George N. Chaldakov

Adipobiology of Disease: Adipokines and Adipokine-Targeted Pharmacology

In recent years, the simple paradigm of adipose tissue as merely a fat store is rapidly evolving into a complex paradigm of this tissue as multipotential secretory organ, partitioned into a few large depots, including visceral and subcutaneous location, and many small depots, associated with a variety of organs in the human body. The major secretory compartment of adipose tissue consists of adipocytes, fibroblasts, and mast cells. These cells, using endocrine, paracrine and autocrine pathways, secrete multiple bioactive molecules, conceptualized as adipokines or adipocytokines. This review examines current information in adipobiology of various diseases besides obesity and related diseases such as type 2 diabetes, metabolic syndrome, and cardiovascular disease. Finally, we emphasize the possibilities for adipokine-targeted pharmacology in adiponectin (Acrp30, apM1, AdipoQ, GBP28), angiotensin II, estrogens, nerve growth factor, tumor necrosis factor-alpha, and also adipose mast cells.

Neurotrophin presence in human coronary atherosclerosis and metabolic syndrome: a role for NGF and BDNF in cardiovascular disease?

The development of atherosclerotic cardiovascular disease is a common comorbidity in patients with the metabolic syndrome, a concurrence of cardiovascular risk factors in one individual. While multiple growth factors and adipokines are identified in atherosclerotic lesions, as well as neurotrophins implicated in both cardiac ischemia and lipid and glucose metabolism, the potential role of neurotrophins in human coronary atherosclerosis and in the metabolic syndrome still remains to be elucidated. Here we describe and discuss our results that represent a novel attempt to study the cardiovascular and metabolic biology of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and mast cells (MC). The local amount of NGF, the immunolocalization of p75 neurotrophin receptor (p75NTR) and the number of MC were correlatively examined in coronary vascular wall and in the surrounding subepicardial adipose tissue, obtained from autopsy cases in humans with advanced coronary atherosclerosis. We also analyzed the plasma levels of NGF, BDNF and leptin and the number of MC in biopsies from abdominal subcutaneous adipose tissue in patients with a severe form of the metabolic syndrome. The results demonstrate that NGF levels are decreased in atherosclerotic coronary vascular tissue but increased in the subepicardial adipose tissue, whereas both tissues express a greater number of MC and a stronger p75NTR immunoreactivity, compared to controls. Metabolic syndrome patients display a significant hyponeurotrophinemia and an increased number of adipose MC; the later correlates with elevated plasma leptin levels. In effect, we provide the first evidence for (i) an altered presence of NGF, p75NTR and MC in both coronary vascular and subepicardial adipose tissue in human coronary atherosclerosis, and (ii) a significant decrease in plasma NGF and BDNF levels and an elevated amount of plasma leptin and adipose MC in metabolic syndrome patients. Together our findings suggest that neuroimmune mediators such as NGF, BDNF, leptin and MC may be involved in the development of cardiovascular disease and related disorders.

Nerve growth factor as a signaling molecule for nerve cells and also for the neuroendocrine-immune systems.

Nerve growth factor (NGF) is a signaling molecule, originally discovered for its role on differentiation and survival of peripheral sensory and sympathetic neurons. It has also been associated with functional activities of cells of the immune and endocrine systems. NGF biological activity is mediated by two classes of receptors: (i) p75 neurotrophin receptor (p75(NTR)), a 75 kDa glycoprotein, belonging to a superfamily of cytokine receptors including TNF receptors, and (ii) TrkA, a transmembrane tyrosine kinase of 140 kDa. Both TrkA and p75(NTR) are known to play a marked action in neurodegenerative disorders, immune-related deficits, and neuroendocrine (including adipoendocrine) mechanisms. This review focuses on these cellular events and presents a working model which attempts to explain the close interrelationships of the neuro-endocrine-immune triad via a modulatory action of NGF.

Differential effects of statins on endogenous H2S formation in perivascular adipose tissue.

Hydrogen sulfide (H(2)S) is a new gasotransmitter synthesized enzymatically from l-cysteine in cytosol and is oxidized in mitochondria. In the cardiovascular system, H(2)S regulates vascular tone, inhibits atherogenesis, and protects against myocardial ischemia-reperfusion injury. We examined the effect of statins on vascular H(2)S production. Male Wistar rats received pravastatin (40mg/kg/day) or atorvastatin (20mg/kg/day) for 3 weeks and then H(2)S formation was measured in aortic media, periaortic adipose tissue (PAAT) and the liver. Only atorvastatin increased H(2)S production in PAAT whereas both statins stimulated its formation in the liver. Neither statin affected H(2)S production in aortic media. H(2)S formation in post-mitochondrial supernatant was higher than in mitochondria-containing supernatant and was not influenced by statins in any tissue. In addition, oxidation of exogenous H(2)S in isolated liver mitochondria was slower in statin-treated than in control rats. These data indicate that statins increase net H(2)S production by inhibiting its mitochondrial oxidation. Statins had no effect on the activity of H(2)S-metabolizing enzyme, sulfide:quinone oxidoreductase, measured at saturating coenzyme Q concentration. Both statins reduced CoQ(9) concentration in plasma and liver, but only atorvastatin decreased CoQ(9) in PAAT. Atorvastatin attenuated phenylephrine-induced contraction of PAAT+ but not of PAAT- aortic rings. Effects of atorvastatin on net H(2)S production, mitochondrial H(2)S oxidation and aortic contractility were abolished by supplementation of exogenous CoQ(9). In conclusion, lipophilic atorvastatin, but not hydrophilic pravastatin, increases net H(2)S production in perivascular adipose tissue by inhibiting its mitochondrial oxidation. This effect is mediated by statin-induced CoQ(9) deficiency and results in the augmentation of anticontractile effect of perivascular adipose tissue.

Nerve growth factor levels and mast cell distribution in human coronary atherosclerosis

Nerve growth factor (NGF), in addition to its neurotrophic function, acts on a variety of non-neuronal cells including immune cells and vascular smooth muscle cells. The aim of the present study was to determine the NGF levels and the distribution of NGF and low-affinity NGF receptor (p75NGFR) and mast cells (MC) in human atherosclerotic coronary arteries. Specimens of human coronary arteries obtained from autopsy cases (n=12, subjects with atherosclerotic lesions; n=9, subjects without atherosclerotic lesions/controls) were used. The present study showed that in the atherosclerosis-lesioned arteries, the amount of NGF decreased, whereas the expression of p75NGFR immunoreactivity and the number, both of MC and vasa vasorum, particularly in the adventitia, significantly increased, compared with the control arteries. Cumulatively, our findings help to set the neurotrophic theory and its currently extended neuroimmune framework into the context of pathobiology of atherosclerosis, suggesting that altered presence of NGF, p75NGFR, and MC may play a role in neuroimmune mechanisms of human coronary atherosclerosis.

Effects of olive polyphenols administration on nerve growth factor and brain-derived neurotrophic factor in the mouse brain.

OBJECTIVE Polyphenols are chemicals derived from plants known to possess antioxidant and anti-inflammatory properties. High intake of fruit and vegetables is believed to be beneficial to human health. Various studies have suggested that dietary polyphenols may protect against cancer and cardiometabolic and neurodegenerative diseases. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are neurotrophins that play key roles in brain cell development, growth, and survival. The aim of this study was to investigate whether or not administration of olive (Olea europaea L.) polyphenols could have an effect on NGF and BDNF content and the expression of their receptors, TrkA and TrkB, respectively, in the mouse brain. METHODS NGF and BDNF were measured by enzyme-linked immunosorbent assay. TrkA and TrkB were measured by Western blotting. RESULTS We found NGF and BDNF elevation in the hippocampus and olfactory bulbs and a decrease in the frontal cortex and striatum. These data were associated with potentiated expression of TrkA and TrkB in the hippocampus and olfactory bulbs but no differences between groups in the striatum and frontal cortex. Polyphenols did not affect some behavioral mouse parameters associated with stressing situations. CONCLUSIONS Altogether, this study shows that olive polyphenols in the mouse may increase the levels of NGF and BDNF in crucial areas of the limbic system and olfactory bulbs, which play a key role in learning and memory processes and in the proliferation and migration of endogenous progenitor cells present in the rodent brain.

Homo obesus: A Metabotrophin-Deficient Species. Pharmacology and Nutrition Insight

In most countries the prevalence of obesity now exceeds 15%, the figure used by the World Health Organization to define the critical threshold for intervention in nutritional epidemics. Here we describe Homo obesus (man the obese) as a recent phenotypic expression of Homo sapiens. Specifically, we classified Homo obesus as a species deficient of metabotrophic factors (metabotrophins), including endogenous proteins, which play essential role in the maintenance of glucose, lipid, energy and vascular homeostasis, and also improve metabolism-related processes such as inflammation and wound healing. Here we propose that pharmaceuticals, nutraceuticals and xenohormetics targeting transcriptional, secretory and/or signaling pathways of metabotrophins, particularly adiponectin, nerve growth factor, brain-derived neurotrophic factor, interleukin-10, and sirtuins, might be new tools for therapy of Homo obesus. Brief comment is also given to (i) exogenous metabotrophic agents represented by various classes of drugs, and (ii) adiponutrigenomics of lifespan.

Neuroadipology: a novel component of neuroendocrinology.

Adipose tissue is a dynamic endocrine and paracrine organ producing a large number of signalling proteins collectively termed adipokines. Some of them are mediators in the cross‐talk between adipose tissue and the brain in regulating food intake and energy homoeostasis. However, the hypothalamus is not the only brain target for adipokines, and food intake is not the only biological effect of these signals. Rather, some adipokines support various cognitive functions and exert neurotrophic activity. Current data on adipose‐derived neuropeptides, neurotrophic factors, pituitary hormones and hypothalamic releasing factors is highlighted in this review. We propose that adipose tissue is a member of the diffuse neuroendocrine system. Cumulatively, this is conceptualized as neuroadipology, a new example of a link between neurobiology and other topics, such as neuroimmunology and neuroendocrinology. Because adipose tissue is a bona fide endocrine organ, neuroadipology may be considered a new discipline in neuroendocrinology. It may have a wide‐ranging potential within a variety of neuronal and metabolic functions in health and disease.

From Adipose Tissue Protein Secretion to Adipopharmacology of Disease

An extensive research in the last few years has identified about hundred adipose tissue-secreted proteins, named adipokines or adipocytokines. However, our knowledge of the structures and molecules involved in the intracellu- lar secretory pathway (synthesis, translocation, folding, targeting, sorting, storage, and exocytosis) of adipokines is at pre- sent limited. Relatively more is known about insulin-responsive trafficking of glucose transporters (GLUTs). Adipokines have multiple biological functions beyond lipid and carbohydrate metabolism, whereas GLUT4 is the major glucose transporter of adipocytes and skeletal muscles. Adipokines play an important role in the pathogenesis of a wide variety of diseases, and dysregulation of GLUT4 transport is implicated in insulin resistance and related disorders. Conceptually, adipobiology of disease has emerged as a novel field of studies in basic and clinical medicine. Here we present a state-of- the-science on some aspects of these studies with a special reference to the intracellular secretory pathway, focusing on adiponectin, GLUT4, and nerve growth factor (NGF), and suggesting that each step of this pathway may be a potential drug target. Given the beneficial effects of adiponectin, NGF and GLUT4 on various metabolic, vascular and inflamma- tory processes, a hypothesis of metabotrophic factor deficit in the pathogenesis of adipose-linked diseases is discussed. Adipopharmacological evaluation of this hypothesis may provide novel targets for drug development. W e respectfully ded ic ate th is rev ie w t o Professor Rita Lev i- M ontalc in i on oc cas ion of her 97 th birthday (born 22 April, 1909) cellular secretory pathways. We propose that, at a mechanis- tic level, each step of these pathways may provide a novel target for drug development against adipose tissue-linked diseases. Given the beneficial effects of adiponectin, NGF and GLUT4 on various metabolic, vascular and inflamma- tory processes, a hypothesis of metabotrophic factor deficit in the pathogenesis of these diseases is discussed.

Adipoparacrinology - Vascular periadventitial adipose tissue (Tunica adiposa) as an example

Human adipose tissue is partitioned into two large depots (subcutaneous and visceral), and many small depots associated with internal organs, e.g. heart, blood vessels, major lymph nodes, pancreas, prostate gland and ovaries. Since the adipose ‘Big Bang’ led to the discovery of leptin (Zhang, Proenca, Maffei, Barone, Leopold and Friedman, Nature 1994;372:425–32), adipose tissue has been seen not merely as a lipid store, but as a secretory – endocrine and paracrine – organ, particularly in the pathogenesis of a number of diseases. Accordingly, two major sub‐fields of adipobiology have emerged, viz. adipoendocrinology and adipoparacrinology, the latter herein being illustrated by PAAT (periadventitial adipose tissue) in vascular walls. A long‐standing paradigm holds that the vascular wall consists of three coats, tunica intima, tunica media and tunica adventitia. It is now imperative that ‘to further elucidate vascular function, we should no longer, as hitherto, separate adventitia and PAAT from the vascular wall, but keep them attached and in place, and subject to thorough examination’ (Chaldakov, Fiore, Ghenev, Stankulov and Aloe, Int Med J 2000;7:43–9; Chaldakov, Stankulov and Aloe, Atherosclerosis 2001;154:237–8; Chaldakov GN, Stankulov IS, Fiore M, Ghenev PI and Aloe L, Atherosclerosis 2001;159:57–66). From the available data, we propose that it is time to rethink about vascular wall composition, and suggest that the PAAT may be considered the fourth and outermost vascular coat, hence, tunica adiposa (regarding the proximal segment of coronary artery, it is the innermost part of the EAT (epicardial adipose tissue) situated around the coronary adventitia). Its significance in the pathogenesis and therapy of CMDs (cardiometabolic diseases), particularly atherosclerosis and hypertension, requires further basic, translational and clinical studies.