triglycerides, free fatty acids and glycerol, as well as improved insulin sensitivity in skeletal muscle, liver and fat. Moreover, these mice are protected from the detrimental effects of high-fat diet feeding, with decreased obesity, lower blood glucose and glucose tolerance, as well as decreased adipose tissue inflammation, insulin resistance and hepatic steatosis. In human studies, plasma levels of KIAA1199 or its expression levels in adipose tissue are positively correlated with insulin resistance and blood levels of cholesterol, triglycerides, free fatty acids, glycerol, fasting glucose and HOMA-IR. Mechanistically, KIAA1199 mediates its effects on adipogenesis through modulating osteopontin-integrin and AKT / ERK signaling. These findings provide evidence for the role of bone secreted factors on coupling bone, fat and whole-body energy homeostasis.
- MeSH
- adipogeneze * fyziologie MeSH
- dieta s vysokým obsahem tuků MeSH
- energetický metabolismus * MeSH
- hyaluronoglukosaminidasa MeSH
- inzulinová rezistence MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- obezita metabolismus MeSH
- proteiny * metabolismus MeSH
- tuková tkáň metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: Insulin-sensitizing drugs, despite their broad use against type 2 diabetes, can adversely affect bone health, and the mechanisms underlying these side effects remain largely unclear. Here, we investigated the different metabolic effects of a series of thiazolidinediones, including rosiglitazone, pioglitazone, and the second-generation compound MSDC-0602K, on human mesenchymal stem cells (MSCs). METHODS: We developed 13C subcellular metabolomic tracer analysis measuring separate mitochondrial and cytosolic metabolite pools, lipidomic network-based isotopologue models, and bioorthogonal click chemistry, to demonstrate that MSDC-0602K differentially affected bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AT-MSCs). In BM-MSCs, MSDC-0602K promoted osteoblastic differentiation and suppressed adipogenesis. This effect was clearly distinct from that of the earlier drugs and that on AT-MSCs. RESULTS: Fluxomic data reveal unexpected differences between this drug's effect on MSCs and provide mechanistic insight into the pharmacologic inhibition of mitochondrial pyruvate carrier 1 (MPC). Our study demonstrates that MSDC-0602K retains the capacity to inhibit MPC, akin to rosiglitazone but unlike pioglitazone, enabling the utilization of alternative metabolic pathways. Notably, MSDC-0602K exhibits a limited lipogenic potential compared to both rosiglitazone and pioglitazone, each of which employs a distinct lipogenic strategy. CONCLUSIONS: These findings indicate that the new-generation drugs do not compromise bone structure, offering a safer alternative for treating insulin resistance. Moreover, these results highlight the ability of cell compartment-specific metabolite labeling by click reactions and tracer metabolomics analysis of complex lipids to discover molecular mechanisms within the intersection of carbohydrate and lipid metabolism.
- MeSH
- adipogeneze * účinky léků MeSH
- buněčná diferenciace účinky léků MeSH
- hypoglykemika farmakologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- metabolomika MeSH
- mezenchymální kmenové buňky * účinky léků metabolismus MeSH
- osteogeneze * účinky léků MeSH
- pioglitazon farmakologie MeSH
- rosiglitazon farmakologie MeSH
- thiazolidindiony * farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The increasing use of industrial chemicals has raised concerns regarding exposure to endocrine-disrupting chemicals (EDCs), which interfere with developmental, reproductive and metabolic processes. Of particular concern is their interaction with adipose tissue, a vital component of the endocrine system regulating metabolic and hormonal functions. The SGBS (Simpson Golabi Behmel Syndrome) cell line, a well-established human-relevant model for adipocyte research, closely mimics native adipocytes' properties. It responds to hormonal stimuli, undergoes adipogenesis and has been successfully used to study the impact of EDCs on adipose biology. In this study, we screened human exposure-relevant doses of various EDCs on the SGBS cell line to investigate their effects on viability, lipid accumulation and adipogenesis-related protein expression. Submicromolar doses were generally well tolerated; however, at higher doses, EDCs compromised cell viability, with cadmium chloride (CdCl2) showing the most pronounced effects. Intracellular lipid levels remained unaffected by EDCs, except for tributyltin (TBT), used as a positive control, which induced a significant increase. Analysis of adipogenesis-related protein expression revealed several effects, including downregulation of fatty acid-binding protein 4 (FABP4) by dibutyl phthalate, upregulation by CdCl2 and downregulation of perilipin 1 and FABP4 by perfluorooctanoic acid. Additionally, TBT induced dose-dependent upregulation of C/EBPα, perilipin 1 and FABP4 protein expression. These findings underscore the importance of employing appropriate models to study EDC-adipocyte interactions. Conclusions from this research could guide strategies to reduce the negative impacts of EDC exposure on adipose tissue.
- MeSH
- adipogeneze * účinky léků MeSH
- buněčné linie MeSH
- endokrinní disruptory * toxicita MeSH
- fluorokarbony toxicita MeSH
- kapryláty toxicita MeSH
- lidé MeSH
- metabolismus lipidů účinky léků MeSH
- proteiny vázající mastné kyseliny * metabolismus genetika MeSH
- trialkylcínové sloučeniny toxicita MeSH
- tuková tkáň účinky léků metabolismus MeSH
- tukové buňky účinky léků metabolismus MeSH
- viabilita buněk * účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Obesity is a major health burden. Preadipocytes proliferate and differentiate in mature adipocytes in the adipogenic process, which could be a potential therapeutic approach for obesity. Deficiency of SIRT6, a stress-responsive protein deacetylase and mono-ADP ribosyltransferase enzyme, blocks adipogenesis. Mutants of SIRT6 (N308K/A313S) were recently linked to the in the long lifespan Ashkenazi Jews. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect adipogenesis at the transcriptional and epigenetic level. METHODS: We analyzed the role of SIRT6 wild-type (WT) or SIRT6 centenarian-associated mutant (N308K/A313S) overexpression in adipogenesis, by creating stably transduced preadipocyte cell lines using lentivirus on the 3T3-L1 model. Histone post-translational modifications (PTM: acetylation, methylation) and transcriptomic changes were analyzed by mass spectrometry (LC-MS/MS) and RNA-Seq, respectively, in 3T3-L1 adipocytes. In addition, the adipogenic process and related signaling pathways were investigated by bioinformatics and biochemical approaches. RESULTS: Overexpression of centenarian-associated SIRT6 mutant increased adipogenic differentiation to a similar extent compared to the WT form. However, it triggered distinct histone PTM profiles in mature adipocytes, with significantly higher acetylation levels, and activated divergent transcriptional programs, including those dependent on signaling related to the sympathetic innervation and to PI3K pathway. 3T3-L1 mature adipocytes overexpressing SIRT6 N308K/A313S displayed increased insulin sensitivity in a neuropeptide Y (NPY)-dependent manner. CONCLUSIONS: SIRT6 N308K/A313S overexpression in mature adipocytes ameliorated glucose sensitivity and impacted sympathetic innervation signaling. These findings highlight the importance of targeting SIRT6 enzymatic activities to regulate the co-morbidities associated with obesity.
- MeSH
- adipogeneze * genetika MeSH
- buňky 3T3-L1 * MeSH
- epigeneze genetická * genetika MeSH
- histony metabolismus genetika MeSH
- lidé MeSH
- mutace MeSH
- myši MeSH
- obezita genetika metabolismus MeSH
- posttranslační úpravy proteinů genetika MeSH
- sirtuiny * genetika metabolismus MeSH
- tukové buňky * metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Obesity and related metabolic diseases are becoming a worldwide epidemic, leading to increased mortality and heavy medical costs. Our Chinese herbal formula Xiao-Gao-Jiang-Zhuo (XGJZ) has remarkable effects on curing obese patients in the clinic, but the cellular and molecular basis remains unknown. This study aimed to reveal the molecular mechanism involved in adipogenesis in vitro. METHODS: Chinese herbal formula XGJZ-containing serum was prepared from XGJZ-treated obesity model rats. The function of XGJZ-containing serum was validated in 3T3-L1 preadipocytes. Oil O staining was performed to determine intracellular lipid accumulation in differentiated 3T3-L1 cells. The expression of pro-adipogenic transcription factors was measured to further validate the adipogenesis of 3T3-L1 adipocytes. The contents of triglyceride (TG), free fatty acid (FFA), and glycerin, along with the activities of lipid metabolism-related enzymes (including FAT, FATP1, DGAT, GPAT, ATGL, and HSL) were measured to study the lipogenesis in 3T3-L1 adipocytes. RESULTS: XGJZ-containing serum inhibited 3T3-L1 differentiation, decreased intracellular lipid accumulation, and suppressed the expression of pro-adipogenic transcription factors in differentiated 3T3-L1 cells. The contents of TG, FFA, and glycerin were decreased when treated with XGJZ-containing serum, which also modulated lipid metabolism-related enzyme activities. The activities of fatty acid transporters (FAT, FATP1) and lipid mobilization enzymes (ATGL, HSL) were promoted, while activities of triglyceride biosynthesis enzymes (DGAT, GPAT) were attenuated in differentiated 3T3-L1 cells. CONCLUSION: XGJZ-containing serum has inhibitory effects on adipogenesis in 3T3-L1 preadipocytes, affirming the effect of XGJZ in treating obesity. It provides evidence for the mechanism of obesity.
- MeSH
- adipogeneze * MeSH
- buňky 3T3-L1 MeSH
- glycerol * metabolismus farmakologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- obezita MeSH
- PPAR gama metabolismus MeSH
- transkripční faktory MeSH
- triglyceridy MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
To date, single-cell studies of human white adipose tissue (WAT) have been based on small cohort sizes and no cellular consensus nomenclature exists. Herein, we performed a comprehensive meta-analysis of publicly available and newly generated single-cell, single-nucleus, and spatial transcriptomic results from human subcutaneous, omental, and perivascular WAT. Our high-resolution map is built on data from ten studies and allowed us to robustly identify >60 subpopulations of adipocytes, fibroblast and adipogenic progenitors, vascular, and immune cells. Using these results, we deconvolved spatial and bulk transcriptomic data from nine additional cohorts to provide spatial and clinical dimensions to the map. This identified cell-cell interactions as well as relationships between specific cell subtypes and insulin resistance, dyslipidemia, adipocyte volume, and lipolysis upon long-term weight changes. Altogether, our meta-map provides a rich resource defining the cellular and microarchitectural landscape of human WAT and describes the associations between specific cell types and metabolic states.
Z endokrinních disruptorů, látek, které zasahují do endokrinní regulace, některé významně ovlivňují tvorbu a distribuci bílého tuku. Označujeme je za obesogeny. Obesogenní vlastnosti byly dosud detailněji testovány různými metodami in vivo a in vitro jen na malém počtu několika desítek látek, většinou aditiv do potravin, jako jsou konzervační prostředky, ochucovadla včetně umělých sladidel, fruktóza, emulzifikátory a barviva. K jejich účinku vedou různé mechanismy stručně uvedené s příklady v této práci.
Some of the endocrine disruptors, compounds that affect endocrine regulations, greatly influence the formation and distribution of white fat. We name them obesogens. The obesogenic characteristics were tested until now by various detailed methods in vitro and in vivo only on a small scale for dozens of compounds, mainly additives to food: preservatives or flavours including artificial sweeteners, fructose, emulsifiers, and colours. Various mechanisms effect the functioning of obesogens; those mechanisms are briefly presented in this article.
- Klíčová slova
- obesogeny,
- MeSH
- adipogeneze MeSH
- endokrinní disruptory analýza škodlivé účinky toxicita MeSH
- látky znečišťující životní prostředí * analýza škodlivé účinky toxicita MeSH
- lidé MeSH
- obezita chemicky indukované etiologie MeSH
- potraviny škodlivé účinky MeSH
- techniky in vitro metody MeSH
- vystavení vlivu životního prostředí škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Acid ceramidase catalyzes the degradation of ceramide into sphingosine and a free fatty acid. Acid ceramidase deficiency results in lipid accumulation in many tissues and leads to the development of Farber disease (FD). Typical manifestations of classical FD include formation of subcutaneous nodules and joint contractures as well as the development of a hoarse voice. Healthy skin depends on a unique lipid profile to form a barrier that confers protection from pathogens, prevents excessive water loss, and mediates cell-cell communication. Ceramides comprise ~50% of total epidermis lipids and regulate cutaneous homeostasis and inflammation. Abnormal skin development including visual skin lesions has been reported in FD patients, but a detailed study of FD skin has not been performed. We conducted a pathophysiological study of the skin in our mouse model of FD. We observed altered lipid composition in FD skin dominated by accumulation of all studied ceramide species and buildup of abnormal storage structures affecting mainly the dermis. A deficiency of acid ceramidase activity also led to the activation of inflammatory IL-6/JAK/signal transducer and activator of transcription 3 and noncanonical NF-κB signaling pathways. Last, we report reduced proliferation of FD mouse fibroblasts and adipose-derived stem/stromal cells (ASC) along with impaired differentiation of ASCs into mature adipocytes.
- MeSH
- adipogeneze MeSH
- ceramidy metabolismus MeSH
- Farberova nemoc * MeSH
- kyselá ceramidasa genetika MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- zánět MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: GDF11 is a member of the TGF-β superfamily that was recently implicated as potential "rejuvenating" factor, which can ameliorate metabolic disorders. The main objective of the presented study was to closely characterize the role of GDF11 signaling in the glucose homeostasis and in the differentiation of white adipose tissue. METHODS: We performed microscopy imaging, biochemical and transcriptomic analyses of adipose tissues of 9 weeks old ob/ob mice and murine and human pre-adipocyte cell lines. RESULTS: Our in vivo experiments employing GDF11 treatment in ob/ob mice showed improved glucose/insulin homeostasis, decreased weight gain and white adipocyte size. Furthermore, GDF11 treatment inhibited adipogenesis in pre-adipocytes by ALK5-SMAD2/3 activation in cooperation with the WNT/β-catenin pathway, whose inhibition resulted in adipogenic differentiation. Lastly, we observed significantly elevated levels of the adipokine hormone adiponectin and increased glucose uptake by mature adipocytes upon GDF11 exposure. CONCLUSION: We show evidence that link GDF11 to adipogenic differentiation, glucose, and insulin homeostasis, which are pointing towards potential beneficial effects of GDF11-based "anti-obesity" therapy.
- MeSH
- adipogeneze * MeSH
- adiponektin metabolismus MeSH
- beta-katenin * metabolismus MeSH
- buněčná diferenciace fyziologie MeSH
- glukosa metabolismus MeSH
- inzulin metabolismus MeSH
- kostní morfogenetické proteiny metabolismus MeSH
- lidé MeSH
- myši MeSH
- protein Smad2 MeSH
- protein Smad3 MeSH
- receptory regulované proteiny Smad MeSH
- růstové diferenciační faktory metabolismus MeSH
- signální dráha Wnt MeSH
- TGF-beta receptor I. typu MeSH
- transformující růstový faktor beta metabolismus MeSH
- tukové buňky metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Obesogens, as environmental endocrine-disrupting chemicals, are supposed to have had an impact on the prevalence of rising obesity around the world over the last forty years. These chemicals are probably able to contribute not only to the development of obesity and metabolic disturbances in individuals, but also in their progeny, having the capability to epigenetically reprogram genetically inherited set-up points for body weight and body composition control during critical periods of development, such as fetal, early life, and puberty. In individuals, they may act on myriads of neuro-endocrine-immune metabolic regulatory pathways, leading to pathophysiological consequences in adipogenesis, lipogenesis, lipolysis, immunity, the influencing of central appetite and energy expenditure regulations, changes in gut microbiota-intestine functioning, and many other processes. Evidence-based medical data have recently brought much more convincing data about associations of particular chemicals and the probability of the raised risk of developing obesity. Foods are the main source of obesogens. Some obesogens occur naturally in food, but most are environmental chemicals, entering food as a foreign substance, whether in the form of contaminants or additives, and they are used in a large amount in highly processed food. This review article contributes to a better overview of obesogens, their occurrence in foods, and their impact on the human organism.
