White adipose tissue is now recognised to be a multifunctional organ; in addition to the central role of lipid storage, it has a major endocrine function secreting several hormones, notably leptin and adiponectin, and a diverse range of other protein factors. These various protein signals have been given the collective name 'adipocytokines' or 'adipokines'. However, since most are neither 'cytokines' nor 'cytokine-like', it is recommended that the term 'adipokine' be universally adopted to describe a protein that is secreted from (and synthesised by) adipocytes. It is suggested that the term is restricted to proteins secreted from adipocytes, excluding signals released only by the other cell types (such as macrophages) in adipose tissue. The adipokinome (which together with lipid moieties released, such as fatty acids and prostaglandins, constitute the secretome of fat cells) includes proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular haemostasis, blood pressure regulation and angiogenesis, as well as the regulation of energy balance. In addition, there is a growing list of adipokines involved in inflammation (TNFalpha, IL-1beta, IL-6, IL-8, IL-10, transforming growth factor-beta, nerve growth factor) and the acute-phase response (plasminogen activator inhibitor-1, haptoglobin, serum amyloid A). Production of these proteins by adipose tissue is increased in obesity, and raised circulating levels of several acute-phase proteins and inflammatory cytokines has led to the view that the obese are characterised by a state of chronic low-grade inflammation, and that this links causally to insulin resistance and the metabolic syndrome. It is, however, unclear as to the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and whether there is a generalised or local state of inflammation. The parsimonious view is that the increased production of inflammatory cytokines and acute-phase proteins by adipose tissue in obesity relates primarily to localised events within the expanding fat depots. It is suggested that these events reflect hypoxia in parts of the growing adipose tissue mass in advance of angiogenesis, and involve the key controller of the cellular response to hypoxia, the transcription factor hypoxia inducible factor-1.

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Adipokines: inflammation and the pleiotropic role of white adipose tissue.

Excess intra-abdominal adipose tissue accumulation, often termed visceral obesity, is part of a phenotype including dysfunctional subcutaneous adipose tissue expansion and ectopic triglyceride storage closely related to clustering cardiometabolic risk factors. Hypertriglyceridemia; increased free fatty acid availability; adipose tissue release of proinflammatory cytokines; liver insulin resistance and inflammation; increased liver VLDL synthesis and secretion; reduced clearance of triglyceride-rich lipoproteins; presence of small, dense LDL particles; and reduced HDL cholesterol levels are among the many metabolic alterations closely related to this condition. Age, gender, genetics, and ethnicity are broad etiological factors contributing to variation in visceral adipose tissue accumulation. Specific mechanisms responsible for proportionally increased visceral fat storage when facing positive energy balance and weight gain may involve sex hormones, local cortisol production in abdominal adipose tissues, endocannabinoids, growth hormone, and dietary fructose. Physiological characteristics of abdominal adipose tissues such as adipocyte size and number, lipolytic responsiveness, lipid storage capacity, and inflammatory cytokine production are significant correlates and even possible determinants of the increased cardiometabolic risk associated with visceral obesity. Thiazolidinediones, estrogen replacement in postmenopausal women, and testosterone replacement in androgen-deficient men have been shown to favorably modulate body fat distribution and cardiometabolic risk to various degrees. However, some of these therapies must now be considered in the context of their serious side effects. Lifestyle interventions leading to weight loss generally induce preferential mobilization of visceral fat. In clinical practice, measuring waist circumference in addition to the body mass index could be helpful for the identification and management of a subgroup of overweight or obese patients at high cardiometabolic risk.

Pathophysiology of Human Visceral Obesity: An Update

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson9s and Huntington9s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB 1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB 1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB 2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients9 need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.

http://www.phytecs.com/wp-content/uploads/2015/02/Pharmacol-Rev-2006-Pacher-389-462.pdf

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

Metabolic syndrome is defined by a constellation of interconnected physiological, biochemical, clinical, and metabolic factors that directly increases the risk of cardiovascular disease, type 2 diabetes mellitus, and all cause mortality. Insulin resistance, visceral adiposity, atherogenic dyslipidemia, endothelial dysfunction, genetic susceptibility, elevated blood pressure, hypercoagulable state, and chronic stress are the several factors which constitute the syndrome. Chronic inflammation is known to be associated with visceral obesity and insulin resistance which is characterized by production of abnormal adipocytokines such as tumor necrosis factor α , interleukin-1 (IL-1), IL-6, leptin, and adiponectin. The interaction between components of the clinical phenotype of the syndrome with its biological phenotype (insulin resistance, dyslipidemia, etc.) contributes to the development of a proinflammatory state and further a chronic, subclinical vascular inflammation which modulates and results in atherosclerotic processes. Lifestyle modification remains the initial intervention of choice for such population. Modern lifestyle modification therapy combines specific recommendations on diet and exercise with behavioural strategies. Pharmacological treatment should be considered for those whose risk factors are not adequately reduced with lifestyle changes. This review provides summary of literature related to the syndrome's definition, epidemiology, underlying pathogenesis, and treatment approaches of each of the risk factors comprising metabolic syndrome.

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A Comprehensive Review on Metabolic Syndrome

ContextAdiponectin, a recently discovered adipocyte-derived peptide, is involved
in the regulation of insulin sensitivity and lipid oxidation and, purportedly,
in the development of atherosclerosis and coronary heart disease in humans.ObjectiveTo assess prospectively whether plasma adiponectin concentrations are
associated with risk of myocardial infarction (MI).Design, Setting, and ParticipantsNested case-control study among 18 225 male participants of the
Health Professionals Follow-up Study aged 40 to 75 years who were free of
diagnosed cardiovascular disease at the time of blood draw (1993-1995). During
6 years of follow-up through January 31, 2000, 266 men subsequently developed
nonfatal MI or fatal coronary heart disease. Using risk set sampling, controls
were selected in a 2:1 ratio matched for age, date of blood draw, and smoking
status (n = 532).Main Outcome MeasureIncidence of nonfatal MI and fatal coronary heart disease by adiponectin
level.ResultsAfter adjustment for matched variables, participants in the highest
compared with the lowest quintile of adiponectin levels had a significantly
decreased risk of MI (relative risk [RR], 0.39; 95% confidence interval [CI],
0.23-0.64; P for trend <.001). Additional adjustment
for family history of MI, body mass index, alcohol consumption, physical activity,
and history of diabetes and hypertension did not substantively affect this
relationship (RR, 0.41; 95% CI, 0.24-0.70; P for
trend <.001). Further adjustment for hemoglobin A1c or C-reactive
protein levels also had little impact, but additional adjustment for low-
and high-density lipoprotein cholesterol levels modestly attenuated this association
(RR, 0.56; 95% CI, 0.32-0.99; P for trend = .02).ConclusionsHigh plasma adiponectin concentrations are associated with lower risk
of MI in men. This relationship can be only partly explained by differences
in blood lipids and is independent of inflammation and glycemic status.

https://jamanetwork.com/journals/jama/articlepdf/198539/JOC32354.pdf

Plasma Adiponectin Levels and Risk of Myocardial Infarction in Men

Obesity is the main risk factor for the development of type 2 diabetes. Activation of the central endocannabinoid system increases food intake and promotes weight gain. Blockade of the cannabinoid type 1 (CB-1) receptor reduces body weight in animals by central and peripheral actions; the role of the peripheral endocannabinoid system in human obesity is now being extensively investigated. We measured circulating endocannabinoid concentrations and studied the expression of CB-1 and the main degrading enzyme, fatty acid amide hydrolase (FAAH), in adipose tissue of lean (n = 20) and obese (n = 20) women and after a 5% weight loss in a second group of women (n = 17). Circulating levels of anandamide and 1/2-arachidonoylglycerol were increased by 35 and 52% in obese compared with lean women (P < 0.05). Adipose tissue mRNA levels were reduced by -34% for CB-1 and -59% for FAAH in obese subjects (P < 0.05). A strong negative correlation was found between FAAH expression in adipose tissue and circulating endocannabinoids. Circulating endocannabinoids and CB-1 or FAAH expression were not affected by 5% weight loss. The expression of CB-1 and FAAH was increased in mature human adipocytes compared with in preadipocytes and was found in several human tissues. Our findings support the presence of a peripheral endocannabinoid system that is upregulated in human obesity.

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Activation of the peripheral endocannabinoid system in human obesity.

Low plasma levels of the anti-inflammatory factor adiponectin characterize obesity and insulin resistance. To elucidate the relationship between plasma levels of adiponectin, adiponectin gene expression in adipose tissue, and markers of inflammation, we obtained blood samples, anthropometric measures, and subcutaneous adipose tissue samples from 65 postmenopausal healthy women. Adiponectin plasma levels and adipose-tissue gene expression were significantly lower in obese subjects and inversely correlated with obesity-associated variables, including high-sensitive C-reactive protein (hs-CRP) and interleukin-6 (IL-6). Despite adjustment for obesity-associated variables, plasma levels of adiponectin were significantly correlated to adiponectin gene expression (partial r = 0.38, P < 0.05). Furthermore, the inverse correlation between plasma levels of hs-CRP and plasma adiponectin remained significant despite correction for obesity-associated variables (partial r = -0.32, P < 0.05), whereas the inverse correlation between adiponectin plasma levels or adiponectin gene expression in adipose tissue with plasma IL-6 were largely dependent on the clustering of obesity-associated variables. In conclusion, our data suggest a transcriptional mechanism leading to decreased adiponectin plasma levels in obese women and demonstrate that low levels of adiponectin are associated with higher levels of hs-CRP and IL-6, two inflammatory mediators and markers of increased cardiovascular risk.

https://diabetes.diabetesjournals.org/content/diabetes/52/4/942.full.pdf

Association Between Adiponectin and Mediators of Inflammation in Obese Women

ENGELI, STEFAN, JANA BO¨ HNKE, MAREIKEFELDPAUSCH, KERSTIN GORZELNIAK, UTEHEINTZE, JU¨ RGEN JANKE, FRIEDRICH C. LUFT,AND ARYA M. SHARMA. Regulation of 11 -HSDgenesin human adipose tissue: influence of central obesity andweight loss. Obes Res. 2004;12:9–17.Objectives: The activity of adipose 11 -hydroxysteroid de-hydrogenase (11 -HSD) 1 is increased in obese subjects,and animal data suggest that increased cortisol formation inadipose tissue contributes to the development of the meta-bolic syndrome. The aim of this study was to determinewhether up-regulation of human adipose 11 -HSD1 in obe-sity can also be found at the gene expression level.Research Methods and Procedures: 11 -HSDgene expres-sion in subcutaneous adipose tissue biopsies of 70 post-menopausal women was studied by real-time reverse-tran-scription polymerase chain reaction. The influence ofweight reduction and in vitro effects of several modulatorsof adipocyte gene expression on 11 -HSDgenes in humanadipocytes were also studied.Results: The 11 -HSD1gene was highly expressed in hu-man adipose tissue. 11 -HSD2mRNA was also detectableat lower levels. Adipose 11 -HSD1gene expression wasincreased by two-fold and was positively correlated withwaist circumference and homeostasis model assessment in-dex of insulin resistance. 11 -HSD2gene expression wasreduced by half in obese women. Weight reduction did notchange gene expression levels of 11 -HSD1or 11 -HSD2.Cortisol increased 11 -HSD1gene expression in isolatedhuman adipocytes in vitro, whereas estradiol, triiodothyro-nine, angiotensin II, and pioglitazone had no influence.Discussion: Our data suggest that increased expression ofthe 11 -HSD1gene is associated with metabolic abnormal-ities in obese women and that increased expression of thisgene may contribute to the previously reported increasedlocal conversion of cortisone to cortisol in adipose tissue ofobese individuals.Key words: central obesity, metabolic syndrome, adi-pose tissue, cortisol, 11 -hydroxysteroid dehydrogenasetype 1

https://onlinelibrary.wiley.com/doi/pdf/10.1038/oby.2004.3

Mareike Feldpausch

Papers

Activation of the peripheral endocannabinoid system in human obesity.

Association Between Adiponectin and Mediators of Inflammation in Obese Women

Regulation of 11β‐HSD Genes in Human Adipose Tissue: Influence of Central Obesity and Weight Loss