Adipose Tissue Formation Research Articles

Alpha Hydroxyl Acids from Mume Fructus and Schisandrae Chinensis Fructus Prevent Obesity by Inhibiting Intestinal Lipase in Diet-Induced Obese Mice.

Restriction of lipid uptake and absorption from the diet is regarded as an efficient strategy for the management of obesity, while lipase inhibition could successfully block the digestion of dietary lipids. Mume Fructus (MF) and Schisandrae Chinensis Fructus (SCF) were used as fruits, the biological effect of which on obesity desired more attention. Herein, the extracts of MF and SCF displayed significant efficacy in managing obesity in mice fed with a high-fat diet, via the inhibition of hydrolase activity of lipase in the digestive tract. Using the bioactivity guidance strategy, citric acid and malic acid were identified as the major lipase inhibitors from MF and SCF, respectively, which could prevent body weight gain, along with adipose tissue formation, and alleviate hyperlipidemia and hepatic steatosis in obese mice. Above all, MF and SCF could be used for the management of obesity via the lipase inhibition by citric acid and malic acid, displaying potential applications in healthy foods, nutritional supplements, and pharmaceutical materials.

The Impact of Gastrointestinal Hormones on Human Adipose Tissue Function

Background: Obesity is a global issue, the development of which depends on many interacting factors. Among these, hormones secreted in the gastrointestinal tract play an important role. The aim of this review was to assess the impact of these hormones on the functions of adipose tissue. Methods: The analysis was based on the latest research concerning both adipose tissue and gastrointestinal hormones. Results: It was found that these hormones can significantly affect adipose tissue, both directly and indirectly. Some hormones, when secreted in excess, can stimulate adipose tissue formation processes, while others can inhibit them. The impact of hormones depends on the location and type of adipose tissue as well as the physiological state of the body. It should also be noted that no hormone acts in isolation but in close cooperation with other factors. Conclusions: The relationship between gastrointestinal hormones and adipose tissue, and their role in obesity, is a complex and evolving field of study. Further research is necessary, particularly into the interactions between hormones and other factors, as well as their mutual interactions.

NOX4-reactive oxygen species axis: critical regulators of bone health and metabolism.

Bone marrow stromal cells (BMSCs) play a significant role in bone metabolism as they can differentiate into osteoblasts, bone marrow adipocytes (BMAds), and chondrocytes. BMSCs chronically exposed to nutrient overload undergo adipogenic programming, resulting in bone marrow adipose tissue (BMAT) formation. BMAT is a fat depot transcriptionally, metabolically, and morphologically distinct from peripheral adipose depots. Reactive oxygen species (ROS) are elevated in obesity and serve as important signals directing BMSC fate. ROS produced by the NADPH oxidase (NOX) family of enzymes, such as NOX4, may be responsible for driving BMSC adipogenesis at the expense of osteogenic differentiation. The dual nature of ROS as both cellular signaling mediators and contributors to oxidative stress complicates their effects on bone metabolism. This review discusses the complex interplay between ROS and BMSC differentiation in the context of metabolic bone diseases.Special attention is paid to the role of NOX4-ROS in regulating cellular processes within the bone marrow microenvironment and potential target in metabolic bone diseases.

MLPH is a novel adipogenic factor controlling redox homeostasis to inhibit lipid peroxidation in adipocytes

Abnormal adipose tissue formation is associated with metabolic disorders such as obesity, diabetes, and liver and cardiovascular diseases. Thus, identifying the novel factors that control adipogenesis is crucial for understanding these conditions and developing targeted treatments. In this study, we identified the melanosome-related factor MLPH as a novel adipogenic factor. MLPH was induced during the adipogenesis of 3T3-L1 cells and human mesenchymal stem cells. Although MLPH did not affect lipid metabolism, such as lipogenesis or lipolysis, adipogenesis was severely impaired by MLPH depletion. We observed that MLPH prevented excess reactive oxygen species (ROS) accumulation and lipid peroxidation during adipogenesis and in mature adipocytes. In addition, increased MLPH expression was observed under cirrhotic conditions in liver cancer cells and its overexpression also reduced ROS and lipid peroxidation. Our findings demonstrate that MLPH is a novel adipogenic factor that maintains redox homeostasis by preventing lipid peroxidation and ROS accumulation, which could lead to metabolic diseases.

CTRP9 Promotes Brown Adipose Tissue Lipolysis in Mice Fed a High-Fat Diet.

This study aimed to elucidate the molecular mechanism through which C1q/tumor necrosis factor (TNF)-related protein 9 (CTRP9) acts in the formation and differentiation of brown adipose tissue (BAT). Adenovirus particles encoding CTRP9 and green fluorescent protein were inoculated into the scapula of C57BL/6J mice and fed a high-fat diet for 8 weeks; the body weight, lipid droplet morphology, glucose tolerance, insulin tolerance, and protein expression levels were analyzed. In addition, CTRP9 adenovirus was transfected into brown preadipocytes, and differentiation was induced to identify the effect of CTRP9 overexpression on adipocyte differentiation. CTRP9 overexpression significantly increased the weight gain of mice. Additionally, the CTRP9 overexpression group exhibited significantly increased adipose tissue weight and glucose clearance rates and decreased insulin sensitivity and serum triglyceride levels compared to the control group. Furthermore, CTRP9 overexpression significantly upregulated the adipose triglyceride lipase (ATGL) and perilipin 1 protein expression levels in BAT. The cell experiment results confirmed that CTRP9 overexpression significantly inhibited the adipogenesis of brown adipocytes as evidenced by the downregulation of uncoupling protein 1, beta-3 adrenergic receptor, ATGL, and hormone-sensitive lipase mRNA levels and the significant suppression of uncoupling protein 1, ATGL, and perilipin 1 protein levels in brown adipocytes. The finding of this study demonstrated that CTRP9 promotes lipolysis by upregulating ATGL expression in vivo and inhibits the differentiation of brown preadipocytes in vitro.

Biofabrication of 3D adipose tissue via assembly of composite stem cell spheroids containing adipo-inductive dual-signal delivery nanofibers

Reconstruction of large 3D tissues based on assembly of micro-sized multi-cellular spheroids has gained attention in tissue engineering. However, formation of 3D adipose tissue from spheroids has been challenging due to the limited adhesion capability and restricted cell mobility of adipocytes in culture media. In this study, we addressed this problem by developing adipo-inductive nanofibers enabling dual delivery of indomethacin and insulin. These nanofibers were introduced into composite spheroids comprising human adipose-derived stem cells (hADSCs). This approach led to a significant enhancement in the formation of uniform lipid droplets, as evidenced by the significantly increased Oil red O-stained area in spheroids incorporating indomethacin and insulin dual delivery nanofibers (56.9 ± 4.6%) compared to the control (15.6 ± 3.5%) with significantly greater gene expression associated with adipogenesis (C/EBPA, PPARG, FABP4, and adiponectin) of hADSCs. Furthermore, we investigated the influence of culture media on the migration and merging of spheroids and observed significant decrease in migration and merging of spheroids in adipogenic differentiation media. Conversely, the presence of adipo-inductive nanofibers promoted spheroid fusion, allowing the formation of macroscopic 3D adipose tissue in the absence of adipogenic supplements while facilitating homogeneous adipogenesis of hADSCs. The approach described here holds promise for the generation of 3D adipose tissue constructs by scaffold-free assembly of stem cell spheroids with potential applications in clinical and organ models.

Endoplasmic reticulum stress: bridging inflammation and obesity-associated adipose tissue.

Obesity presents a significant global health challenge, increasing the susceptibility to chronic conditions such as diabetes, cardiovascular disease, and hypertension. Within the context of obesity, lipid metabolism, adipose tissue formation, and inflammation are intricately linked to endoplasmic reticulum stress (ERS). ERS modulates metabolism, insulin signaling, inflammation, as well as cell proliferation and death through the unfolded protein response (UPR) pathway. Serving as a crucial nexus, ERS bridges the functionality of adipose tissue and the inflammatory response. In this review, we comprehensively elucidate the mechanisms by which ERS impacts adipose tissue function and inflammation in obesity, aiming to offer insights into targeting ERS for ameliorating metabolic dysregulation in obesity-associated chronic diseases such as hyperlipidemia, hypertension, fatty liver, and type 2 diabetes.

Adipose tissue reconstruction facilitated with low immunogenicity decellularized adipose tissue scaffolds.

There is currently an urgent need to develop engineered scaffolds to support new adipose tissue formation and facilitate long-term maintenance of function and defect repair to further generate prospective bioactive filler materials capable of fulfilling surgical needs. Herein, adipose regeneration methods were optimized and decellularized adipose tissue (DAT) scaffolds with good biocompatibility were fabricated. Adipose-like tissues were reconstructed using the DAT and 3T3-L1 preadipocytes, which have certain differentiation potential, and the regenerative effects of the engineered adipose tissuesin vitroandin vivowere explored. The method improved the efficiency of adipose removal from tissues, and significantly shortened the time for degreasing. Thus, the DAT not only provided a suitable space for cell growth but also promoted the proliferation, migration, and differentiation of preadipocytes within it. Following implantation of the constructed adipose tissuesin vivo, the DAT showed gradual degradation and integration with surrounding tissues, accompanied by the generation of new adipose tissue analogs. Overall, the combination of adipose-derived extracellular matrix and preadipocytes for adipose tissue reconstruction will be of benefit in the artificial construction of biomimetic implant structures for adipose tissue reconstruction, providing a practical guideline for the initial integration of adipose tissue engineering into clinical medicine.

Association of adiponectin with thyroid dysfunction in diabetes mellitus type II

The two most prevalent endocrine-related conditions seen in clinical practice are thyroid diseases (TD) and diabetes mellitus (DM). Diabetes mellitus and thyroid dysfunction are strongly related conditions. Numerous research investigations have reported that individuals with diabetes mellitus are more likely to have thyroid issues, and vice versa. Compared to individuals without diabetes, Type 2 Diabetes Mellitus (T2DM) patients have higher rates of both hypothyroidism and hyperthyroidism. Thyroid hormones are circulating hormones that impact various organs and tissues, have a vital role in the metabolism of proteins, fats, and carbohydrates, and can exacerbate glycemic control in individuals with Type II Diabetes Mellitus (T2DM). At the Specialized Center for Endocrinology and Diabetes – Al-Kindi Teaching Hospital in Baghdad, a case-control research was carried out. The samples were gathered between January 1, 2021, and April 1, 2021. The current study had one hundred twenty (120) volunteers, all of whom fasted for eight to twelve hours before to the test: · Thirty (30) patients suffered from diabetic mellitus type II seventeen (17) females and thirteen (13) males. · Thirty (30) were control with, sixteen (16) females and fourteen (14) males. · Thirty (30) patients had thyroid dysfunction eighteen (18) females and twelve (12) males. · Thirty (30) patients had thyroid dysfunction and diabetes mellitus type II, sixteen (16) females and fourteen (14) males. Variables such as gender, age, Body Mass Index (BMI), thyroid hormones ,Fasting Blood Sugar (FBS), Glycated Hemoglobin (HbA1c), lipid profile (TG, CHOL, LDL-C, HDL-C, VLDL-C), Adiponectin (ADP)were measured and documented from participants included in this study. According to the results of hormones, there were substantial variations in all of the hormone levels. Thyroid Stimulating Hermon (TSH) was the highest level in Thyroid Dysfunction with Diabetes Mellitus type II: Hypothyroidism patients(0.46 ± 6.26) µIU/mL. T3 hormone was (187.84 ± 6.12) ng/dL, the highest resultin Thyroid Dysfunction with Diabetes Mellitus type Ⅱ: Hyperthyroidism patients. T4 was highest hormonal level in Thyroid Dysfunction with Diabetes Mellitus type II: Hyperthyroidism patients which was (14.02 ± 0.56) ng/dL. Fasting blood sugar (serum) measured a highly significant differences and highest level in patients who suffered from thyroid Dysfunction with Diabetes Mellitus type II: Hypothyroidism with (190.50 ± 12.72) mg/dL. Glycated hemoglobin (HbA1c) measured high significant differences with (11.13 ± 0.55) mmoL/L in patients of diabetes type II. Cholesterol, Triglyceride, LDL-C and VLDL-C high significant differences and highest levels were among patients with Thyroid Dysfunction with Diabetes Mellitus type II: Hypothyroidism with (209.45 ±12.29, 268.18 ±31.57, 114.24 ±13.74 and 55.98 ±5.63) mg/dL respectively, while HDL-C was significantly higher in control group. The Adiponectin had high significant differences among Thyroid Dysfunction: Hyperthyroidism patients with (17.98 ±1.43) ng/mL. In conclusion this data backs up the theory that inducing or suppressing adiponectin in individuals with thyroid dysfunction can help them in losing weight. Hypothyroid individuals with DM Type II and lipid abnormalities in their blood. This data is attributed to the idea that inducing or suppressing adiponectin in individuals with thyroid dysfunction might be a promising new treatment strategy. Adiponectin has been shown that’s involved in numerous physiological and pathological processes, including as inflammation and tissue remodeling. They may be crucial in the formation of adipose tissue and insulin resistance, and they have been linked to a number of inflammatory illnesses.

The potential of DNA methylation markers in the study of obesity

Obesity is a complex, heterogeneous, actively progressive disease manifested by excessive formation of adipose tissue in the body and usually has a high cardiometabolic risk and specific complications. Currently, new data are emerging that explain the pathogenesis of obesity not only by genetic variations and imbalance between energy intake and expenditure, but also by the influence of epigenetic mechanisms, such as DNA methylation. DNA methylation is the most studied epigenetic modification, whose status in the cell can be altered by various external and internal environmental factors, including diet, lifestyle, and hormones. These changes may lead to dysregulation of genes responsible for metabolic processes associated with the development of obesity. However, studies investigating epigenetic marks as potential mediators of obesity are heterogeneous in design, methodology, and results. This review discusses a conceptual framework analyzing the relationship between DNA methylation, obesity, inflammation, and response to weight loss, including after bariatric surgery, as well as material selection and methodology issues to consider when designing studies in this area.

Evaluation of adipogenesis over time using a novel bioabsorbable implant without the addition of exogenous cells or growth factors

BackgroundBreast reconstruction is crucial for patients who have undergone mastectomy for breast cancer. Our bioabsorbable implants comprising an outer poly-l-lactic acid mesh and an inner component filled with collagen sponge promote and retain adipogenesis in vivo without the addition of exogenous cells or growth factors. In this study, we evaluated adipogenesis over time histologically and at the gene expression level using this implant in a rodent model. MethodsThe implants were inserted in the inguinal and dorsal regions of the animals. At 1, 3, 6, and 12 months post-operation, the weight, volume, and histological assessment of all newly formed tissue were performed. We analyzed the formation of new adipose tissue using multiphoton microscopy and RNA sequencing. ResultsBoth in the inguinal and dorsal regions, adipose tissue began to form 1 month post-operation in the peripheral area. Angiogenesis into implants was observed until 3 months. At 6 months, microvessels matured and the amount of newly generated adipose tissue peaked and was uniformly distributed inside implants. The amount of newly generated adipose tissue decreased from 6 to 12 months but at 12 months, adipose tissue was equivalent to the native tissue histologically and in terms of gene expression. ConclusionsOur bioabsorbable implants could induce normal adipogenesis into the implants after subcutaneous implantation. Our implants can serve as a novel and safe material for breast reconstruction without requiring exogenous cells or growth factors.

A review of the role of transcription factors in regulating adipogenesis and lipogenesis in beef cattle.

In the past few decades, genomic selection and other refined strategies have been used to increase the growth rate and lean meat production of beef cattle. Nevertheless, the fast growth rates of cattle breeds are often accompanied by a reduction in intramuscular fat (IMF) deposition, impairing meat quality. Transcription factors play vital roles in regulating adipogenesis and lipogenesis in beef cattle. Meanwhile, understanding the role of transcription factors in regulating adipogenesis and lipogenesis in beef cattle has gained significant attention to increase IMF deposition and meat quality. Therefore, the aim of this paper was to provide a comprehensive summary and valuable insight into the complex role of transcription factors in adipogenesis and lipogenesis in beef cattle. This review summarizes the contemporary studies in transcription factors in adipogenesis and lipogenesis, genome-wide analysis of transcription factors, epigenetic regulation of transcription factors, nutritional regulation of transcription factors, metabolic signalling pathways, functional genomics methods, transcriptomic profiling of adipose tissues, transcription factors and meat quality and comparative genomics with other livestock species. In conclusion, transcription factors play a crucial role in promoting adipocyte development and fatty acid biosynthesis in beef cattle. They control adipose tissue formation and metabolism, thereby improving meat quality and maintaining metabolic balance. Understanding the processes by which these transcription factors regulate adipose tissue deposition and lipid metabolism will simplify the development of marbling or IMF composition in beef cattle.

Le tissu adipeux dans tous ses états : dernières avancées: The different colours and functions of adipose tissue: what’s new?

Obesity represents a growing global health issue today. Understanding the mechanisms underlying the formation, growth, and function of adipose tissue is crucial in combating this disease and its associated complications, such as type 2 diabetes and cardiovascular diseases. In France, obesity is on the rise, particularly among young adults and children. In this review, we discuss the cellular composition of white adipose tissue, highlighting recent advances in the characterisation of various cell populations. We also explore the metabolic implications of body fat distribution, emphasizing the importance of brown and beige adipose tissues in metabolism regulation. These thermogenic tissues offer significant metabolic benefits, opening up promising opportunities in research and development of therapeutic strategies to address obesity-related metabolic disorders. Furthermore, we discuss the relationship between cellular senescence and obesity-related metabolic dysfunction, along with new research in the field of intercellular communication and mitochondrial recycling. Finally, this review provides a comprehensive overview of recent developments in the understanding of obesity at adipose cells level.© 2023 Société francophone nutrition clinique et métabolisme (SFNCM).Published by Elsevier Masson SAS. All rights reserved.

Intraoperative bioprinting of human adipose-derived stem cells and extra-cellular matrix induces hair follicle-like downgrowths and adipose tissue formation during full-thickness craniomaxillofacial skin reconstruction

Craniomaxillofacial (CMF) reconstruction is a challenging clinical dilemma. It often necessitates skin replacement in the form of autologous graft or flap surgery, which differ from one another based on hypodermal/dermal content. Unfortunately, both approaches are plagued by scarring, poor cosmesis, inadequate restoration of native anatomy and hair, alopecia, donor site morbidity, and potential for failure. Therefore, new reconstructive approaches are warranted, and tissue engineered skin represents an exciting alternative. In this study, we demonstrated the reconstruction of CMF full-thickness skin defects using intraoperative bioprinting (IOB), which enabled the repair of defects via direct bioprinting of multiple layers of skin on immunodeficient rats in a surgical setting. Using a newly formulated patient-sourced allogenic bioink consisting of both human adipose-derived extracellular matrix (adECM) and stem cells (ADSCs), skin loss was reconstructed by precise deposition of the hypodermal and dermal components under three different sets of animal studies. adECM, even at a very low concentration such as 2 % or less, has shown to be bioprintable via droplet-based bioprinting and exhibited de novo adipogenic capabilities both in vitro and in vivo. Our findings demonstrate that the combinatorial delivery of adECM and ADSCs facilitated the reconstruction of three full-thickness skin defects, accomplishing near-complete wound closure within two weeks. More importantly, both hypodermal adipogenesis and downgrowth of hair follicle-like structures were achieved in this two-week time frame. Our approach illustrates the translational potential of using human-derived materials and IOB technologies for full-thickness skin loss.

Gastric inhibitory polypeptide receptor antagonism suppresses intramuscular adipose tissue accumulation and ameliorates sarcopenia.

Intramuscular adipose tissue (IMAT) formation derived from muscle fibro-adipogenic progenitors (FAPs) has been recognized as a pathological feature of sarcopenia. This study aimed to explore whether genetic and pharmacological gastric inhibitory polypeptide (GIP) receptor antagonism suppresses IMAT accumulation and ameliorates sarcopenia in mice. Whole body composition, grip strength, skeletal muscle weight, tibialis anterior (TA) muscle fibre cross-sectional area (CSA) and TA muscle IMAT area were measured in young and aged male C57BL/6 strain GIP receptor (Gipr)-knockout (Gipr-/- ) and wild-type (Gipr+/+ ) mice. FAPs isolated from lower limb muscles of 12-week-old Gipr+/+ mice were cultured with GIP, and their differentiation into mature adipocytes was examined. Furthermore, TA muscle IMAT area and fibre CSA were measured in untreated Gipr-/- mice and GIP receptor antagonist-treated Gipr+/+ mice after glycerol injection into the TA muscles. Body composition analysis revealed that 104-week-old Gipr-/- mice had a greater proportion of lean tissue mass (73.7±1.2% vs. 66.5±2.7%, P<0.05 vs. 104-week-old Gipr+/+ mice) and less adipose tissue mass (13.1±1.3% vs. 19.4±2.6%, P<0.05 vs. 104-week-old Gipr+/+ mice). Eighty-four-week-old Gipr-/- mice exhibited increases in grip strength (P<0.05), weights of TA (P<0.05), soleus (P<0.01), gastrocnemius (P<0.05) and quadriceps femoris (P<0.01) muscles, and average TA muscle fibre CSA (P<0.05) along with a reduction in TA muscle IMAT area assessed by the number of perilipin-positive cells (P<0.0001) compared with 84-week-old Gipr+/+ mice. Oil Red O staining analysis revealed 1.6- and 1.7-fold increased adipogenesis in muscle FAPs cultured with 10 and 100nM of GIP (P<0.01 and P<0.001 vs. 0nM of GIP, respectively). Furthermore, both untreated Gipr-/- mice and GIP receptor antagonist-treated Gipr+/+ mice for 14days after glycerol injection into the TA muscles at 12weeks of age showed reduced TA muscle IMAT area (1.39±0.38% and 2.65±0.36% vs. 6.54±1.30%, P<0.001 and P<0.01 vs. untreated Gipr+/+ mice, respectively) and increased average TA muscle fibre CSA (P<0.01 and P<0.05 vs. untreated Gipr+/+ mice, respectively). GIP promotes the differentiation of muscle FAPs into adipocytes and its receptor antagonism suppresses IMAT accumulation and promotes muscle regeneration. Pharmacological GIP receptor antagonism may serve as a novel therapeutic approach for sarcopenia.

OR26-03 Treatment With Linsitinib, An IGF-1 Receptor Inhibitor, Prevents Disease Development And Progression In An Experimental Model Of Thyroid Eye Disease

Abstract Disclosure: A. Gulbins: Grant Recipient; Self; Sling therapeutics, Inc. M. Horstmann: Grant Recipient; Self; Sling therapeutics, Inc. A. Daser: None. U. Flögel: None. M. Oeverhaus: Grant Recipient; Self; Sling therapeutics, Inc. B.E. Nikolaos: None. J.P. Banga: None. G. Krause: None. G.D. Hammer: Research Investigator; Self; Sling therapeutics, Inc. A.G. Spencer: Research Investigator; Self; Sling therapeutics, Inc. R. Zeidan: Research Investigator; Self; Sling therapeutics, Inc. A. Eckstein: Grant Recipient; Self; Sling therapeutics, Inc. S. Philipp: Grant Recipient; Self; Sling therapeutics, Inc. G. Görtz: Grant Recipient; Self; Sling therapeutics, Inc. Study objective: We investigated the effect of linsitinib, a small molecule inhibitor of the Insulin like growth factor 1 receptor (IGF-1R), on Graves’ disease and thyroid eye disease. Graves‘ disease (GD), also known as “Basedow's disease“, is the most common cause for hyperthyroidism, typically presenting in patients between 40-60 years. GD is an autoimmune condition of the thyroid which is caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR). Thyroid eye disease (TED) is the most common extra thyroidal manifestation of GD and occurs in about 50% of the clinical cases. Methods: To induce Graves’ Disease in mice we immunized mice 3-times with a plasmid encoding for the A-subunit of the TSHR. During each active (early) and chronic (late) states of the autoimmune disease, linsitinib was administered orally for four weeks. Endocrine orbitopathy and inflammation were determined by histology and MRI. Results: As seen in the histology, linsitinib prevented autoimmune hyperthyroidism, morphological changes, formation of brown adipose tissue in the orbita and orbital T-cell and macrophage infiltration into the orbit in the active state as well as the chronic phase. To evaluate the effect of linsitinib during the course of therapy, living mice were examined via MRI. A distinctive migration of immune cells in the orbit with consecutive inflammation can be seen in the TSHR-immunized group, which is completely blocked by treatment with linsitinib. In addition, the orbital inflammation was partnered with the onset of muscle edema and formation of brown adipose tissue in TSHR-immunized mice, effects that were abrogated upon application of linsitinib. Conclusion: In summary, we demonstrate the development of GD and TED in a mouse model upon immunization against the TSHR. The IGF-1R antagonist linsitinib blocks the development of the local pathologies of GD and TED in an early and late phase of the autoimmune disorder and also prevents development of the autoimmune response. We show that treatment of immunized mice with linsitinib after disease onset significantly limited the severity of the disease, indicating the clinical significance of the findings and providing a path to therapeutic intervention of Graves’ Disease. Our data support the use of linsitinib as a novel first line treatment of thyroid eye disease. Presentation: Saturday, June 17, 2023

Sphingosine kinase 1 is involved in triglyceride breakdown by maintaining lysosomal integrity in brown adipocytes

Sphingosine 1-phosphate (S1P) has been implicated in brown adipose tissue (BAT) formation and energy consumption; however, the mechanistic role of sphingolipids, including S1P, in BAT remains unclear. Here, we showed that, in mice, BAT activation by cold exposure upregulated mRNA and protein expression of the S1P-synthesizing enzyme sphingosine kinase 1 (SphK1) and S1P production in BAT. Treatment of wild-type brown adipocytes with exogenous S1P or S1P receptor subtype-selective agonists stimulated triglyceride (TG) breakdown only marginally, compared with noradrenaline. However, genetic deletion of Sphk1 resulted in hypothermia and diminished body weight loss upon cold exposure, suggesting that SphK1 is involved in thermogenesis through mechanisms different from receptor-mediated, extracellular action of S1P. In BAT of wild-type mice, SphK1 was localized largely in the lysosomes of brown adipocytes. In the brown adipocytes of Sphk1−/− mice, the number of lysosomes was reduced and lysosomal function, including proteolytic activity, acid esterase activity, and motility, was impaired. Concordantly, nuclear translocation of transcription factor EB, a master transcriptional regulator of lysosome biogenesis, was reduced, leading to decreased mRNA expression of the lysosome-related genes in Sphk1−/− BAT. Moreover, BAT of Sphk1−/− mice showed greater TG accumulation with dominant larger lipid droplets in brown adipocytes. Inhibition of lysosomes with chloroquine resulted in a less extent of triglyceride accumulation in Sphk1−/− brown adipocytes compared with wild-type brown adipocytes, suggesting a reduced lysosome-mediated TG breakdown in Sphk1−/− mice. Our results indicate a novel role of SphK1 in lysosomal integrity, which is required for TG breakdown and thermogenesis in BAT.

Effectiveness of a New Enzyme-Free Method for the Preparation of a Decellularized Adipose-Derived Matrix.

Decellularized adipose-derived matrix (DAM) represents a new alternative to tissue fillers. The function of DAM is closely associated with the decellularization technique used for its preparation. However, most techniques are time-consuming and expensive, and this might reduce the popularity of DAM. The study aimed to investigate an enzyme-free adipose decellularization method and generate a DAM capable of adipose tissue regeneration. DAMs prepared by the enzyme-free and Flynn's methods were compared and co-cultured with human adipose-derived stem cells (hADSCs) to investigate cytocompatibility. Adipose tissue formation was evaluated by injecting the DAMs into the backs of nude mice over 4 weeks. Samples were harvested for gross and perilipin immunohistochemistry analysis at 1 and 4 weeks. The enzyme-free method is effective for adipose decellularization because it removes adipocytes and preserves the microstructure. In vitro, the DAM made by the enzyme-free method could support the attachment, growth, proliferation, and differentiation of hADSCs, and promote the enhanced secretion of vascular endothelial growth factor by hADSCs; this DAM also induced the formation and maturity of adipocytes in vivo. This study describes a highly effective enzyme-free method for adipose tissue decellularization that also promotes adipocyte formation and adipose tissue volume stability in vitro and in vivo, resulting in a new alternative tissue filler.

From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy.

Lipodystrophy is a rare disorder characterised by abnormal or deficient adipose tissue formation and distribution. It poses significant challenges to affected individuals, including the development of severe metabolic complications like diabetes and fatty liver disease. These conditions are often chronic, debilitating and life-threatening, with limited treatment options and a lack of specialised expertise. This review aims to raise awareness of lipodystrophy disorders and highlights therapeutic strategies to restore adipose tissue functionality. Extensive research has been conducted, including both historical and recent advances. We have examined and summarised the literature to provide an overview of potential strategies to restore adipose tissue functionality and treat/reverse metabolic complications in lipodystrophy disorders. A wealth of basic and clinical research has investigated various therapeutic approaches for lipodystrophy. These include ground-breaking methods such as adipose tissue transplantation, innovative leptin replacement therapy, targeted inhibition of lipolysis and cutting-edge gene and cell therapies. Each approach shows great potential in addressing the complex challenges posed by lipodystrophy. Lipodystrophy disorders require urgent attention and innovative treatments. Through rigorous basic and clinical research, several promising therapeutic strategies have emerged that could restore adipose tissue functionality and reverse the severe metabolic complications associated with this condition. However, further research and collaboration between academics, clinicians, patient advocacy groups and pharmaceutical companies will be crucial in transforming these scientific breakthroughs into effective and viable treatment options for individuals and families affected by lipodystrophy. Fostering such interdisciplinary partnerships could pave the way for a brighter future for those battling this debilitating disorder.

Long term observation of de novo adipogenesis using novel bioabsorbable implants with larger size in a porcine model

IntroductionThe regeneration of adipose tissue in patients after breast cancer surgery would be desirable without the use of growth factors or cells to avoid potential recurrence and metastasis. We reported that prolate spheroidal-shaped poly-L-lactic acid (PLLA) mesh implants of approximately 18-mm polar diameter and 7.5-mm greatest equatorial diameter containing collagen sponge (CS) would be replaced by regenerated adipose tissue after implantation, thereby suggesting an innovative method for breast reconstruction. Our study aimed to evaluate the adipose tissue regeneration ability of implant aggregates in a porcine model. MethodsWe prepared implant aggregates consisting of thirty PLLA mesh implants containing CS packed in a woven poly (glycolic acid) bag. The implant aggregates were inserted under the mammary glands in the porcine abdomen for a year. Single and double groups were classified by inserting either one or two implant aggregates on each side of the abdomen, respectively. ResultsIn both groups, the volume of the implant aggregates decreased over time, and the formation of adipose tissue peaked between 6 and 9 months. Histologically, the formation of adipose tissue was confirmed in the area that was in contact with native adipose tissue. ConclusionsOur implant aggregates could induce the autologous adipose tissue after long term implantation in vivo, without the use of any growth factor or cell treatment, presenting a potential novel method of breast reconstruction.