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Endocannabinoids and the regulation of body fat: the smoke is clearing
Tamas L. Horvath
Department of Obstetrics and Gynecology, and Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA
Address correspondence to: Tamas L. Horvath, Department of Obstetrics and Gynecology, and Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, FMB 339, New Haven, Connecticut 06520, USA. Phone: (203) 785-4597; Fax: (203) 785-4747; E-mail: tamas.horvath@yale.edu.
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Published August 1, 2003 - More info
J Clin Invest. 2003;112(3):323–326. https://doi.org/10.1172/JCI19376.
© 2003 The American Society for Clinical Investigation
Chronically elevated energy expenditure without a corresponding increase in energy intake leads to wasting and death. Almost all species in the wild, and the great majority of the human race, struggle with such negative energy balance in their daily battle for survival. In sharp contrast, however, modern industrialized societies are threatened by the exact opposite: chronically increased energy intake without a respective increase in energy expenditure. This constellation leads to obesity and diabetes as well as a variety of life-threatening consequences of such diseases, such as cancer and cardiovascular diseases (1, 2). While it appears intuitively obvious that in the majority of cases, positive energy balance should be corrected by changes in lifestyle and/or diet, the impressive dynamics of the spreading obesity epidemic (3) certainly suggests that, in modern industrialized civilizations, an efficient and safe pharmacological approach to treat obesity would be useful. In light of this, it is not surprising that within the past decades, increasing attention has been paid to central and peripheral regulatory components of energy metabolism to develop pharmacological modulators of appetite and energy expenditure. From this perspective, one of the great, and surprising, discoveries of the past decade was the revelation of an endocannabinoid system and its influences on appetite and metabolism (4–8).
Cannabinoids and endocannabinoids act via G protein–coupled receptors. The strongest effects of endocannabinoids on behavior, including those related to food intake, appear to be mediated by cannabinoid receptor type 1 (CB1), which is the predominant receptor type in the CNS. The molecular cascade triggered by CB1 activation has been studied in depth (reviewed in ref. 8). In short, the dominant G protein subtypes activated by CB1 belong to the Gi/o family; these in turn alter electric properties of membranes, second-messenger systems, and immediate-early genes. CB1 activation inhibits voltage-gated L, N, and P/Q Ca2+ currents, while activating K+ currents; and while agonists of CB1 induce the inhibition of adenylyl cyclase, they also induce the activation of focal adhesion kinase and MAPK. CB1-associated activation of G proteins also underlies the stimulation of NO synthase. Current ideology suggests that the activation or inhibition of CB1 (mainly by fatty acid ethanolamides) influences the aforementioned subcellular events and results in changes in neurotransmitter release at the level of axon terminals (7). However, to date, the phenotype of neurons in the hypothalamic appetite center that are directly affected by cannabinoids has not been elucidated. In this issue of the JCI, a report by Cota et al. (9) greatly advances our understanding of this critical issue by pinpointing those neuropeptide systems in the hypothalamus that most likely mediate cannabinoid-induced changes in energy homeostasis.
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Central and peripheral mode of action of endocannabinoids
The work by Cota et al. (9) and previous studies on cannabinoids will give rise to guarded optimism — yet again — that pharmacological strategies, now targeting the cannabinoid system, may succeed in counterbalancing overeating and a sedentary lifestyle. Previously, similar hopes were generated every time a novel molecule (hormone, peptide, or neurotransmitter) was discovered to affect energy metabolism. Cota et al. provide compelling evidence that endocannabinoids act at various regions of the hypothalamus that regulate energy homeostasis, including the lateral hypothalamus, arcuate nucleus, and paraventricular nucleus, in conjunction with direct effects in fat cells on lipogenesis to promote a positive energy balance. If the receptor, CB1, is blocked (in this case by knockout of the gene), the overall effect will be to decrease appetite and lipogenesis in white fat: CB–/– animals are leaner because their caloric intake is lower when they are young. However, in older animals, increased peripheral energy expenditure appears to be the predominant defense against adiposity in these animals compared with their wild-type littermates (9). Cota and colleagues show that CB1 is expressed in key hypothalamic peptidergic systems of appetite regulation, including those producing corticotropin-releasing hormone (CRH) in the paraventricular nucleus, cocaine amphetamine–regulated transcript (CART) in the arcuate nucleus, and melanin-concentrating hormone (MCH) and orexin/hypocretin in the lateral hypothalamus–perifornical region. Therefore, it is likely that by modulating food intake and mechanisms regulating energy expenditure, endocannabinoids or their antagonists will affect the signaling flow between these hypothalamic circuits and other neuronal networks with which these peptidergic systems interact (Figure 1). This central mechanism may dominate cannabinoid effects at younger ages but appears to diminish with age (9). Whether it is chronological aging per se or other developmental processes, for example, puberty, that affects the function of relevant hypothalamic circuitry and thereby enables this impairment of cannabinoid signaling still needs to be clarified. In addition, it must be determined whether such a shift in endocannabinoid signaling during the aging process also occurs in humans. Nevertheless, the observation that CB1 is present in adipocytes and that CB1 activation affects lipogenesis provides an alternative and/or complementary mechanism for the unidirectional effect of cannabinoids on energy balance.
Figure 1Schematic illustration showing the relationship between hypothalamic peptidergic circuits that express CB1 receptors (yellow cirlces), as described by Cota et al. (9), and some of those that do not. The former include cells that produce CART and pro-opiomelanocortin (POMC) in the arcuate nucleus (ARC); neurons that express MCH (blue) and orexin (ORX; red) in the lateral hypothalamic (LH) region; and neurons that produce CRH (brown) in the paraventricular nucleus (PVN). CB1 receptors are produced in the cytosol of these cells (yellow circles outlined in black) and are transported (white arrows) to axon terminals. Here, the receptors, upon activation (black arrowheads) by endocannabinoids (ECB) or other agonists, are thought to affect the release of neuromodulators (MCH, ORX, CART, corticotropin-releasing factor) to the synaptic cleft. A population of neurons in the medial arcuate nucleus produces neuropeptide Y (NPY) and agouti-related protein (AgRP), both of which are considered regulators of energy homeostasis. The NPY/AgRP–producing neurons, as well as those that produce ghrelin (GHR), were not found to contain CB1 receptors (9). GHR is also produced in the stomach and, together with the adipose hormone leptin, reaches hypothalamic peptidergic circuits via the circulation. The source of endocannabinoids in the hypothalamus is yet to be determined. Similarly, the hierarchical relationship between CB1-containing axon terminals and other axon terminals and their postsynaptic targets needs to be established to allow a better understanding of the hypothalamic signaling of cannabinoids. Putative inhibitory (–) and stimulatory (+) influences on food intake of the various elements of the peptidergic system are shown. Note that this influence on food intake may not reflect electrophysiological effects of the respective peptides. III, third ventricle.
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