Background: Facial fat grafting for rejuvenation is one of the most popular facial aesthetic procedures in plastic surgery. It is always challenging and since there are a lot of techniques for adipose tissue (AT) harvesting, there are no standard procedures that guarantee natural and long-lasting results. We developed the selective tissue engineering photo stimulation technique (One STEP™) in which we used a novel infrared 1210-nm wavelength laser diode for fat preserved harvesting and direct fat injection that we named PicoGraft™, with no fat manipulation. Methods: This is a retrospective descriptive study in which we included all senior author’s patients that got facial fat grafting using the One STEP™ technique. We compared the AT aspirated, after laser emission (STEP-PicoGraft) and the standard assisted liposuction samples (SAL) in cultures. We study the mitochondrial activity of the ASC between STEP and SAL in fresh samples and after 24 h. The evaluation of the results included subjective changes regarding wrinkles, grooves, palpebral bags, hyperchromic spots, and fat hypotrophy of our patients. Results: Between July 2013 and May 2018, a total of 245 patients underwent facial fat grafting using this novel technique. We observed adipocytes preserved after STEP harvesting comparing morphologic changes in SAL samples with a high concentration of inflammatory particles in cultures. ASC mitochondrial activity shows an important difference of more than 7 times in STEP samples in fresh analysis that increase 12 times in 24 h. The subjective results show a good improvement in the periorbital area. The changes on the skin and subcutaneous tissue are seen from the second month and continue to improve up to 12 months. Conclusions: Facial fat grafting using the PicoGraft™ obtained by One STEP™ technique gives excellent volumetric and regenerative results in a single treatment without volumetric hypercorrection, and it is a good alternative for facial rejuvenation. The fat graft obtained with this novel technique is homogenous, without lumps, and has high concentration of viable stimulated ADSC and a high number of viable adipocytes. Level of evidence: Level III, therapeutic study. / Revisión por pares

Obesity and associated metabolic disorders, e. g. metabolic syndrome, represent a considerable health threat for modern society. Due to sedentary lifestyle, high caloric intake and changes in composition of diet, prevalence of obesity is increasing worldwide. One of the possible causes contributing to higher prevalence of obesity in recent population could be the change of fatty acids (FA) composition of dietary lipids, with the shift in the content of n-6 and n-3 FA toward n-6 FA. In contrast to n-6 FA, n-3 FA are known for their anti-atherogenic, anti-obesogenic and anti-inflammatory properties. In our experiments in mice, the capability of naturally occurred and chemically modified n- 3 long chain polyunsaturated fatty acids (LC-PUFA) in prevention and reversal of specific parts of metabolic syndrome was demonstrated. A specific chemical derivative of docosahexaenoic acid was proven to be very effective in preventing and improving metabolic conditions of animals exposed to high-fat (HF) diet challenge. Further, the involvement of AMP-activated protein kinase (AMPK), a master regulator of lipid metabolism, in skeletal muscle thermogenesis induced by HF-feeding was investigated. Activation of AMPK in the HF-fed mice is most possibly caused by increased leptin levels and represents an important link...

Univerzita Karlova v Praze 1. lékařská fakulta Doktorský studijní program Studijní obor: Experimentální chirurgie MUDr. Filip Thieme Název závěrečné práce Chirurgické modely studia proinflamačního vlivu tukové tkáně v rozvoji aterosklerózy Title Surgical models of the study of the pro-inflammatory effect of adipose tissue in the development of atherosclerosis Typ závěrečné práce Disertační Školitel: doc. MUDr. Jiří Froněk, Ph.D., FRSC Konzultant doc. MUDr. Libor Janoušek, Ph.D. Klinika transplantační chirurgie, IKEM Praha, 2021 Abstract Background: Atherosclerosis is a serious inflammatory systemic disease. Surgery mainly addresses its vascular complications. Conversely, surgery may also lead to the development and acceleration of atherosclerosis, e.g., in a living kidney donor. This would especially be the case in a donor who meets internationally recognized donation criteria but suffers from metabolic syndrome. The effort to refine assessments of living kidney donors in terms of eliminating the risk of developing atherosclerosis is a long-term project. Our aim is to determine risk factors for living kidney donors and to prevent long-term complications after donation. Collecting tissue from a living donor involves not oly subcutaneous tissue (SCAT) but also visceral (VAT) and perivascular tissue (PVAT),...

Obesity and associated metabolic disorders, e. g. metabolic syndrome, represent a considerable health threat for modern society. Due to sedentary lifestyle, high caloric intake and changes in composition of diet, prevalence of obesity is increasing worldwide. One of the possible causes contributing to higher prevalence of obesity in recent population could be the change of fatty acids (FA) composition of dietary lipids, with the shift in the content of n-6 and n-3 FA toward n-6 FA. In contrast to n-6 FA, n-3 FA are known for their anti-atherogenic, anti-obesogenic and anti-inflammatory properties. In our experiments in mice, the capability of naturally occurred and chemically modified n- 3 long chain polyunsaturated fatty acids (LC-PUFA) in prevention and reversal of specific parts of metabolic syndrome was demonstrated. A specific chemical derivative of docosahexaenoic acid was proven to be very effective in preventing and improving metabolic conditions of animals exposed to high-fat (HF) diet challenge. Further, the involvement of AMP-activated protein kinase (AMPK), a master regulator of lipid metabolism, in skeletal muscle thermogenesis induced by HF-feeding was investigated. Activation of AMPK in the HF-fed mice is most possibly caused by increased leptin levels and represents an important link...

The prevalence of type 2 diabetes mellitus is increasing worldwide and is considered one of the top health concerns globally. The occurrence of type 2 diabetes is linked to the rapidly increasing trend of obesity in both adults and children, which is proposed to be a contributing factor in the development of insulin resistance and type 2 diabetes. White adipose tissue, an insulin target tissue, is an important endocrine organ involved in the control of energy homeostasis through its direct influence on metabolism, insulin sensitivity and food intake. To better understand these functions, we studied adipocyte differentiation in 3T3-Ll cells, a white adipose tissue cell line. Many mitochondrial proteins exhibit an increase in expression levels during adipogenesis as identified by mass spectrometry. Moreover, increased mitochondrial mass and altered morphology was observed by light microscopy. Qualitative changes in mitochondrial gene expression were also observed during adipogenesis as revealed by Affymetrix GeneChip analysis. Additionally, striking changes in mitochondrial protein expression and morphology were identified following treatment with the insulin sensitizing agent, rosiglitazone. These results suggest that mitochondrial biogenesis and remodeling is inherent to white adipocyte differentiation. To investigate the physiological relevance of these findings, mRNA and protein expression profiles and mitochondrial morphology were studied during the development of insulin resistance and obesity and following treatment with rosiglitazone in ob/ob mice. These studies reveal a marked decrease in transcript levels for over 50% of mitochondrial genes with the onset of obesity in ob/ob mice. Rosiglitazone treatment stimulates enhanced expression in approximately half of these genes, as well as changes in mitochondrial mass and remodeling. Furthermore, these studies reveal that depressed oxygen consumption and fatty acid oxidation occur with obesity development and these alterations can be reversed with rosiglitazone treatment. This work identifies the previously underscored plasticity of mitochondria in white fat and suggests that mitochondrial biogenesis and remodeling in white adipose tissue may lead to systemic changes in insulin sensitivity and energy homeostasis. Lastly, these studies suggest that mitochondria may be an important therapeutic target for antidiabetic drugs.

Obesity and diabetes are major public health problems facing the world today. Extending our understanding of adipose tissue biology, and how it changes in obesity, will hopefully better equip our society in dealing with the obesity epidemic. Macrophages and other immune cells accumulate in the adipose tissue in obesity and secrete cytokines that can promote insulin resistance. Adipose tissue macrophages (ATMs) are thought to originate from bone marrow-derived monocytes, which infiltrate the tissue from the circulation. Much work has been done to demonstrate that inhibition of monocyte recruitment to the adipose tissue can ameliorate insulin resistance. While monocytes can enter the adipose tissue, we have shown here that local macrophage proliferation may be the predominant mechanism by which macrophages self-renew in the adipose tissue. We demonstrated that two cell proliferation markers, Ki67 and EdU, can be readily detected in macrophages isolated from adipose tissue of both lean and obese mice. These analyses revealed that 2-4% of ATMs in lean and 10-20% of ATMs in obese mice express the proliferation marker Ki67. Importantly, Ki67+ macrophages were identified within the adipose tissue in crown-like structures. Similarly, a 3-hour in vivo pulse with the thymidine analog EdU showed that nearly 5% of macrophages in epididymal adipose tissue of ob/ob mice were in the S-phase of cell division. Interestingly, obesity increased the rate of macrophage proliferation in adipose tissue but did not affect macrophage proliferation in other tissues. We also used clodronate liposomes to deplete circulating monocytes in obese mice. Surprisingly, monocyte depletion for a total of at least 80 hours did not cause a decrease in ATM content in adipose tissue. Prolonged exposure of mice to EdU in drinking water revealed that approximately half of the ATMs in the epididymal fat pads of ob/ob mice had proliferated locally within 80 hours. Amazingly, these rates were the same with or without monocyte depletion, meaning that the proliferating cells were not freshly recruited monocytes. Overall, these results suggest that local proliferation unexpectedly makes a major contribution to maintaining the large population of macrophages present in the obese adipose tissue in the steady state. This suggests that increased rates of local macrophage proliferation may also be partly responsible for the massive increase in ATM content that occurs in obesity. This information could have implications for future therapeutic strategies in the management of diabetes.

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The human metabolic syndrome is characterized by a heterogenic complex of symptoms, including central obesity. Obesity itself is linked to major features of the metabolic syndrome such as insulin resistance, dyslipidemia or type 2 diabetes mellitus. It has been shown that obesity risk and resulting metabolic alterations are associated with adipose tissue distribution, adipocyte size and secretion of adipocytokines, which are in turn influenced by environmental factors and genetic susceptibility. It might be assumed that currently known genetic variants associated with obesity and/or BMI (body mass index) as well as fat distribution explain up to 20 % of the variability in BMI and so, studies employing novel strategies are inevitable. In addition to the role of genetic variation, mRNA levels of several genes have been shown to be differentially expressed in subcutaneous (SC) and visceral (Vis) adipose tissue and to be correlated with obesity-related traits. It is scarcely investigated whether the obesity risk variants also might account for the variability in mRNA expression. The present thesis deals with novel obesity candidate genes, characterized by a differential mRNA expression in various fat depots. The association of genetic variants in these genes with obesity as part of the metabolic syndrome, and related traits was investigated in well characterized German cohorts. The main method used for genotyping was described in detail in a comprehensive review providing explicit troubleshooting and description of modified protocols for specific experimental needs. Further, the influence of genotypes on the gene expression levels was examined. While the differential expression for FTO could be described for the first time, the variant rs8050136 was shown to be significantly associated with obesity but not with the expression. Genetic variants in FASN were shown to be significantly associated with obesity and related traits in a cohort of European ancestry for the very first time. Moreover, one polymorphism showed effects on the ratio of Vis/SC FASN mRNA expression. While CNR1 is controversially discussed in the literature, the present work showed rather moderate effects of genetic variants on obesity. BMPR2 could be described as a novel obesity candidate gene. Amongst others, one variant was associated with obesity in a case-control design and with BMPR2 mRNA expression in Vis adipose tissue. In conclusion, the present study revealed novel genetic variants promoting obesity, and therefore a metabolic risk, which might be partly explicable through an influence of these variants on the mRNA expression levels of the genes in the adipose tissue depots. These findings contribute to better understanding of the genetic background of obesity which is essential in order to translate experimental data into diagnostic, preventive and treatment strategies.

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