Number Of Adipocytes Research Articles

Defining the Contribution of Adipocyte Subpopulations to Dermal White Adipose Tissue

Introduction: Our lab has previously identified three distinct subtypes of developmentally and functionally white adipocytes and have shown that they each differentially contribute to adipose depots (Lee, KY et al. EMBO J. 2019). Dermal white adipose tissue (dWAT), a layer of adipocytes embedded in the skin below the dermis, has recently been shown to play a role in crucial physiologic processes including thermogenesis, the regulation of aging, scar formation, and wound healing. The purpose of this proposal is to investigate the contribution of three adipocyte subtypes to dWAT. Objectives: The primary objectives of this project are to determine the number of preadipocytes and adipocytes from each of three subtypes present in dWAT. Methodology: Lineage tracing analysis was performed by crossing transgenic mice harboring cre-recombinase under the control of promoter/enhancer elements of each of the three marker genes, Wilms tumor 1, transgelin, or myoxovirus 1 to dual- fluorescent reporter mice. These three mice lines mark Type 1–3 preadipocytes and adipocytes, respectively. dWAT was collected from X week old mice, and adipocyte identities were determined by confocal microscopy. Preadipocyte contribution of these subpopulations was determined by FACS analysis. Results: We found that Type 2 (~45%) and Type 3 (~25%), but not Type 1 preadipocytes significantly contributed to the dWAT preadipocyte cellular population. We also found a similar pattern for the adipocyte populations. Type 1, 2, and 3 adipocytes were found to comprise ~3%, 17%, and 7% of mature adipocytes, respectively. These studies demonstrate that Type 2 and Type 3 adipocytes contribute to the composition of dWAT. Summary/Conclusion: These studies demonstrate that Type 2 and Type 3 adipocytes and preadipocytes significantly contribute to the composition of dWAT. Since these adipocyte subpopulations have different functional properties, including metabolism and response to inflammatory cytokines, the contribution of these adipocyte subtypes may impact the crucial physiologic processes mediated by dWAT.

Gut Microbiota Accelerates Bone Growth and Marrow Adiposity of the Adolescent Gnotobiotic Rat

Skeletal growth and bone homeostasis are significant holobiome components strongly tied to the gut microbiota. We aimed to explore the requirement of gut microbiome for skeletal maturation in an adolescent organism. For our approach, we co-housed young (7-week-old) germ-free (GF) rats with conventional rats of the same age, sex (male), and strain (Sprague Dawley) for 10 days to naturally conventionalize GF (GFC) rats with the gut microbiota by coprophagy. Bone morphometry by micro-CT scanning and histological staining revealed accelerated longitudinal and radial bone growth in GFC rats when compared to GF rats. Changes in bone mass and structure for GFC rats encompassed an increase of bone accrual in cortical and trabecular compartments, greater tissue mineral density, improved proliferation and hypertrophy of growth plate chondrocytes, bone lengthening, and preferential deposition of periosteal bone in the tibia diaphysis. Analysis of bone marrow at the tibia midshaft depicted more adipocyte number, greater adipocyte density, and altered cell size distribution to favor small adipocytes, but reduced megakaryocytes, in GFC rats. Interestingly, putative effector genes responsible for bone mass accumulation were found to be comparable between GF and GFC rats, which shifted our focus onto systemic host and microbial regulatory factors. Assessment of serum markers indicated that the active bone formation could be due to elevated levels of 25-hydroxy vitamin D and alkaline phosphatase. Importantly, 16S ribosomal RNA gene sequencing demonstrated that the prominent bacterial colonizers were Clostridiaceae and Clostridium members, which are potent short chain fatty acid (SCFA) producers. 1H-NMR metabolomics in the cecal contents showed a dramatic increase of SCFA, specifically butyrate, following bacterial colonization. In relation with the literature, our observation of increased hepatic insulin-like growth factor-1 (IGF-1) expression and systemic IGF-1 levels suggest that butyrate promotes bone growth through the somatotropic axis. Collectively, our study demonstrates that gut microbiota can deliver signals to the skeleton for accelerating bone expansion and accumulating marrow fat.

Alternative regulatory mechanism for the maintenance of bone homeostasis via STAT5-mediated regulation of the differentiation of BMSCs into adipocytes

STAT5 is a transcription factor that is activated by various cytokines, hormones, and growth factors. Activated STAT5 is then translocated to the nucleus and regulates the transcription of target genes, affecting several biological processes. Several studies have investigated the role of STAT5 in adipogenesis, but unfortunately, its role in adipogenesis remains controversial. In the present study, we generated adipocyte-specific Stat5 conditional knockout (cKO) (Stat5fl/fl;Apn-cre) mice to investigate the role of STAT5 in the adipogenesis of bone marrow mesenchymal stem cells (BMSCs). BMSC adipogenesis was significantly inhibited upon overexpression of constitutively active STAT5A, while it was enhanced in the absence of Stat5 in vitro. In vivo adipose staining and histological analyses revealed increased adipose volume in the bone marrow of Stat5 cKO mice. ATF3 is the target of STAT5 during STAT5-mediated inhibition of adipogenesis, and its transcription is regulated by the binding of STAT5 to the Atf3 promoter. ATF3 overexpression was sufficient to suppress the enhanced adipogenesis of Stat5-deficient adipocytes, and Atf3 silencing abolished the STAT5-mediated inhibition of adipogenesis. Stat5 cKO mice exhibited reduced bone volume due to an increase in the osteoclast number, and coculture of bone marrow-derived macrophages with Stat5 cKO adipocytes resulted in enhanced osteoclastogenesis, suggesting that an increase in the adipocyte number may contribute to bone loss. In summary, this study shows that STAT5 is a negative regulator of BMSC adipogenesis and contributes to bone homeostasis via direct and indirect regulation of osteoclast differentiation; therefore, it may be a leading target for the treatment of both obesity and bone loss-related diseases.

Effects of Whole-Body Adenylyl Cyclase 5 (Adcy5) Deficiency on Systemic Insulin Sensitivity and Adipose Tissue.

Genome-wide association studies have identified adenylyl cyclase type 5 (ADCY5) as candidate gene for diabetes-related quantitative traits and an increased risk of type 2 diabetes. Mice with a whole-body deletion of Adcy5 (Adcy5–/–) do not develop obesity, glucose intolerance and insulin resistance, have improved cardiac function and increased longevity. Here, we investigated Adcy5 knockout mice (Adcy5–/–) to test the hypothesis that changes in adipose tissue (AT) may contribute to the reported healthier phenotype. In contrast to previous reports, we found that deletion of Adcy5 did not confer any physiological or biochemical benefits. However, this unexpected finding allowed us to investigate the effects of Adcy5 depletion on AT independently of lower body weight and a metabolically healthier phenotype. Adcy5–/– mice exhibited an increased number of smaller adipocytes, lower mean adipocyte size and a distinct AT gene expression pattern with midline 1 (Mid1) as the most significantly downregulated gene compared to control mice. Our Adcy5–/– model challenges previously described beneficial effects of Adcy5 deficiency and suggests that targeting Adcy5 does not improve insulin sensitivity and may therefore limit the relevance of ADCY5 as potential drug target.

بررسی اثر گرده خرما و تمرینات مقاومتی بر تنظیم سطح هورمون آدیپونکتین در بافت چربی احشایی موشهای صحرایی نر

Introduction: In this study, the effect of date palm extract and resistance training on adipose tissue metabolism and adiponectin factor expression in male rats was investigated. Methods: 30 male rat were divided into 6 groups: control, resistance training, and treatment with date pollen extract, treatment with testosterone, treatment with date palm extract and resistance training, testosterone treatment and resistance training. Date pollen extract was prepared by ethanolic extraction method and fed to rats by gavage at a dose of 100 mg / kg for four weeks. Testosterone enanthate at a dose of 2 mg / kg was injected subcutaneously daily into the target groups. Evaluations of tissue changes under the influence of treatment with date pollen extract and exercise were performed by staining with hematoxylin and eosin. Finally, the expression changes of adiponectin factor in the studied groups were investigated by real-time PCR. Results: The results of this study showed that the application of combination treatments with date palm extract and performing resistance exercises in terms of histology reduced the number of adipocytes in adipose tissue and increased their diameter compared to the groups receiving each of the treatments. Be alone. Also, the results of genetic evaluations showed that treatment with date pollen extract and performing resistance exercises simultaneously can increase the level of adiponectin factor in adipose tissue of the studied male rats. Conclusion: The results of this study showed that resistance training with treatment with date pollen extract is significantly effective in regulating the body's metabolism and establishing homeostasis of adipose tissue, including adiponectin.

Loss of function of lysosomal acid lipase (LAL) profoundly impacts osteoblastogenesis and increases fracture risk in humans.

Lysosomal acid lipase (LAL) is essential for cholesteryl ester (CE) and triacylglycerol (TAG) hydrolysis in the lysosome. Clinically, an autosomal recessive LIPA mutation causes LAL deficiency (LALD), previously described as Wolman Disease or Cholesteryl Ester Storage Disease (CESD). LAL-D is associated with ectopic lipid accumulation in the liver, small intestine, spleen, adrenal glands, and blood. Considering the importance of unesterified cholesterol and fatty acids in bone metabolism, we hypothesized that LAL is essential for bone formation, and ultimately, skeletal health. To investigate the role of LAL in skeletal homeostasis, we used LAL-deficient (-/-) mice, in vitro osteoblast cultures, and novel clinical data from LAL-D patients. Both male and female LAL-/- mice demonstarted lower trabecular and cortical bone parameters , which translated to reduced biomechanical properties. Further histological analyses revealed that LAL-/- mice had fewer osteoblasts, with no change in osteoclast or marrow adipocyte numbers. In studying the cell-autonomous role of LAL, we observed impaired differentiation of LAL-/- calvarial osteoblasts and in bone marrow stromal cells treated with the LAL inhibitor lalistat. Consistent with LAL's role in other tissues, lalistat resulted in profound lipid puncta accumulation and an altered intracellular lipid profile. Finally, we analyzed a large de-identified national insurance database (i.e. 2016/2017 Optum Clinformatics®) which revealed that adults (≥18years) with CESD (n=3076) had a higher odds ratio (OR=1.21; 95% CI=1.03-1.41) of all-cause fracture at any location compared to adults without CESD (n=13.7M) after adjusting for demographic variables and osteoporosis. These data demonstrate that alterations in LAL have significant clinical implications related to fracture risk and that LAL's modulation of lipid metabolism is a critical for osteoblast function.

Knockdown of ANGPTL4 May Reduce the Expression of LPL during Differentiation of 3T3-L1 Preadipocyte

Adipose tissue is a complex, highly metabolically active tissue. The expansion of adipose tissue is mainly affected by two processes: the number of adipocytes and the change of adipocyte size. Adipocyte differentiation is regulated by multiple factors. 3T3-L1 preadipocyte line has become the most widely studied cell line for adipocyte proliferation, differentiation and regulation of related genes. In our previous study, we found that ANGPTL4 was related to preadipocyte differentiation through PPAR signaling pathway. Recent studies have shown that ANGPTL4 has functions of regulating oncogenesis, vascular permeability, glucose homeostasis, lipid metabolism, energy homeostasis. In this study, we observed the changes of key genes expression before and after inhibiting ANGPTL4 to explore how ANGPTL4 influence on lipid metabolism. Results shows that, ANGPTL4 and LPL have similar expression pattern. We suspect that, ANGPTL4 and LPL may form a pathway, when ANGPTL4 is suppressed it may block the pathway and inhibit LPL.

Quantification of adipocyte numbers following adipose tissue remodeling.

To analyze the capacity of white and brown adipose tissue remodeling, we developed two mouse lines to label, quantitatively trace, and ablate white, brown, and brite/beige adipocytes at different ambient temperatures. We show here that the brown adipocytes are recruited first and reach a peak after 1week of cold stimulation followed by a decline during prolonged cold exposure. On the contrary, brite/beige cell numbers plateau after 3weeks of cold exposure. At thermoneutrality, brown adipose tissue, in spite of being masked by a white-like morphology, retains its brown-like physiology, as Ucp1+ cells can be recovered immediately upon beta3-adrenergic stimulation. We further demonstrate that the recruitment of Ucp1+ cells in response to cold is driven by existing adipocytes. In contrast, the regeneration of the interscapular brown adipose tissue following ablation of Ucp1+ cells is driven by de novo differentiation.

Unbiased analysis of obesity related, fat depot specific changes of adipocyte volumes and numbers using light sheet fluorescence microscopy.

In translational obesity research, objective assessment of adipocyte sizes and numbers is essential to characterize histomorphological alterations linked to obesity, and to evaluate the efficacies of experimental medicinal or dietetic interventions. Design-based quantitative stereological techniques based on the analysis of 2D-histological sections provide unbiased estimates of relevant 3D-parameters of adipocyte morphology, but often involve complex and time-consuming tissue processing and analysis steps. Here we report the application of direct 3D light sheet fluorescence microscopy (LSFM) for effective and accurate analysis of adipocyte volumes and numbers in optically cleared adipose tissue samples from a porcine model of diet-induced obesity (DIO). Subcutaneous and visceral adipose tissue samples from DIO-minipigs and lean controls were systematically randomly sampled, optically cleared with 3DISCO (3-dimensional imaging of solvent cleared organs), stained with eosin, and subjected to LSFM for detection of adipocyte cell membrane autofluorescence. Individual adipocytes were unbiasedly sampled in digital 3D reconstructions of the adipose tissue samples, and their individual cell volumes were directly measured by automated digital image analysis. Adipocyte numbers and mean volumes obtained by LSFM analysis did not significantly differ from the corresponding values obtained by unbiased quantitative stereological analysis techniques performed on the same samples, thus proving the applicability of LSFM for efficient analysis of relevant morphological adipocyte parameters. The results of the present study demonstrate an adipose tissue depot specific plasticity of adipocyte growth responses to nutrient oversupply. This was characterized by an exclusively hypertrophic growth of visceral adipocytes, whereas adipocytes in subcutaneous fat tissue depots also displayed a marked (hyperplastic) increase in cell number. LSFM allows for accurate and efficient determination of relevant quantitative morphological adipocyte parameters. The applied stereological methods and LSFM protocols are described in detail and can serve as a guideline for unbiased quantitative morphological analyses of adipocytes in other studies and species.

Novel adipokine asprosin modulates browning and adipogenesis in white adipose tissue.

Obesity is an increasingly serious epidemic worldwide characterized by an increase in the number and size of adipocytes. Adipose tissue maintains the balance between lipid storage and energy utilization. Therefore, adipose metabolism is of great significance for the prevention, treatment and intervention of obesity. Asprosin, a novel adipokine, is a circulating hormone mainly secreted by white adipose tissue. Previous studies have shown that asprosin plays a role in fasting-induced homeostasis, insulin resistance, and glucose tolerance. However, whether it can regulate the metabolism of adipose tissue itself has not been studied. This study intended to examine the roles and potential mechanisms of asprosin in adipose regulation. We first demonstrated that the expression level of asprosin was significantly downregulated in subcutaneous white adipose tissue (scWAT) of high-fat diet (HFD)-fed or cold-stimulated mice. Overexpression of asprosin in scWAT reduced heat production, decreased expression of the browning marker uncoupling protein 1 (UCP1) and other browning-related genes, along with upregulation of adipogenic gene expression. Mechanistically, we found that Nrf2 was activated upon cold exposure, but this activation was suppressed after asprosin overexpression. In primary cultured adipocytes, adenovirusmediated asprosin overexpression inhibited adipose browning and aggravated lipid deposition, while Nrf2 agonist oltipraz could reverse these changes. Our findings suggest that novel adipokine asprosin negatively regulated browning and elevate lipid deposition in adipose tissue via a Nrf2-mediated mechanism. Asprosin may be a promising target for the prevention and treatment of obesity and other metabolic diseases.

Myonectin inhibits adipogenesis in 3T3-L1 preadipocytes by regulating p38 MAPK pathway

In current times, obesity is a major health problem closely associated with metabolic disease such as diabetes, dyslipidemia, and cardiovascular disease. The direct cause of obesity is known as an abnormal increase in fat cell size and the adipocyte pool. Hyperplasia, the increase in number of adipocytes, results from adipogenesis in which preadipocytes differentiate into mature adipocytes. Adipogenesis is regulated by local and systemic cues that alter transduction pathways and subsequent control of adipogenic transcription factors. Therefore, the regulation of adipogenesis is an important target for preventing obesity. Myonectin, a member of the CTRP family, is a type of myokine released by skeletal muscle cells. Although several studies have shown that myonectin is associated with lipid metabolism, the role of myonectin during adipogenesis is not known. Here, we demonstrate the role of myonectin during adipocyte differentiation of 3T3-L1 cells. We found that myonectin inhibits the adipogenesis of 3T3-L1 preadipocytes with a reduction in the expression of adipogenic transcription factors such as C/EBPα, β and PPARγ. Furthermore, we show that myonectin has an inhibitory effect on adipogenesis through the regulation of the p38 MAPK pathway and CHOP. These findings suggest that myonectin may be a novel therapeutic target for the prevention of obesity.

A White Grape Juice Extract Reduces Fat Accumulation through the Modulation of Ghrelin and Leptin Expression in an In Vivo Model of Overfed Zebrafish.

A caloric surplus and a sedentary lifestyle are undoubtedly known to be the leading causes of obesity. Natural products represent valuable allies to face this problematic issue. This study was planned to assess the effect of a white grape (Vitis vinifera) juice extract (WGJe) in diet-induced obese zebrafish (Danio rerio). Fish were divided into four different diet groups: (i) normally fed (NF); (ii) overfed (OF); (iii) WGJe-supplemented NF (5 mL/L in fish water); (iv) WGJe-supplemented OF. Body mass index (BMI) was extrapolated each week. After the fourth week, euthanized zebrafish were processed for both microscopic evaluations and gene expression analyses. OF zebrafish showed higher BMI values with respect to NF counterparts, an effect that was hindered by WGJe treatment. Moreover, histological analyses showed that the area of the adipose tissue, as well as the number, size, and density of adipocytes was significantly higher in OF fish. On the other hand, WGJe was able to avoid these outcomes both at the subcutaneous and visceral levels, albeit to different extents. At the gene level, WGJe restored the altered levels of ghrelin and leptin of OF fish both in gut and brain. Overall, our results support the anti-obesity property of WGJe, suggesting its potential role in weight management.

MiR-99b-5p Attenuates Adipogenesis by Targeting SCD1 and Lpin1 in 3T3-L1 Cells.

The number and distribution of adipocytes directly affect the quality of livestock meat products. The analysis of the adipogenesis mechanism is the basis for improving meat quality. The formation of adipocytes is regulated by many factors, including a class of endogenous small RNAs, named microRNA (miRNA). Previous studies have shown that miRNAs could affect adipogenesis by post-transcriptional regulation of target genes. In our study, a decreased miR-99b-5p expression level was found in the adipose tissue of obese mice. Overexpression of miR-99b-5p could increase cell proliferation by promoting the cell cycle while inhibiting cell differentiation. In addition, interference with miR-99b-5p obtained the opposite result. Furthermore, the proteomics sequencing analysis screened 1154 differentially expressed proteins, which are closely related to adipocyte differentiation and fatty acid metabolism. In addition, the results of the dual-luciferase test showed that miR-99b-5p can directly target the proteins SCD1 and Lpin1 with significantly different expression levels in proteomic sequencing. Then, this result was verified at the level of mRNA and protein in a further study. Collectively, these results suggested that miR-99b-5p may be a target for improving meat quality.

The effects of high fat diet, bone healing, and BMP-2 treatment on endothelial cell growth and function.

Angiogenesis is a vital process during the regeneration of bone tissue. The aim of this study was to investigate angiogenesis at the fracture site as well as at distal locations from obesity-induced type 2 diabetic mice that were treated with bone morphogenetic protein-2 (BMP-2, local administration at the time of surgery) to heal a femoral critical sized defect (CSD) or saline as a control. Mice were fed a high fat diet (HFD) to induce a type 2 diabetic-like phenotype while low fat diet (LFD) animals served as controls. Endothelial cells (ECs) were isolated from the lungs (LECs) and bone marrow (BMECs) 3weeks post-surgery, and the fractured femurs were also examined. Our studies demonstrate that local administration of BMP-2 at the fracture site in a CSD model results in complete bone healing within 3weeks for all HFD mice and 66.7% of LFD mice, whereas those treated with saline remain unhealed. At the fracture site, vessel parameters and adipocyte numbers were significantly increased in BMP-2 treated femurs, irrespective of diet. At distal sites, LEC and BMEC proliferation was not altered by diet or BMP-2 treatment. HFD increased the tube formation ability of both LECs and BMECs. Interestingly, BMP-2 treatment at the time of surgery reduced tube formation in LECs and humeri BMECs. However, migration of BMECs from HFD mice treated with BMP-2 was increased compared to BMECs from HFD mice treated with saline. BMP-2 treatment significantly increased the expression of CD31, FLT-1, and ANGPT2 in LECs and BMECs in LFD mice, but reduced the expression of these same genes in HFD mice. To date, this is the first study that depicts the systemic influence of fracture surgery and local BMP-2 treatment on the proliferation and angiogenic potential of ECs derived from the bone marrow and lungs.

Oxidative Stress, Plant Natural Antioxidants, and Obesity.

Oxidative stress is important in the pathophysiology of obesity, altering regulatory factors of mitochondrial activity, modifying the concentration of inflammation mediators associated with a large number and size of adipocytes, promoting lipogenesis, stimulating differentiation of preadipocytes to mature adipocytes, and regulating the energy balance in hypothalamic neurons that control appetite. This review discusses the participation of oxidative stress in obesity and the important groups of compounds found in plants with antioxidant properties, which include (a) polyphenols such as phenolic acids, stilbenes, flavonoids (flavonols, flavanols, anthocyanins, flavanones, flavones, flavanonols, and isoflavones), and curcuminoids (b) carotenoids, (c) capsaicinoids and casinoids, (d) isothiocyanates, (e) catechins, and (f) vitamins. Examples are analyzed, such as resveratrol, quercetin, curcumin, ferulic acid, phloretin, green tea, Hibiscus Sabdariffa, and garlic. The antioxidant activities of these compounds depend on their activities as reactive oxygen species (ROS) scavengers and on their capacity to prevent the activation of NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells), and reduce the expression of target genes, including those participating in inflammation. We conclude that natural compounds have therapeutic potential for diseases mediated by oxidative stress, particularly obesity. Controlled and well-designed clinical trials are still necessary to better know the effects of these compounds.

Raman Spectroscopy for Adipose Tissue Assessment in Rat Models of Obesity and Type 1 Diabetes.

Adipose tissue presents structural and functional changes in obesity and type 1 diabetes mellitus (T1DM). In obesity, the size and number of adipocytes and adipokine secretion increases. In T1DM, a loss of adipose tissue suggests changes in the metabolic activity of this tissue. A significant challenge is to find alternative noninvasive methods to evaluate molecular changes in adipose tissue related to obesity and T1DM. Recently, Raman spectroscopy and chemometrics techniques have emerged as a tool for biological tissue analysis. In this work, we propose the use of Raman spectroscopy to characterize spectral differences in adipose tissue from different rat groups (control, obese, and T1DM). The Raman spectra were analyzed using direct band analysis, ratiometric analysis, and chemometric methods (principal component analysis (PCA) and support vector machines (SVMs)). We found that the Raman spectra of obese rats showed significant spectral differences compared to control and diabetic groups related to fatty acids Raman bands. Also, the obese group has a significant decrease in the degree of unsaturation of lipids. The PCA-SVM models showed classification performance ranging from 71.43% to 71.79% accuracy for brown and white adipose tissue samples, respectively. In conclusion, the results demonstrate that Raman spectroscopy can be used as a nondestructive method to assess adipose tissue according to a metabolic condition.

Dermal Adipose Tissue Secretes HGF to Promote Human Hair Growth and Pigmentation

Hair follicles (HFs) are immersed within dermal white adipose tissue (dWAT), yet human adipocyte‒HF communication remains unexplored. Therefore, we investigated how perifollicular adipocytes affect the physiology of human anagen scalp HFs. Quantitative immunohistomorphometry, X-ray microcomputed tomography, and transmission electron microscopy showed that the number and size of perifollicular adipocytes declined during anagen‒catagen transition, whereas fluorescence-lifetime imaging revealed increased lipid oxidation in adipocytes surrounding the bulge and/or sub-bulge region. Exvivo, dWAT tendentially promoted hair shaft production, and significantly stimulated hair matrix keratinocyte proliferation and HF pigmentation. Both dWAT pericytes and PREF1/DLK1+ adipocyte progenitors secreted HGF during human HF‒dWAT co-culture, for which the c-Met receptor was expressed in the hair matrix and dermal papilla. These effects were reproduced using recombinant HGF and abrogated by an HGF-neutralizing antibody. Laser-capture microdissection‒based microarray analysis of the hair matrix showed that dWAT-derived HGF upregulated keratin (K) genes (K27, K73, K75, K84, K86) and TCHH. Mechanistically, HGF stimulated Wnt/β-catenin activity in the human hair matrix (increased AXIN2, LEF1) by upregulating WNT6 and WNT10B, and inhibiting SFRP1 in the dermal papilla. Our study demonstrates that dWAT regulates human hair growth and pigmentation through HGF secretion, and thus identifies dWAT and HGF as important novel molecular and cellular targets for therapeutic intervention in human hair growth and pigmentation disorders.

Hypertrophy and Insulin Resistance of Epicardial Adipose Tissue Adipocytes: Association with the Coronary Artery Disease Severity.

Changes in the structural and functional characteristics of the epicardial adipose tissue (EAT) are recognized as one of the factors in the development of cardiometabolic diseases. However, the generally accepted quantitative assessment of the accumulation of EAT does not reflect the size of adipocyte and presence of adipocyte hypertrophy in this fat depot. Overall contribution of adipocyte hypertrophy to the development and progression of coronary atherosclerosis remains unexplored. Objective: To compare the morphological characteristics of EAT adipocyte and its sensitivity to insulin with the CAD severity, as well as to identify potential factors involved in the realization of this relationship. The present study involved 24 patients (m/f 16/8) aged 53–72 years with stable CAD, who underwent coronary artery bypass graft surgery. Adipocytes were isolated enzymatically from EAT explants obtained during the operation. The severity of CAD was assessed by calculating the Gensini score according to selective coronary angiography. Insulin resistance of EAT adipocytes was evaluated by reactivity to insulin. In patients with an average size of EAT adipocytes equal to or exceeding the median (87 μm) the percentage of hypertrophic adipocytes was twice as high as in patients in whom the average size of adipocytes was less than 87 μm. This group of patients was also characterized by the higher rate of the Gensini score, lower adiponectin levels, and more severe violation of carbohydrate metabolism. We have revealed direct nonparametric correlation between the size of EAT adipocytes and the Gensini score (rs = 0.56, p = 0.00047). The number of hypertrophic EAT adipocytes showed a direct nonparametric correlation with the Gensini score (rs = 0.6, p = 0.002). Inverse nonparametric correlations were found between the serum adiponectin level and size (rs = −0.60, p = 0.001), hypertrophy of adipocytes (rs = −0.67, p = 0.00), and Gensini score (rs = −0.81, p = 0.00007). An inverse nonparametric correlation was found between the Gensini score and sensitivity of EAT adipocytes to insulin, estimated by the intracellular redox response (rs = −0.90, p = 0.037) and decrease in lipolysis rate upon insulin addition (rs = −0.40, p = 0.05). The intracellular redox response of adipocytes to insulin was directly correlated with fasting insulin and inversely with postprandial insulin. Our data indicate that the size and degree of hypertrophy of the epicardial adipocytes are related to the CAD severity. According to our results, insulin resistance of adipocytes may be considered as one of the factors mediating this relationship.

Nutmeg extract potentially alters characteristics of white adipose tissue in rats.

BackgroundBrowning of white adipose tissue (WAT) is a promising approach to obesity treatment. During browning, WAT transforms into beige adipose tissue through stimulation of the peroxisome proliferator activated receptor γ (PPARγ). Nutmeg, one of the Indonesian herbs, reportedly has dual roles as a PPARα/γ partial agonist. Even though nutmeg has been traditionally used in body weight reduction, there is limited information regarding the potential role of nutmeg in browning of WAT.ObjectivesIn this study, we explored the effect of nutmeg seed extract (NuSE) as a potential inductor of WAT browning.MethodsTwelve male Wistar rats, 5–6 weeks old, were divided into control and nutmeg groups. The rats in nutmeg group were given NuSE for 12 weeks by oral gavage. After 12 weeks, the rat's inguinal WAT and brown adipose tissue (BAT) were collected, weighed and stored at − 80°C until use.ResultsWe observed that even though NuSE did not reduce the final body weight, it significantly reduced body weight gain. NuSE also increased protein levels of peroxisome proliferator activated receptor γ coactivator 1α (PGC‐1α) and uncoupling protein 3 (UCP3) significantly and tended to increase UCP2 and UCP1 levels. Furthermore, NuSE induced macroscopic and microscopic morphological changes of inguinal WAT, marked by significantly increased adipocyte numbers and decreased adipocyte size.ConclusionsEven though NuSE did not increase UCP1 significantly, it potentially alters inguinal WAT characteristics and leads to browning through PGC‐1α and UCP3 induction. However, UCP3’s specific mechanism in WAT browning remains unclear. Our findings could contribute to obesity treatment in the future.

Dysfunctional adiposity index as a marker of adipose tissue morpho-functional abnormalities and metabolic disorders in apparently healthy subjects

ABSTRACT Compared to body mass index, waist circumference (WC), and adiposity measurements, adipose tissue (AT) morpho-functionality evaluations are better predictors of cardiometabolic abnormalities (CA). The present study establishes a dysfunctional adiposity index (DAI) as an early marker of CA based on adipocytes morpho-functional abnormalities. DAI was established in 340 subjects without cardiovascular risk factors selected from a cross-sectional study (n=1600). Then, DAI was calculated in 36 healthy subjects who underwent subcutaneous AT biopsy. The correlation of DAI with adipocyte morphology (size/number) and functionality (adiponectin/leptin ratio) was analyzed. The DAI cut-off point was identified and its independent association with CA was determined in 1418 subjects from the cross-sectional study. The constant parameters to calculate the DAI were [WC/[22.79+[2.68*BMI]]]*[triglycerides (TG, mmol/L)/1.37]*[1.19/high density lipoprotein-cholesterol (HDL-C, mmol/L)] for males, and [WC/[24.02+[2.37*BMI]]]*[TG(mmol/L)/1.32]*[1.43/HDL-C(mmol/L)] for females. DAI correlated with adipocytes mean area, adipocyte number and adiponectin/leptin ratio. DAI ≥1.065 was independently associated with diabetes, non-alcoholic fatty liver disease, subclinical atherosclerosis, and hypertension. The present study highlights that DAI is associated with early CA independently of adiposity and other risk factors. Since DAI is obtained using accessible parameters, it can be easily incorporated into clinical practice for early identification of AT abnormalities in apparently healthy subjects.