Cannabis in Fat: High Hopes to Treat Obesity

COMMENTARY The Journal of Clinical Investigation Cannabis in fat: high hopes to treat obesity

Melody N. Hawkins1,2 and Tamas L. Horvath2,3 1Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, 2Yale University School of Medicine, and 3Department of Comparative Medicine, Program of Integrative Cell Signaling and Neurobiology of Metabolism, New Haven, Connecticut, USA.

Europe in June 2006 as Acomplia, promis- ing to decrease appetite and body weight. Cannabinoid receptor type-1 (CB1) is known to have a substantial impact Rimonabant showed effectiveness in the on the regulation of energy metabolism via central and peripheral treatment of obesity and improved cardio- mechanisms. In this issue of the JCI, Ruiz de Azua and colleagues provide metabolic risk factors (2, 8). Unfortunately, important insights into the regulation of adipocyte physiology by CB1. Mice it was also associated with psychiatric side with adipocyte-specific deletion of the CB1-encoding gene had an overall effects (4, 5) that were predicted based improved metabolic profile in addition to reduced body weight and total on a known mechanism of action. As a adiposity. These changes were associated with an increase in sympathetic high–binding affinity CB1 antagonist with tone of the adipose tissue and expansion of activated macrophages, both of full inverse agonist activity, rimonabant which occurred prior to changes in body weight, lending support to a causal blocked reward pathways and contributed relationship between loss of CB1 in adipocytes and systemic metabolic to mood disorders and depression (4). In changes. This work identifies adipocyte CB1s as a potential novel peripheral October of 2008, use of rimonabant was target for affecting systemic metabolism with diminished CNS effects. suspended in European nations due to the serious psychiatric side effects, and the drug is no longer used clinically. The ECS regulates appetite and food Effective obesity treatment en its involvement in feeding control and intake via the hypothalamus, while the with tolerable side effects peripheral metabolic regulation (3). mesolimbic system modulates the reward Obesity is caused by a chronic imbalance function of food (4, 6). This system also acts between energy intake and expenditure. The endocannabinoid system on peripheral tissues to control metabolic The growing incidence of obesity, especial- regulates energy metabolism functions (6). CB1 is expressed abundantly ly in children and adolescents, is a major The endocannabinoid system (ECS) is a in the CNS and found peripherally in hepa- public health concern. Obesity amplifies neuromodulatory system composed of tocytes, adipocytes, skeletal muscle, and the risk of developing metabolic syndrome, endogenously produced lipid cannabi- the pancreas (3, 8, 9). Endocannabinoids which has devastating consequences, noids that activate two well-characterized and CB1s are present in peripheral cells including decreased quality of life and cannabinoid receptors, namely, CB1 and and tissues that control energy homeosta- shortened life span. Additionally, obese CB2, and several regulating enzymes (4). sis (2, 6). For example, in white adipose individuals have increased rates of depres- These cannabinoid receptors were first tissue, CB1 signaling is coupled to stimula- sion (1, 2). The pharmacologic treatment identified in 1988, and the first endog- tion of lipoprotein lipase activity, suggest- of obesity has been fraught with complica- enous ligands, anandamide (AEA) and ing that CB1 modulators act directly on tions, including the inability to maintain 2-arachidonoylglycerol (2-AG), were dis- adipose tissue and contribute to fat accu- weight loss, serious cardiovascular risks, covered in 1992 and 1995, respectively. mulation independently of the amount of and gastrointestinal symptoms (1). The G protein–coupled CB1 is the most food ingested (9). The next step in phar- Several pharmacologic therapies have studied and relevant cannabinoid target macologic development of CB1-targeting been attempted to address the growing obe- (5) and is also the most abundant GPCR in drugs for treating obesity was to design a sity epidemic. Unfortunately, the major- the brain (6, 7). One function of CB1 is in cannabinoid receptor antagonist that could ity of these therapies have been associated the control of energy homeostasis. Induc- not cross the blood-brain barrier in order to with side effects that many would deem tion of CB1 signaling stimulates feeding avoid CNS effects. While CB1 antagonists intolerable. Drugs that target pathways by increasing appetite, whereas blocking restricted to the periphery have been devel- in metabolic tissues, such as adipocytes, CB1 signaling induces hypophagia by an oped in rats (4), such antagonists have not liver, and skeletal muscle, show promise, appetite-suppressant effect (5). been evaluated in humans. but none have been clinically developed to The cannabinoid receptor blocker In this issue of the JCI, Ruiz de Azua date. Cannabinoid receptor type-1 (CB1) is rimonabant was the first successful obesity and colleagues provide valuable insight a rational target for obesity treatment, giv- drug in this class (8) and was introduced in into CB1-dependent regulation of adipocyte physiology. Specifically, Ruiz de Related Article: p. 4148 Azua and colleagues developed a mouse model in which adipocyte-specific dele-

Conflict of interest: The authors have declared that no conflict of interest exists. tion of the CB1-encoding gene could be Reference information: J Clin Invest. 2017;127(11):3918–3920. https://doi.org/10.1172/JCI97042. induced. Using these mice, the authors

3918 jci.org Volume 127 Number 11 November 2017 The Journal of Clinical Investigation COMMENTARY

Figure 1. CB1 is essential for control of body weight and energy balance. Excessive CB1 signaling is associated with accumulation of adipose tissue, increased body mass, and hunger. In this issue, Ruiz de Azua and colleagues reveal that loss of CB1 specifically in adipocytes improves metabolic profile. These improve- ments are associated with an elevation of activated macrophages and increased sympathetic tone. This work supports further efforts in the development of peripherally restricted CB1 inverse agonists for treating obesity.

demonstrated that peripheral blockage of disease states, these drugs continue to be Melanin-concentrating hormone recep CB1 in adult obese mice caused fat redis- used without significant side effects. Addi- tor 1 (MCH-R1) antagonists have also tribution, with lower total adiposity and tionally, abuse of nabilione and dronabinol shown promise as a pharmacotherapy for weight loss. Additionally, loss of CB1 in is an uncommon problem (11). The suc- the treatment of obesity (1), as numerous adipocytes prevented diet-induced obe- cess of these synthetic cannabinoid recep- studies suggest that melanin-concentrat- sity and led to overall improved metabolic tor–targeting analogs proves the utility of ing hormone (MCH) is involved in feeding profile and browning of white adipocytes pharmacotherapy in the management of and energy homeostasis (1). These neuro- (10). These beneficial effects were accom- appetite control. Despite the setbacks asso- peptides are found in hypothalamic neu- panied by an increase in sympathetic tone ciated with negative psychiatric side effects rons, the peripheral nervous system, the of the adipose tissue along with expansion after use of rimonabant, several alterna- immune system, intestine, and the repro- of activated macrophages, both of which tives, including CB1 partial agonists, neu- ductive system and are strongly expressed occurred prior to changes in body weight tral antagonists, allosteric modulators, and in the lateral hypothamalic area, a central (10). Together, these results lend support periphery-restricted CB1 antagonists (4), area of feeding behavior regulation. Mice to and strengthen current evidence that make cannabinoid-based therapy attractive displayed hypophagia, increased metabol- suggests a causal relationship between loss for the management of obesity (3). ic activity, and weight loss after targeted of CB1 in adipocytes and systemic meta- ECS overactivity is associated with deletion of MCH. Overexpression of MCH, bolic changes. Findings associated with metabolic and eating disorders that con- on the other hand, led to increased body CB1 blockade are summarized in Figure tribute to abdominal obesity, dyslipidemia, weight, hyperphagia, hyperlinsulinemia, 1. A better understanding of this relation- and hyperglycemia (3, 5, 9). CB1 signaling and hyperglycemia after a high-fat diet (1). ship provides much needed insight into the inhibition decreases body weight in animal Rare genetic mutations that result in proo- anticipated effects of peripherally restrict- studies (11) by reducing food intake and piomelanocortin (POMC) deficiency are ed cannabinoid receptor antagonists on abdominal adiposity. There is general inter- characterized by hyperphagia and early adipose tissue. Future work with similar est in the idea of blocking the hyperactivity onset lifelong obesity. In the hypothalamic experiments in hepatocytes, skeletal mus- of the ECS as an obesity treatment (8). leptin/melanocortin signaling pathway, cle, and the pancreas have the potential to Dronabinol has been approved for the melanocyte-stimulating hormone (MSH) better elucidate the effects of cannabinoid treatment of HIV-induced wasting since transmits the anorexic effect of leptin receptor antagonists in the periphery. 1992. In all studies, dronabinol mildly through the melanocortin-4 receptor. To increased appetite; however, a marked date, there has been no effective treatment Therapeutic implications: improvement in mood was also noted. This for the hyperphagia and early onset obe- ECS system for body weight observation raised the question of whether sity; however, a recent brief report in the regulation these effects are secondary to the appetite- New England Journal of Medicine showed Phytocannabinoids, namely Δ9-tetrahy regulating actions of cannabinoids or the clinically significant weight loss in two drocannabinol (Δ9-THC) and the endo- result of a general improvement in the female POMC-deficient patients follow- cannabinoid AEA, are CB1 partial agonists sense of well-being or a decrease in pain. ing treatment with setmelanotide, a mela- that cause increased hunger sensation and Mounting evidence shows that ECS activa- nocortin-4 receptor agonist (12). stimulate food intake (11). Nabilone and tion significantly increases body fat mass, Unlike many classic neurotransmit- dronabinol are synthetic Δ9–THC analogs despite minimal changes in food intake ters, endocannabinoids are not stored in that act as partial CB1 agonists and are FDA or appetite (6). The work of Ruiz de Azua synaptic vesicles (7). Instead, endocan- approved for the treatment of cancer and et al. strengthens the hypothesis that the nabinoids are produced on demand from HIV cachexia for increasing appetite and increased fat mass is due to a direct lipo- lipid precursors, often have a short half- body weight. Despite use in cases of severe genic action of CB1 activation (10). life, and frequently work in a paracrine

jci.org Volume 127 Number 11 November 2017 3919 COMMENTARY The Journal of Clinical Investigation manner (5). Tight regulation of transcrip- a greater influence in obesity than in the 2. Aronne LJ, Pagotto U, Foster GD, Davis SN. The tion and degrading enzymes also contrib- aforementioned chronic conditions, a endocannabinoid system as a target for obesity treatment. Clin Cornerstone. 2008;9(1):52–64. utes to endocannabinoid production. Fat- multitargeted treatment approach may be 3. Muller T, et al. Overactivation of the endocan- ty acid amide hydrolase (FAAH) degrades dictated for treating obesity. One reason nabinoid system alters the antilipolytic action AEA, while monoacylglycerol lipase the ECS system is an attractive therapeutic of insulin in mouse adipose tissue. Am J Physiol (MAGL) is primarily responsible for the target is that this system modulates both Endocrinol Metab. 2017;313(1):E26–E36. degradation of 2-AG. These enzymes are food intake and energy expenditure (4) and 4. Bermudez-Silva FJ, Viveros MP, McPartland JM, thought to link the ECS to a broader lipid current evidence implicates coordination Rodriguez de Fonseca F. The endocannabinoid system, eating behavior and energy homeo- signaling network. Further characteriza- between central and peripheral CB1s in the stasis: the end or a new beginning? Pharmacol tion of degrading enzyme regulation has regulation of energy homeostasis (4). Biochem Behav. 2010;95(4):375–382. the potential for identifying therapeutic Although an increased endocannabi- 5. Koch M. Cannabinoid receptor signaling in targets outside the CB1 (5). noid tone has been associated with obesity central regulation of feeding behavior: a mini- (4, 5, 9), it is also the assumption that drugs review. Front Neurosci. 2017;11:293. 6. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali Conclusions and future acting to increase endocannabinoid tone R. The emerging role of the endocannabinoid directions could be used to treat anxiety disorders and system in endocrine regulation and energy bal- The primary defect associated with obesi- neurodegenerative diseases. The use of CB1 ance. Endocr Rev. 2006;27(1):73–100. ty is excessive endocannabinoid levels, not antagonists would need to be approached 7. Piomelli D. The molecular logic of endo- excessive CB1 expression (4); therefore, cautiously in patients with epilepsy, anxiety, cannabinoid signalling. Nat Rev Neurosci. focusing on endocannabinoid levels rather or neurodegenerative disorders (6). How- 2003;4(11):873–884. 8. André A, Gonthier MP. The endocannabinoid than CB1 blockade has been proposed as ever, the work by Ruiz de Azua et al. indi- system: its roles in energy balance and potential a more physiological approach for obe- cates that targeting CB1-mediated meta- as a target for obesity treatment. Int J Biochem sity treatment (4, 8). This is especially so bolic functions in adipose tissue remains an Cell Biol. 2010;42(11):1788–1801. because there is concern that blockade of attractive obesity treatment option in order 9. Matias I, Di Marzo V. Endocannabinoids and CB1 following treatment could adversely to avoid CNS side effects. the control of energy balance. Trends Endocrinol cause a feedback loop that would drive Metab. 2007;18(1):27–37. 10. Ruiz de Azua I, et al. Adipocyte cannabinoid endocannabinoid levels even higher (4). Address correspondence to: Melody Haw receptor CB1 regulates energy homeostasis Other studies suggest that a polyther- kins, 300 Cedar St., TAC S425 New Hav- and alternatively activated macrophages. apeutic strategy may be the wave of the en, Connecticut 06519, USA. Phone: 203. J Clin Invest. 2017;127(11):4148–4162. future (8). Additionally, several common 824.4654; Email: melody.hawkins@yale. 11. Engeli S. Central and peripheral cannabinoid diseases, such as hypertension, diabetes, edu or [email protected]. receptors as therapeutic targets in the control of food intake and body weight. Handb Exp Phar- and asthma, all use multiple medications macol. 2012;(209):357–381. to target different pathways in the treat- 1. Cheon HG. Antiobesity effects of melanin-con- 12. Kühnen P, et al. Proopiomelanocortin deficiency ment approach. As lifestyle, environment, centrating hormone receptor 1 (MCH-R1) antago- treated with a melanocortin-4 receptor agonist. and psychological factors possibly have nists. Handb Exp Pharmacol. 2012;(209):383–403. N Engl J Med. 2016;375(3):240–246.

3920 jci.org Volume 127 Number 11 November 2017