Uberto Pagotto

Cannabinoid Type 1 Receptor Blockade Promotes Mitochondrial Biogenesis Through Endothelial Nitric Oxide Synthase Expression in White Adipocytes

OBJECTIVE—Cannabinoid type 1 (CB1) receptor blockade decreases body weight and adiposity in obese subjects; however, the underlying mechanism is not yet fully understood. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) induces mitochondrial biogenesis and function in adipocytes. This study was undertaken to test whether CB1 receptor blockade increases the espression of eNOS and mitochondrial biogenesis in white adipocytes. RESEARCH DESIGN AND METHODS—We examined the effects on eNOS and mitochondrial biogenesis of selective pharmacological blockade of CB1 receptors by SR141716 (rimonabant) in mouse primary white adipocytes. We also examined eNOS expression and mitochondrial biogenesis in white adipose tissue (WAT) and isolated mature white adipocytes of CB1 receptor–deficient (CB1−/−) and chronically SR141716-treated mice on either a standard or high-fat diet. RESULTS—SR141716 treatment increased eNOS expression in cultured white adipocytes. Moreover, SR141716 increased mitochondrial DNA amount, mRNA levels of genes involved in mitochondrial biogenesis, and mitochondrial mass and function through eNOS induction, as demonstrated by reversal of SR141716 effects by small interfering RNA–mediated decrease in eNOS. While high-fat diet–fed wild-type mice showed reduced eNOS expression and mitochondrial biogenesis in WAT and isolated mature white adipocytes, genetic CB1 receptor deletion or chronic treatment with SR141716 restored these parameters to the levels observed in wild-type mice on the standard diet, an effect linked to the prevention of adiposity and body weight increase. CONCLUSIONS—CB1 receptor blockade increases mitochondrial biogenesis in white adipocytes by inducing the expression of eNOS. This is linked to the prevention of high-fat diet–induced fat accumulation, without concomitant changes in food intake.

The Endocannabinoid System and Energy Metabolism

Many different regulatory actions have been attributed to endocannabinoids, and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors [cannabinoid receptor type 1 (CB1) and CB2] participate in the physiological modulation of many central and peripheral functions. The ability of the endocannabinoid system to control appetite, food intake and energy balance has recently received considerable attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptors and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control several metabolic functions by acting on peripheral tissues such as adipocytes, hepatocytes, the gastrointestinal tract, the skeletal muscles and the endocrine pancreas. The relevance of the system is further strengthened by the notion that visceral obesity seems to be a condition in which an overactivation of the endocannabinoid system occurs, and therefore drugs interfering with this overactivation by blocking CB1 receptors are considered as potentially valuable candidates for the treatment of obesity and related cardiometabolic risk factors.

Cannabinoid Type 1 Receptor: Another Arrow in the Adipocytes’ Bow

The endocannabinoid system has recently emerged as an important modulator of several functions of adipose tissue, including cell proliferation, differentiation and secretion. Here, we will review the effects of cannabinoid type 1 (CB1) receptor activation/blockade in adipocytes by summarising the data in the literature since the discovery of the presence of this receptor in adipose tissue. We will also discuss our original data obtained in mouse 3T3‐L1 adipocyte cells using WIN55 212, a CB1/CB2 receptor agonist and SR141716 (rimonabant), a specific CB1 receptor antagonist, respectively, in different experimental settings.

Sex-dependent role of glucocorticoids and androgens in the pathophysiology of human obesity

Obesity, particularly its abdominal phenotype, a harbinger of the metabolic syndrome, cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2D), is becoming one of the most significant public health problems worldwide. Among many other potential factors, derangement of multiple hormone systems have increasingly been considered for their potential importance in the pathophysiology of obesity and the metabolic syndrome, with particular reference to glucocorticoids and sex hormones. These systems have a fundamental and coordinating role in the physiology of intermediate metabolism and cardiovascular function, and in the response to acute and chronic stress challenge. Abdominal obesity is associated with a hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis and impaired androgen balance, although these alterations differ according to sex. As there is also increasing evidence that there are many differences between the sexes in the susceptibility and development of obesity, T2D and CVDs, we support the hypothesis that alterations of the HPA axis and androgen balance may have an important function in this context. This is further supported by the fact that there are important differences between males and females in their ability to adapt to both internal and particularly to environmental (external) stressors. In addition, there is also evidence that, in both physiological and pathological conditions, a close cross talk exists between sex hormones and glucocorticoids at both neuroendocrine and peripheral level, again with different specificities according to sex.

Tumor ZAC1 expression is associated with the response to somatostatin analog therapy in patients with acromegaly

Somatostatin analogs (SSA) with their potent antisecretory and antiproliferative effects are the main medical treatment option for patients with neuroendocrine tumors, such as gastroenteropancreatic and acromegaly‐associated growth hormone secreting pituitary tumors. Although a good portion of acromegalic patients gets normalized after SSA treatment, strict hormonal control is not achieved in a sizeable proportion of these patients. The reasons for this incomplete response to SSA treatment are unclear. We have found that the tumor suppressor ZAC1 (LOT1/PLAGL1) is essential for the antiproliferative effect of SSA in pituitary tumor cells. The aim of the present retrospective cohort study was to determine whether ZAC1 immunoreactivity in archival somatotrophinoma tissue derived from 45 patients with acromegaly routinely pretreated with SSA before surgery, was associated with response to SSA (normalization of GH, IGF‐I and presence of tumor shrinkage). All tumors displayed ZAC1 immunoreactivity [weak (+; n = 15), moderate (++; n = 16) and strong (+++; n = 14)]. A significant positive correlation was found between strong ZAC1 immunoreactivity and IGF‐I normalization and presence of tumor shrinkage after SSA treatment, which was not affected by age at diagnosis, gender or duration of SSA treatment. These in vivo data combined with the antiproliferative properties of ZAC1/Zac1 provide evidence of a mechanistic role for this transcription factor on SSA induced tumor shrinkage and hormone normalization.

Where Does Insulin Resistance Start?: The brain

During the last two decades, many studies have focused on the pivotal role of the hypothalamus in the control of energy metabolism (1). Hypothalamic nuclei, particularly the arcuate and the ventromedial, receive numerous peripheral inputs from adipokines (leptin, adiponectin, and resistin) and free fatty acids. These signals of “nutrient abundance” lead to the activation of multiple hypothalamic pathways that overlap and generate a plethora of central and peripheral responses (2). In this context, the central neuronal signals generated by insulin have been the most extensively studied (3). The pivotal experiment performed by Woods et al. (4) in the late 1970s showed that intracerebral infusion of insulin in baboons reduced food intake and body weight and paved the way for intense scientific investigation over subsequent years by highlighting the key role of insulin at the central nervous system (CNS) level. Insulin receptors (5) and components of the insulin signaling pathway (6) are widely distributed in the brain. Insulin interacts with its binding sites by crossing the blood-brain barrier through a receptor-mediated and saturable transport mechanism (7), although it has been hypothesized that insulin is also synthesized in the brain (7). Considerable evidence has been generated to indicate that insulin can modulate the expression of neuropeptides involved in the regulation of food intake within the CNS (8) and also can influence glucoregulation via CNS connections that regulate hepatic glucose production (9), glycogen synthesis in the skeletal muscle (10), and fat metabolism in adipocytes (11). By activating its receptors, insulin directly suppresses prepro-NPY mRNA transcription in the arcuate nucleus, leading to a reduction in NPY and a decrease in food intake (12), whereas intracerebroventricular delivery of insulin increases the expression of pro-opiomelanocortin (POMC) (13) (Fig. 1). This hypothalamic mode of insulin action resembles the well-known effect of leptin, suggesting that these …

Plasma acylated ghrelin levels are higher in patients with chronic atrophic gastritis.

Objectives  Ghrelin is mainly produced by the endocrine cells of the gastric oxyntic mucosa. For this reason we decided to investigate the modification of the circulating levels not only of total but also of acylated ghrelin in a series of patients with chronic atrophic gastritis.

Cannabinoid Receptor Antagonists and the Metabolic Syndrome: Novel Promising Therapeutical Approaches

Recent findings in animals and in humans have shown that cannabinoid type 1 receptor antagonists are suitable to become the most promising validated class of drugs to tackle obesity and related disorders. This mini-review will provide a concise and updated revision of the state of art on this topic.

Here, There and Everywhere: the Endocannabinoid System

Although the biology of cannabinoids and the variety of their central and peripheral actions have been studied for over half a century, these early findings have gone largely unnoticed by the overwhelming majority of physicians and scientists (Fig. 1). In fact, the widespread medical and recreational use of marijuana throughout the ages was not sufficient to initiate careful and extensive research on cannabinoids until the last few decades of the twentieth century. Cannabinoid research received, however, a pivotal boost from the characterisation of the chemical structure of D-tetrahydrocannabinol (D-THC), the main psychoactive constituent of marijuana, the impulse is documented by the relevant increase of publications (Fig. 1). However, it took many years more to expand our knowledge in understanding the marijuana’s mechanisms of action. Only after the cloning of the two receptor subtypes that are able to bind exogenous cannabinoids, named cannabinoid receptor type 1 (CB1 receptor) and type 2 (CB2 receptor), respectively, and to the identification of their endogenous ligands, the endocannabinoids, the research in this field exploded (Fig. 1). Cannabinoid receptors, endocannabinoids and the machinery for their synthesis and degradation represent the elements of an endogenous signalling system (the so-called endocannabinoid system). These landmark discoveries, along with the subsequent development of highly selective CB1 and CB2 receptor antagonists gave rise to an exponential increase in publications highlighting the potential role of the endocannabinoid system in physiological and pathological processes. With the clinical studies in which rimonabant, the first CB1 receptor antagonist to be synthesised, was tested in humans and further approved as drug to tackle obesity and related comorbidities, the topic started to become familiar to most part of the clinicians. This supplement to the Journal of Neuroendocrinology is aimed to provide an overview of the endocannabinoid system and its recent exploitations. The papers collated in this supplement are highly relevant to the current endocannabinoids research with a particular focus on endocrinology, metabolism and cardiovascular system. The main purpose of this issue is to present thoughtful and practical guidance to research workers involved and to activate thoughtful dissertations on a wide range of subjects that may have an impact on this so stimulating area of research. This issue has been generated from the lectures presented in the Workshop, ‘Endocannabinoids in Endocrinology, Metabolism and Cardiovascular Diseases, Scientific Background and Clinical Perspectives’ held at Padua (Italy) in July 2007 organised by Professor Roberto Vettor, Professor Renato Pasquali and their co-workers. We are grateful to the speakers for their lectures and for their kindness to extend their participation with the contributions that appear in this Issue. We would like to thank the Editor-in-Chief of the Journal of Neuroendocrinology, Professor Julia C. Buckingham and the Editorial Manager, Dr Pallab Seth who hosted this supplement and provided us with continuous support. We cannot forget the valuable help in editing (both language and technical) provided by Dr Christopher D. John, Dr Tanya Tierney and Dr Felicity N.E. Gavins of Imperial College London and we thank them for their work. The articles compiled in this supplement should be of broad interest to both physicians and scientists of different disciplines who only recently began to realise the importance of the endocannabinoid system in many physiological processes and in the development and progression of several diseases. The manuscripts are grouped according to the topics faced. After a very comprehensive revision of the latest findings aimed at summarising the chemistry and pharmacology of the endocannabinoid system, subsequent articles are divided according to the role played by the endocannabinoids in different physiological functions such as immunity, behaviour, the gastrointestinal system, the cardiovascular system, reproduction, and metabolism. The first two articles are dedicated to the biochemical description of the elements composing the endocannabinoid system. Tiziana

The endocannabinoid system as a target for obesity treatment.

Overweight and obesity are major factors contributing to the development of type 2 diabetes mellitus (DM) and cardiovascular disease (CVD). In addition to the many physical and metabolic consequences of obesity, there are also mental health consequences, in particular, the risk for depression. Depression can lead to poor self-care, poor treatment compliance, and possible increased morbidity and mortality from such illnesses as type 2 DM and CVD. Lifestyle modification for the treatment of overweight and obesity is rarely successful over the long term, and use of surgery is limited by eligibility criteria; therefore, researchers and clinicians continue to explore pharmacotherapy, with intense efforts being directed toward the development of agents that, optimally, will reduce weight and simultaneously reduce or eliminate modifiable cardiovascular and metabolic risk factors. Among the promising new agents are the CB(1) receptor antagonists. These agents target receptors of the endocannabinoid system, a neuromodulatory system recently found to influence energy balance, eating behavior, and metabolic homeostasis via central and peripheral mechanisms. In animal and clinical studies, antagonism of CB(1) receptors has resulted in meaningful weight loss and improvement of lipid and glycemic profiles. Thus, these agents may provide a rational and effective approach for the management of not only overweight and obesity but also their metabolic and cardiovascular sequelae.