ULTRASTRUCTURAL ASPECTS OF ENDOTHELIAL CELLS` SECRETORY FUNCTION IN RABBIT MAJOR BLOOD VESSELS

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STUDY OF COLCHICINE EFFECTS ON ELECTROCONVULSIVE EPILEPTIC EQUIVALENT IN RATS

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Leptin 21 years later: From fat`s big bang to central stage never before has adipose tissue been so active

Here we focus on Fat`s Big Bang exploring officially by the discovery of leptin by Jeffrey Friedman and colleagues on 1 December 1994 in Nature. We recall their journey of discovery and discuss perspective on the further research in adipobiology and adipopharmacology of cardiometabolic, neuropsychiatric and cancer diseases. Friedman`s seminal discovery makes a paradigm shift in our knowledge of adipose tissue biology - from merely a fat storage and metabolizer to a major endocrine and paracrine organ of the human body, producing more than 600 signaling proteins collectively termed adipokines. Leptin thus became the fundament in the obesity research and related diseases.Adipobiology 2015; 7: 9-13Key words: adipose tissue, adipokines, adipobiology, Jeffrey M. Friedman, leptin, disease, therap

NGF-ome: its metabotrophic expression. Homage to Rita Levi-Montalcini

Nowadays, in the postgenome time, many "-ome" studies have emerged including proteome, transcriptome, interactome, metabolome, adipokinome, connectome. In this vein, the catchall term NGF-ome embodies all the actions of NGF in health and disease. Accordingly, the present Festschrift, also tabula gratulatoria, is to honor and acknowledge the contributions of the distinguished neuroscientist and magistra Rita Levi-Montalcini, the Nobel Prize winner-1986 for the discoverer of NGF. Today, NGF and another neurotrophin, brain-derived neuroptrophic factor (BDNF), are well recognized to mediate multiple biological phenomena, ranging from the neurotrophic through immunotrophic and epitheliotrophic to metabotrophic effects. These latter effects are involved in the maintenance of cardiometabolic homeostasis (glucose and lipid metabolism as well as energy balance, and cardioprotection). Circulating and/or tissue levels of NGF and BDNF are altered in cardiometabolic diseases (atherosclerosis, obesity, type 2 diabetes, metabolic syndrome, and type 3 diabetes/Alzheimer's disease). A hypothesis thus emerged that a metabotrophic deficit due to the reduction of NGF/BDNF availability and/or utilization may be implicated in the pathogenesis of cariometabolic and neurodegenerative diseases. The present challenge is therefore to cultivate a metabotrophic thinking about how we can modulate NGF/BDNF secretion and signaling for the benefit of human cardiometabolic and mood health.Biomedical Reviews 2010; 21: 25-29

Deficiency of histone variant macroH2A1.1 is associated with sexually dimorphic obesity in mice

Obesity has a major socio-economic health impact. There are profound sex differences in adipose tissue deposition and obesity-related conditions. The underlying mechanisms driving sexual dimorphism in obesity and its associated metabolic disorders remain unclear. Histone variant macroH2A1.1 is a candidate epigenetic mechanism linking environmental and dietary factors to obesity. Here, we used a mouse model genetically depleted of macroH2A1.1 to investigate its potential epigenetic role in sex dimorphic obesity, metabolic disturbances and gut dysbiosis. Whole body macroH2A1 knockout (KO) mice, generated with the Cre/loxP technology, and their control littermates were fed a high fat diet containing 60% of energy derived from fat. The diet was administered for three months starting from 10 to 12 weeks of age. We evaluated the progression in body weight, the food intake, and the tolerance to glucose by means of a glucose tolerance test. Gut microbiota composition, visceral adipose and liver tissue morphology were assessed. In addition, adipogenic gene expression patterns were evaluated in the visceral adipose tissue. Female KO mice for macroH2A1.1 had a more pronounced weight gain induced by high fat diet compared to their littermates, while the increase in body weight in male mice was similar in the two genotypes. Food intake was generally increased upon KO and decreased by high fat diet in both sexes, with the exception of KO females fed a high fat diet that displayed the same food intake of their littermates. In glucose tolerance tests, glucose levels were significantly elevated upon high fat diet in female KO compared to a standard diet, while this effect was absent in male KO. There were no differences in hepatic histology. Upon a high fat diet, in female adipocyte cross-sectional area was larger in KO compared to littermates: activation of proadipogenic genes (ACACB, AGT, ANGPT2, FASN, RETN, SLC2A4) and downregulation of antiadipogenic genes (AXIN1, E2F1, EGR2, JUN, SIRT1, SIRT2, UCP1, CCND1, CDKN1A, CDKN1B, EGR2) was detected. Gut microbiota profiling showed increase in Firmicutes and a decrease in Bacteroidetes in females, but not males, macroH2A1.1 KO mice. MacroH2A1.1 KO mice display sexual dimorphism in high fat diet-induced obesity and in gut dysbiosis, and may represent a useful model to investigate epigenetic and metabolic differences associated to the development of obesity-associated pathological conditions in males and female

In the heart of adipobiology: cardiometabolic disease

Published on 1 December 1994 issue of Nature, the Jeffrey Friedman's discovery "gave leptin in the beginning" of the endocrine saga of adipose tissue. Onwards, studies on this tissue have enjoyed an explosive growth that conceptualized a novel field of research, adipobiology. Arguably, in the heart of adipobiology and adipopharmacology are studies focusing on the pathogenesis, prevention and therapy of cardiometabolic diseases (CMD) including atherosclerosis, hypertension, obesity, type 2 diabetes, metabolic syndrome (global cardiometabolic risk), and lipodystrophies.Biomedical Reviews 2009; 20: 1-5

SOS for Homo sapiens obesus

Published on 1 December 1994 issue of Nature, the Jeffrey Friedman's discovery "gave leptin in the beginning" of the endocrine saga of adipose tissue. Onwards, studies on this tissue have enjoyed an explosive growth that conceptualized a novel field of research, adipobiology. Arguably, in the heart of adipobiology and adipopharmacology are studies focusing on the pathogenesis, prevention and therapy of cardiometabolic diseases (CMD) including atherosclerosis, hypertension, obesity, type 2 diabetes, metabolic syndrome (global cardiometabolic risk), and lipodystrophies.Adipobiology 2010; 2: 5-8

The adipose tissue: a new member of the diffuse neuroendocrine system?

Adipose tissue is a sophisticated module, consisting of adipocytes and non-adipocyte cellular elements including stromal, vascular, nerve and immune cells. There is at present evidence that sharing of ligands and their receptors constitutes a molecular language of the human's body, which is also the case for adipose tissue and hypothalamus-pituitary gland. Historically, Nikolai Kulchitsky's identification of the enterochromaffin cell in 1897 formed the basis for the subsequent delineation of the diffuse neuroendocrine system (DNES) by Friedrich Feyrter in 1938. In DNES paradigm, the secretion of hormones, neuropeptides and neurotrophic factors is executed by cells disseminated throughout the body, for example, Kulchitsky (enterochromaffin) cells, testicular Leydig cells, and hepatic stellate cells. Here we propose that the adipose tissue might be a new member of DNES. Today (dnes, in Bulgarian), adipose tissue is "getting nervous" indeed: (i) synthesizes neuropeptides, neurotrophic factors, neurotransmitters, hypothalamic hormones/releasing factors and their receptors, (ii) like brain expresses endocannabinoids and amyloid precursor protein and, for steroidogenesis, the enzyme aromatase (P450arom), (iii) adipocytes may originate from the neural crest cells, and (iv) adipose-derived stem cells may differentiate into neuronal cells. Further molecular profiling of adipose tissue may provide new biological insights on its neuroendocrine potential. Overall this may frame a novel field of study, neuroadipobiology; its development and clinical application may contribute to the improvement of human's health.Adipobiology 2009; 1: 87-93

Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant

Background: Obesity is a major health burden. Preadipocytes proliferate and differentiate in mature adipocytes in the adipogenic process, which could be a potential therapeutic approach for obesity. Deficiency of SIRT6, a stress-responsive protein deacetylase and mono-ADP ribosyltransferase enzyme, blocks adipogenesis. Mutants of SIRT6 (N308K/A313S) were recently linked to the in the long lifespan Ashkenazi Jews. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect adipogenesis at the transcriptional and epigenetic level. Methods: We analyzed the role of SIRT6 wild-type (WT) or SIRT6 centenarian-associated mutant (N308K/A313S) overexpression in adipogenesis, by creating stably transduced preadipocyte cell lines using lentivirus on the 3T3-L1 model. Histone post-translational modifications (PTM: acetylation, methylation) and transcriptomic changes were analyzed by mass spectrometry (LC–MS/MS) and RNA-Seq, respectively, in 3T3-L1 adipocytes. In addition, the adipogenic process and related signaling pathways were investigated by bioinformatics and biochemical approaches. Results: Overexpression of centenarian-associated SIRT6 mutant increased adipogenic differentiation to a similar extent compared to the WT form. However, it triggered distinct histone PTM profiles in mature adipocytes, with significantly higher acetylation levels, and activated divergent transcriptional programs, including those dependent on signaling related to the sympathetic innervation and to PI3K pathway. 3T3-L1 mature adipocytes overexpressing SIRT6 N308K/A313S displayed increased insulin sensitivity in a neuropeptide Y (NPY)-dependent manner. Conclusions: SIRT6 N308K/A313S overexpression in mature adipocytes ameliorated glucose sensitivity and impacted sympathetic innervation signaling. These findings highlight the importance of targeting SIRT6 enzymatic activities to regulate the co-morbidities associated with obesity