Food energy efficiency, cannabinoids, and a slow death of the weight loss dogma

Weight loss is achieved by simply burning more calories through physical activity than are consumed, at least according to a commonly counseled dogma that seems to be solidly based on thermodynamic principles. The beauty of this simplicity not withstanding, biological systems are rarely so simple. Mounting evidence from more than 2 decades of research has shown that the energy efficiency of consumed food is in fact modulated and energy consumed in the form of food calories can be lost by seemingly futile wastage not taken into account in the current simplistic paradigm. Much attention has been given to the roles of uncoupling proteins in such energy wastage, but now increasing attention is also being given to the role of the endogenous cannabinoid signaling system as a major regulator of food energy efficiency. Cannabis use spans more than 5 millennia of written history, yet discussions of its value in modern medicine continue to evoke a spectrum of opinions and emotions that is arguably unmatched by any other member of the natural pharmacopoeia. Historically used to treat a diversity of ailments, the active ingredients of cannabis plants were isolated in the late nineteenth century, and the primary psychoactive component was identified as delta-9 tetrahydrocannabinol by Gaoni and Mechoulam in 1964.1 Debate ensued as to its mechanism of action, but the issue was settled with the discovery of a cannabinoid receptor by Allyn Horvath working at Saint Louis University in 1988.2 Its primary function in retrograde presynaptic regulation of neurotransmission in the central nervous system was soon discovered (Fig. 1). The fact that the cannabinoid receptor CB1 is the most abundant G protein–coupled receptor in the brain provides some hints as to its importance in global neurological function. The other characterized receptor, CB2, appears to be restricted to cells of the immune system. The early work describing the functions of CB1 has now been further expanded by recent studies describing important functions of this receptor outside the central nervous system that play a major role in regulating energy efficiency. Although the discovery of cannabinoid signaling was driven by the need to understand the psychopharmacology of Cannabis sativa, the finding of specific receptors suggested the presence of endogenous ligands.3 Such ligands, or endocannabinoids (ECs), are locally synthesized arachidonic acid derivatives originating from membrane phospholipids that are rapidly degraded near their sites of action.4 The 2 most studied ECs are the respective ester and amide of arachidonic acid, 2-arachidonoyl glycerol (2-AG) and arachidonyl ethanolamide (AEA, anandamide). In the central nervous system, these are synthesized on demand by postsynaptic neurons from membrane phospholipids via diacylglycerol lipase and phospholipase D, respectively. ECs bind CB1 receptors on presynaptic neurons to activate G protein signaling cascades that include activation of mitogen-activated protein kinases, phosphoinositide-3 kinases, calcium signaling and inhibition of adenylyl cyclase (Fig. 1). Degradation of ECs requires reuptake and destruction by enzymes such as fatty acid amide hydrolase in the case of 2-AG.5 How endocannabinoid signaling is mediated outside the central nervous system has not been similarly elucidated, but 2-AG is a major monoacylglycerol in rat liver.6 The history of cannabis use provides ample evidence that cannabinoids are potent appetite stimulants. Endocannabinoid signaling tonically activates hypothalamic CB1 receptors to maintain food intake7 and it interacts with opiate signaling pathways and reward centers in the central nervous system to increase the hedonic desire for pleasurable foods in particular.4,8 Based on the role of EC signaling in eating behaviors, rimonabant in obesity (RIO) trials were carried out in Europe and North America to determine if the cannabinoid receptor antagonist rimonabant (SR141716A)4,9 would be an effective treatment of obesity when given for 2 years.10,11 In the first year of RIO-Europe, subjects lost weight and the major side effects were nausea, dizziness, diarrhea, and arthralgias, whereas depression was the most common reason for drug cessation in both the treatment and placebo groups. The final report of this 2-year trial has not yet been published. The RIO-North America trial of 3045 subjects was weakened by a 49% dropout rate, but it demonstrated similar weight loss and improved metabolic abnormaliAbbreviations: 2-AG, arachidonoyl glycerol; AEA, anandamide; EC, endocannabinoid; RIO, rimonabant in obesity; TNF, tumor necrosis factor. Address reprint requests to: Brent A. Neuschwander-Tetri, Division of Gastroenterology and Hepatology, Saint Louis University Liver Center, 3635 Vista Avenue, St. Louis, MO 63110. E-mail: tetriba@slu.edu; fax: 314-577-8125. Copyright © 2007 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.21821 Potential conflict of interest: Nothing to report.