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

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

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

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

Prelude 1

Abstract: Our acute awareness of the cosmetic, psychosocial and sexual importance of subcutaneous adipose tissue contrasts dramatically with how poorly we have understood the biology of this massive, enigmatic, often ignored and much-abused skin compartment. Therefore, it is timely to recall the exciting, steadily growing, yet underappreciated body of evidence that subcutaneous adipocytes are so much more than just 'fat guys', hanging around passively to conspire, at most, against your desperate attempts to maintain ideal weight. Although the subcutis, quantitatively, tends to represent the dominant architectural component of human skin, conventional wisdom confines its biological key functions to those of energy storage, physical buffer, thermoregulation and thermoinsulation. However, already the distribution of human superficial adipose tissue, by itself, questions how justified the popular belief is that 'skin fat' (which actually may be more diverse than often assumed) serves primarily thermoinsulatory purposes. And although the metabolic complications of obesity are well appreciated, our understanding of how exactly subcutaneous adipocytes contribute to extracutaneous disease -and even influence important immune and brain functions! -is far from complete. The increasing insights recently won into subcutaneous adipose tissue as a cytokine depot that regulates innate immunity and cell growth exemplarily serve to illustrate the vast open research expanses that remain to be fully explored in the subcutis. The following public debate carries you from the evolutionary origins and the key functional purposes of adipose tissue, via adipose-derived stem cells and adipokines straight to the neuroendocrine, immunomodulatory and central nervous effects of signals that originate in the subcutis -perhaps, the most underestimated tissue of the human body. The editors are confident that, at the end, you shall agree: No basic scientist and no doctor with a serious interest in skin, and hardly anyone else in the life sciences, can afford to ignore the subcutaneous adipocyte -beyond its ample impact on beauty, benessence and body mass

Homage to George E. Palade: the human body viewed as a multicrine system

`Seldom has a field owed so much to a single man` - in 1971, George Emil Palade wrote these words for Albert Claude, the founder of biological electron microscopy. Now, expressing my profound homage to him, I would like to articulate the same words for George E. Palade, the scientific father of many generations in cell biology research and education. In 1981, I met Palade for first time during the World Physiology Congress held in Budapest, Hun­gary, and said to him that I know every single word and micrograph published in his articles on pancreatic exo­crine secretion. They have driven my research on the secretory pathway in vascular smooth muscle cells (VSMC) studied by electron microscopy (1972-1992). In the present lecture I will focus on two paradigm shifts, namely (i) the transition from light to electron microscopy in studying cell structures and functions made by Albert Claude, George Palade, Christian de Duve and Günter Blobel from the famous Rockefeller group in New York, and (ii) the transition from a `classical` to secretory phenotype of various cell types, e.g. cardiomyocytes, skeletal muscles and liver, bone, stomach, gut and adipose cells, also VSMC, the latter initiated in the 1970s by Maria Daria Haust in Canada and Russell Ross in USA and by our Laboratory of Electron Microscopy in Varna, later renamed Labo­ratory of Cell Biology. Altogether, these will be discussed in a sense that the human body may be viewed as a mul­ticrine system

Adipoendocrinology and adipoparacrinology: emerging fields of study on the adipose tissue

Adipose tissue was conceived originally as merely passive, space-filling, fat storage tissue. However, in the last 10 years, investigations aimed at studying the endocrine secretion by adipose tissue have enjoyed explosive growth. The major secretory compartment of adipose tissue consists of adipocytes and stromal fibroblasts (adipofibroblasts). These cells secrete multiple bioactive molecules, conceptualized as adipokines or adipocytokines. Overall, this intellectual grown process framed an emerging field of study, adipoendocrinology. "Adipoendocrinology" connotes the study of the cellular and molecular biology of the endocrine function of adipose tissue in normal and diseased conditions. In humans, white adipose tissue is partitioned into a few large depots, including visceral and subcutaneous location, and many small depots, associated with heart, large blood vessels, major lymph nodes and other organs. The possibility that the endocrine secretory activity of large adipose depots may directly contribute to the elevated plasma levels of disease-associated adipokines has recently gained considerable attention. However, the paracrine secretory activity of organ-associated adipose tissue (the small adipose depots) has until now attracted little attention in the adipobiology of disease. Here we attempt to emphasize that studies aimed at evaluation of the paracrine secretion of organ-associated adipose tissue are becoming mandatory, since identification of the secreted molecules, particularly, adipokines, may yield clues to a possible transmission of pathogenic and/or protective stimuli, from the associated adipose tissue towards the interior of the associating organ. In this review we summarize most of the current information about adipoendocrinology and adipoparacrinology of various diseases.Biomedical Reviews 2001; 12: 31-39