The emerging role of the endocannabinoid system in endocrine regulation and energy balance

During the last few years, the endocannabinoid system has emerged as a highly relevant topic in the scientific community. Many different regulatory actions have been attributed to endocannabinoids, and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors, named CB1 receptor and CB2 receptor, first discovered as the molecular targets of the psychotropic component of the plant Cannabis sativa, participate in the physiological modulation of many central and peripheral functions. CB2 receptor is mainly expressed in immune cells, whereas CB1 receptor is the most abundant G protein-coupled receptor expressed in the brain. CB1 receptor is expressed in the hypothalamus and the pituitary gland, and its activation is known to modulate all the endocrine hypothalamic-peripheral endocrine axes. An increasing amount of data highlights the role of the system in the stress response by influencing the hypothalamic-pituitary-adrenal axis and in the control of reproduction by modifying gonadotropin release, fertility, and sexual behavior. The ability of the endocannabinoid system to control appetite, food intake, and energy balance has recently received great 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 receptor and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the gastrointestinal tract, and, possibly, skeletal muscle. The relevance of the system is further strenghtened by the notion that drugs interfering with the activity of the endocannabinoid system are considered as promising candidates for the treatment of various diseases, including obesity.     

The central melanocortin system and its role in energy homeostasis]

Obesity is an important health concern, and the central melanocortin system is likely to play an important role in both normal regulation of energy homeostasis as well as genetic predisposition to obesity. Three different mouse models of obesity have been created by virtue of mutations which alter the function of the melanocortin system, and a rare form of human obesity has been characterized in two families with mutations in the proopiomelanocortin gene [26]. More recently published works suggests an association between common childhood obesity and dominant inheritance of a single null allele of the melanocortin-4 receptor [44, 49]. Experimental work in the rodent suggests that the central melanocortin system may be a fundamental component of the adipostat, the mechanism by which constant energy stores are maintained. This hypothesis is the subject of this review.     

Peripheral effects of the endocannabinoid system in energy homeostasis: Adipose tissue,liver and skeletal muscle

The endocannabinoid system (ECS) is composed of lipid signalling ligands, their G-protein coupled receptors and the enzymes involved in ligand generation and metabolism. Increasingly, the ECS is emerging as a critical agent of energy metabolism regulation through its ability to modulate caloric intake centrally as well as nutrient transport, cellular metabolism and energy storage peripherally. Visceral obesity has been associated with an upregulation of ECS activity in several systems and inhibition of the ECS, either pharmacologically or genetically, results in decreased energy intake and increased metabolic output. This review aims to summarize the recent advances that have been made regarding our understanding of the role the ECS plays in crucial peripheral systems pertaining to energy homeostasis: adipose tissues, the liver and skeletal muscle.     

Metaplastic control of the endocannabinoid system at inhibitory synapses in hippocampus

The modifiability of neuronal response plasticity is called "metaplasticity." In suppressing synaptic inhibition and facilitating induction of long-term excitatory synaptic plasticity, endocannabinoids (eCBs) act as agents of metaplasticity. We now report the discovery of a calcium-dependent mechanism that regulates eCB mobilization by metabotropic glutamate receptor (mGluR) activation. The switch-like mechanism primes cells to release eCBs and requires a transient rise in intracellular Ca2+ concentration ([Ca2+]i) but not concurrent activation of mGluRs. Conversely, short-term, [Ca2+]i-dependent eCB release can be persistently enhanced by mGluR activation. Hence, eCBs are also objects of metaplasticity, subject to higher levels of physiological control.     

The role of gut hormones in the regulation of body weight and energy homeostasis

Obesity is one of the greatest public health challenges of the 21st century with 1.6 billion adults currently classified as being overweight and 400 million as obese. Obesity is causally associated with type 2 diabetes, hypertension, cardiovascular disease, obstructive sleep apnoea and certain forms of cancer and is now one of the leading causes of mortality and morbidity worldwide.     

A role for the endogenous opioid beta-endorphin in energy homeostasis

Proopiomelanocortin (POMC) neurons in the hypothalamus are direct targets of the adipostatic hormone leptin and contribute to energy homeostasis by integrating peripheral and central information. The melanocortin and beta-endorphin neuropeptides are processed from POMC and putatively coreleased at axon terminals. Melanocortins have been shown by a combination of pharmacological and genetic methods to have inhibitory effects on appetite and body weight. In contrast, pharmacological studies have generally indicated that opioids stimulate food intake. Here we report that male mice engineered to selectively lack beta-endorphin, but that retained normal melanocortin signaling, were hyperphagic and obese. Furthermore, beta-endorphin mutant and wild-type mice had identical orexigenic responses to exogenous opioids and identical anorectic responses to the nonselective opioid antagonist naloxone, implicating an alternative endogenous opioid tone to beta-endorphin that physiologically stimulates feeding. These genetic data indicate that beta-endorphin is required for normal regulation of feeding, but, in contrast to earlier reports suggesting opposing actions of beta-endorphin and melanocortins on appetite, our results suggest a more complementary interaction between the endogenously released POMC-derived peptides in the regulation of energy homeostasis.     

The endocannabinoid system in prostate cancer

Cannabinoids, their receptors and their metabolizing enzymes are emerging as a new regulatory system, which is involved in multiple physiological functions. Normal prostate tissue expresses several constituents of the endocannabinoid system including the CB(1) receptor, receptors belonging to the transient receptor potential family and fatty acid amide hydrolase, a hydrolyzing enzyme, all of which have been localized in the glandular epithelia. Accumulating evidence indicate that the endocannabinoid system is dysregulated in prostate cancer, suggesting that it has a role in prostate homeostasis. Overexpression of several components of the endocannabinoid system correlate with prostate cancer grade and progression, potentially providing a new therapeutic target for prostate cancer. Moreover, several cannabinoids exert antitumoral properties against prostate cancer, reducing xenograft prostate tumor growth, prostate cancer cell proliferation and cell migration. Although the therapeutic potential of cannabinoids against prostate cancer is very promising, future research using animal models is needed to evaluate the influence of systemic networks in their antitumoral action.     

内源性大麻素样系统与肥胖

内源性大麻素样系统主要由内源性大麻素及其受体组成,后者分为CB1受体和CB2受体两种,激活后可引起摄食增加。与正常小鼠相比,CB1受体(-/-)小鼠的体重和脂肪明显减少,即使在致肥胖饮食条件下也不会发生肥胖或胰岛素抵抗。研究证实,CB1受体拮抗剂可通过中枢和外周两种机制抑制摄食并改善代谢;其中,利莫那班已进入Ⅲ期临床试验,可有效抑制食欲、减轻体重,并且尚未发现明显的副作用。