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This is a book about the research process that led scientists to the discovery of a group of molecules that act as carriers of information among the cells of our body, which the book refers to collectively as \"body messages.\" Among the thousands of body messages, the author selected those that are part of her own research, the cytokines, adipokines, and other proteins that regulate inflammation and metabolism. She also interviewed twenty researchers who contributed significantly to the field, asking details about their discoveries while also inquiring about their life and education. Along with scientists' personal recollections, the book reconstructs the discovery process based on published reports of the original experimental findings. Though the book's main theme is the process of discovery, it devotes considerable space to the biology of body messages and the consequence of their identification for medical practice.-- Provided by publisher

Obesity: Fat cell numbers are for life The storage of lipids in pre-existing fat cells is thought to be a major factor in obesity, but beyond that it is not known for certain when in life adipocytes are generated and whether alterations in this process may contribute to obesity. Now a survey of total adipocyte numbers in hundreds of individuals, combined with analysis of the integration of carbon-14 derived from nuclear bomb tests into genomic DNA, has provided a clear picture of metabolism of adipose tissues. The number of fat cells in the body is a major determinant for fat mass in adults, but that number is set during childhood and adolescence and hardly varies during adulthood. Surprisingly, there is a remarkably high turnover of adipocytes within a constant total population. Neither adipocyte death nor generation rate alters during early onset obesity. This newly discovered phenomenon of adipocyte turnover could provide a new target for therapeutic intervention in obesity. This paper finds that the number of fat cells is set during childhood and adolescence, and adipocyte numbers for lean or obese individuals are subject to little variation during adulthood. Even after significant weight loss in adulthood and reduced adipocyte volume, adipocyte number remains the same. Obesity is increasing in an epidemic manner in most countries and constitutes a public health problem by enhancing the risk for cardiovascular disease and metabolic disorders such as type 2 diabetes 1 , 2 . Owing to the increase in obesity, life expectancy may start to decrease in developed countries for the first time in recent history 3 . The factors determining fat mass in adult humans are not fully understood, but increased lipid storage in already developed fat cells (adipocytes) is thought to be most important 4 , 5 . Here we show that adipocyte number is a major determinant for the fat mass in adults. However, the number of fat cells stays constant in adulthood in lean and obese individuals, even after marked weight loss, indicating that the number of adipocytes is set during childhood and adolescence. To establish the dynamics within the stable population of adipocytes in adults, we have measured adipocyte turnover by analysing the integration of 14 C derived from nuclear bomb tests in genomic DNA 6 . Approximately 10% of fat cells are renewed annually at all adult ages and levels of body mass index. Neither adipocyte death nor generation rate is altered in early onset obesity, suggesting a tight regulation of fat cell number in this condition during adulthood. The high turnover of adipocytes establishes a new therapeutic target for pharmacological intervention in obesity.

The increasing prevalence of obesity has prompted intensive research into understanding its role in pathogenesis and designing appropriate treatments. To determine the signals generated from the interaction of fat cells with a target organ, a reliable white adipocyte model in vitro is needed. Differentiated fibroblasts are the most extensively studied using in vitro cell models of white adipocytes. However, it can be argued that differentiated fibroblasts minimally recapitulate the consequences of obesity. Here, we describe 3T3-L1 MBX cells as a culture model for studying obese adipocytes and their effects. Differentiation of 3T3-L1 MBX cells was at first optimized and then maintained in the presence of fatty acids cocktail combination to induce the obese condition. Lipid accumulation and adipokine secretion profiles were analyzed. Results showed that fatty acid-maintained, differentiated 3T3-L1 MBX cells had significantly greater accumulation of lipids and significant changes in the adipokine secretions in comparison to differentiated 3T3-L1 MBX cells maintained in medium without fatty acids. To elucidate the molecular changes associated with adipogenesis and lipid accumulation profile of 3T3-L1 MBX cells, we have also explored the expression of some of the regulatory proteins related to the development and maintenance of adipocytes from the preadipocyte lineage.

Mechanical and resorbable scaffolds are in high demand for stem cell-based regenerative medicine, to treat refractory bone defects in craniofacial abnormalities and injuries. Multipotent progenitor cells, such as dedifferentiated fat (DFAT) cells, are prospective sources for regenerative therapies. Herein, we aimed to demonstrate that a composite gelatin sponge (α-TCP/GS) of alfa-tricalcium phosphate (α-TCP) mixed with gelatin scaffolds (GS), with/without DFATs, induced bone regeneration in a rat calvarial defect model in vivo. α-TCP/GS was prepared by mixing α-TCP and 2% GS using vacuum-heated methods. α-TCP/GS samples with/without DFATs were transplanted into the model. After 4 weeks of implantation, the samples were subjected to micro-computed tomography (μ-CT) and histological analysis. α-TCP/GS possessed adequate mechanical strength; α-TCP did not convert to hydroxyapatite upon contact with water, as determined by X-ray diffraction. Moreover, stable α-TCP/GS was formed by electrostatic interactions, and verified based on the infrared peak shifts. μ-CT analyses showed that bone formation was higher in the α-TCP/GS+ DFAT group than in the α-TCP/GS group. Therefore, the implantation of α-TCP/GS comprising DFAT cells enhanced bone regeneration and vascularization, demonstrating the potential for healing critical-sized bone defects.

Despite advances in stem cell biology, there are few effective techniques to promote the osteogenic differentiation of human primary dedifferentiated fat (DFAT) cells. We attempted to investigate whether epigallocatechin-3-gallate (EGCG), the main component of green tea catechin, facilitates early osteogenic differentiation and mineralization on DFAT cells in vitro. DFAT cells were treated with EGCG (1.25–10 μM) in osteogenic medium (OM) with or without 100 nM dexamethasone (Dex) for 12 days (hereafter two osteogenic media were designated as OM(Dex) and OM). Supplementation of 1.25 μM EGCG to both the media effectively increased the mRNA expression of collagen 1 (COL1A1) and runt-related transcription factor 2 (RUNX2) and also increased proliferation and mineralization. Compared to OM(Dex) with EGCG, OM with EGCG induced earlier expression for COL1A1 and RUNX2 at day 1 and higher mineralization level at day 12. OM(Dex) with 10 μM EGCG remarkably hampered the proliferation of the DFAT cells. These results suggest that OM(without Dex) with EGCG might be a preferable medium to promote proliferation and to induce osteoblast differentiation of DFAT cells. Our findings provide an insight for the combinatory use of EGCG and DFAT cells for bone regeneration and stem cell-based therapy.

Endothelial cells and leptin receptor + (LepR + ) stromal cells are critical sources of haematopoietic stem cell (HSC) niche factors, including stem cell factor (SCF), in bone marrow. After irradiation or chemotherapy, these cells are depleted while adipocytes become abundant. We discovered that bone marrow adipocytes synthesize SCF. They arise from Adipoq -Cre/ER + progenitors, which represent ∼5% of LepR + cells, and proliferate after irradiation. Scf deletion using Adipoq -Cre/ER inhibited haematopoietic regeneration after irradiation or 5-fluorouracil treatment, depleting HSCs and reducing mouse survival. Scf from LepR + cells, but not endothelial, haematopoietic or osteoblastic cells, also promoted regeneration. In non-irradiated mice, Scf deletion using Adipoq -Cre/ER did not affect HSC frequency in long bones, which have few adipocytes, but depleted HSCs in tail vertebrae, which have abundant adipocytes. A-ZIP/F1 ‘fatless’ mice exhibited delayed haematopoietic regeneration in long bones but not in tail vertebrae, where adipocytes inhibited vascularization. Adipocytes are a niche component that promotes haematopoietic regeneration. Zhou et al. demonstrate that bone marrow adipocytes, but not intraperitoneal adipocytes, express high levels of stem cell factor (SCF), which is essential for the regeneration of haematopoietic stem cells and haematopoiesis after irradiation.

Autologous fat grafting and implant surgery are used for volume restoration in plastic surgery. With the aim of producing a treatment superior to current solutions, we report a randomized, controlled, data assessor‐blinded clinical trial comparing fat grafts enriched with ex vivo‐expanded autologous adipose‐derived stromal cells (ASCs) to nonenriched fat grafts in breast augmentation. The intervention group received ASC‐enriched fat grafts (≥20 × 106 viable ex vivo‐expanded ASCs per milliliter fat), and the control group received conventional nonenriched fat grafts. Volume retention was measured by magnetic resonance imaging, and clinical photographs were taken simultaneously for outcome evaluation. ASC‐enriched fat grafts had significantly higher retention rates (mean = 80.2%) compared with conventional fat grafts (mean = 45.1%). Clinical photos showed statistically significant superior results in the intervention group, assessed by independent clinical experts. These results improve the prospects for using culture‐expanded ASCs in both reconstructive and cosmetic volume restoration and make the procedure an attractive alternative to conventional fat grafting and implants. This study is registered at www.ClinicalTrials.gov, number H‐16046960. Ex vivo‐expanded adipose tissue‐derived stromal cells ensure enhanced fat graft retention and superior clinical outcomes in breast augmentation. With a high survival of the injected volume, no second augmentation procedure was needed. The results improve the prospects for using expanded ASCs in reconstructive and cosmetic volume restoration and make the procedure an attractive alternative to conventional fat grafting and implants.

The interplay between intracellular and intravascular lipolysis is crucial for maintaining circulating lipid levels and systemic energy homeostasis. Adipose triglyceride lipase (ATGL) and lipoprotein lipase (LPL), the primary triglyceride (TG) lipases responsible for these two spatially separate processes, are highly expressed in adipose tissue. Yet the mechanisms underlying their coordinated regulation remain undetermined. Here, we demonstrate that genetic ablation of G0S2, a specific inhibitory protein of ATGL, completely abolished diet-induced hypertriglyceridemia and significantly attenuated atherogenesis in mice. These effects were attributable to enhanced whole-body TG clearance, not altered hepatic TG secretion. Specifically, G0S2 deletion increased circulating LPL concentration and activity, predominantly through LPL production from white adipose tissue (WAT). Strikingly, transplantation of G0S2-deficient WAT normalized plasma TG levels in mice with hypertriglyceridemia. In conjunction with improved insulin sensitivity and decreased ANGPTL4 expression, the absence of G0S2 enhanced the stability of LPL protein in adipocytes, a phenomenon that could be reversed upon ATGL inhibition. Collectively, these findings highlight the pivotal role of adipocyte G0S2 in regulating both intracellular and intravascular lipolysis, and the possibility of targeting G0S2 as a viable pharmacological approach to reducing levels of circulating TGs.

Background Preimplantation embryos in vivo are exposed to various growth factors in the female reproductive tract that are absent in in vitro embryo culture media. Cell-free fat extract exerts antioxidant, anti-ageing, and ovarian function-promoting effects. However, its effects on embryo quality are yet to be investigated. Methods We assessed the effect of cell-free fat extract supplementation on embryo culture using a naturally ageing mouse model. We assessed the model’s efficacy in influencing embryo development and pregnancy rates in older women with in vitro fertilization failure. In addition, we performed immunofluorescence staining, multiplex immunoassay, whole-genome amplification and DNA sequencing, time-lapse embryo monitoring, and in vitro experiments. Results Cell-free fat extract-supplemented media has a suitable osmolarity and pH and contains high levels of bioactive growth factors. Cell-free fat extract promoted embryo development and implantation in aged mice, probably by increasing embryo growth rate, inhibiting cell apoptosis, and promoting blastocyst adhesion. Clinical results showed that the cell-free fat extract group had significantly higher rates of the day 3 available and high-quality embryos than the control group, and the rate of usable embryos tended to be higher in the cell-free fat extract group. Furthermore, implantation and clinical pregnancy rates improved in the cell-free fat extract group than in the control group. Conclusions Our study implies that cell-free fat extract supplementation can promote embryo development and clinical outcomes and may serve as a rescue strategy for older women with in vitro fertilization failure.

Bone is maintained by coupled activities of bone-forming osteoblasts/osteocytes and bone-resorbing osteoclasts. Alterations in this relationship can lead to pathologic bone loss such as osteoporosis. It is well known that osteogenic cells support osteoclastogenesis via production of RANKL. Interestingly, our recently identified bone marrow mesenchymal cell population-marrow adipogenic lineage precursors (MALPs) that form a multidimensional cell network in bone-was computationally demonstrated to be the most interactive with monocyte-macrophage lineage cells through high and specific expression of several osteoclast regulatory factors, including RANKL. Using an adipocyte-specific Adipoq-Cre to label MALPs, we demonstrated that mice with RANKL deficiency in MALPs have a drastic increase in trabecular bone mass in long bones and vertebrae starting from 1 month of age, while their cortical bone appears normal. This phenotype was accompanied by diminished osteoclast number and attenuated bone formation at the trabecular bone surface. Reduced RANKL signaling in calvarial MALPs abolished osteolytic lesions after LPS injections. Furthermore, in ovariectomized mice, elevated bone resorption was partially attenuated by RANKL deficiency in MALPs. In summary, our studies identified MALPs as a critical player in controlling bone remodeling during normal bone metabolism and pathological bone loss in a RANKL-dependent fashion.