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Energy Balance and Metabolic Regulation—Clinical Data

ECSN Faculty

Daniela Cota, MD
Chargée de Recherche (CR1) and Avenir Group Leader
Institut François Magendie
Bordeaux, France

Vincenzo Di Marzo, PhD
Endocannabinoid Research Group
Institute of Biomolecular Chemistry
Consiglio Nazionale delle Ricerche
Pozzuoli, Italy

Kenneth Mackie, MD
Professor of Psychology
Department of Psychological and Brain Sciences
Indiana University
Bloomington, Indiana

Billy R. Martin, PhD
Harris Professor of Medicine
Chairman, Department of Pharmacology & Toxicology
Medical College of Virginia Commonwealth University
Richmond, Virginia

Introduction: Energy Balance and Metabolic Regulation

The high prevalence of obesity represents a major public health concern. Obesity is associated with serious medical conditions, such as type 2 diabetes and cardiovascular disease, which increase mortality and morbidity.1 The high prevalence of obesity has made understanding the biological mechanisms involved in feeding behavior and metabolic regulation an important focus of biomedical research.2 Interactions between the human thrifty genotype and reduced physical activity and increased food intake have been posited as the root cause of the rising prevalence of obesity and its associated complications.3 Understanding the biological mechanisms underlying energy balance may lead to more effective treatments for obesity, type 2 diabetes, and other diseases associated with excessive energy intake and the dysregulation of metabolism.

Appetite regulation and energy homeostasis are complex physiologic processes involving interactions among multiple neuromodulatory systems in the brain.4 The hypothalamus and hindbrain are the two key areas that regulate food intake, energy homeostasis, and body weight, while the limbic system is believed to contain the neuronal circuitry determining perceptions of food palatability and appetite.5, 6 Two populations of neurons in the lateral hypothalamus project to key cortical, limbic, and basal forebrain areas, indicating these neurons may have an important role in determining the hedonic or motivational aspects of feeding behavior.7-9 Over the last decade, a large body of experimental and clinical evidence has demonstrated the involvement of the endocannabinoid system (ECS) in this regulatory network. This module reviews the role of the ECS in feeding behavior and energy balance.

Clinical Data

Interactions between the human thrifty genotype, reduced physical activity, and increased food intake have been posited as the root cause of the rising prevalence of obesity and its associated complications.3 A growing body of data indicate that the ECS may play an important role in human feeding behavior and energy balance.

Figure 1
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Figure 2
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Figure 3
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Results from clinical studies indicate that the ECS is present in human adipose tissue and is stimulated in female subjects who are obese.10 Plasma levels of anandamide (AEA) were two-fold higher in obese women with a binge eating disorder than in normal weight healthy women or normal weight bulimic women (Figure 1).11 Although the clinical significance of this alteration awaits further studies to be clarified, it suggests a possible involvement of AEA in the mediation of the rewarding aspects of some aberrant eating behaviors.11 In another study, circulating endocannabinoid concentrations were measured in postmenopausal women who were lean or obese and in a second group of women who had a 5% weight loss.10 Circulating levels of both anandamide and 2-AG were significantly increased in obese compared with lean women (Figure 2).10 Circulating levels of endocannabinoids were not altered by a 5% weight loss.10 Matias et al.12 found that visceral, but not subcutaneous, adipose tissue from obese patients also contains significantly higher levels of the endocannabinoid 2-AG than the visceral fat from nonobese volunteers, thus paralleling the findings in mice with diet-induced obesity (Figure 3).12 Finally, elevated endocannabinoid levels were found also in the blood of nonobese patients with type 2 diabetes with respect to age-, BMI- and gender-matched normoglycemic volunteers.12


A population study in humans provided crucial practical insights into how increased activity of the ECS is associated with overweight and obesity.13 This study investigated the relationship between a relatively common missense polymorphism for the gene encoding FAAH and overweight/obesity in subjects of multiple ethnic backgrounds attending a medical screening clinic.13 The polymorphism studied occurs at chromosomal DNA encoding for FAAH, and involves a single substitution of the nucleotide adenine for cytosine.13 This leads to a substitution in the amino acids comprising FAAH, which may result in a functionally deficient protein (subjects with this polymorphism have approximately half the FAAH enzymatic activity of normal subjects).13

Results showed that, in the population screened, the overall frequency of the homozygous FAAH polymorphism genotype was 3.6% in Asian subjects, 3.7% in white subjects, and 10.8% in black subjects.13 Significantly more white and black subjects with this FAAH genotype were overweight or obese than normal weight.13 The median body mass index for all subjects was significantly greater in the homozygous FAAH polymorphism genotype group compared with subjects with a heterozygous or normal genotype.13 In white subjects, there was an increasing frequency of the homozygous FAAH polymorphism genotype with increasing body mass index categories of overweight and obesity, and the same was seen in black subjects but was significant only in the obese group.13 Taken together, these results suggest a role for the FAAH missense polymorphism as an endocannabinoid risk factor in overweight/obesity and provide indirect evidence to support the use of ECS antagonism in the treatment of overweight and obesity.13

The functional significance of ECS activity in metabolic disorders such as obesity indicates that pharmacologic agents that selectively block the metabolic actions of this system may be beneficial treatment strategies for these disorders. This hypothesis was confirmed in two recent large randomized, double-blind, placebo-controlled clinical trials of rimonabant (SR141716), termed Rimonabant In Obesity (RIO)-Europe and RIO-Lipids. Each study included over 1,000 randomized overweight or obese subjects with other metabolic and cardiovascular risk factors.14, 15

Figure 4
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At 1 year, weight loss with rimonabant 20 mg (6.6 and 6.9 kg reductions) was similar in both studies and was statistically significantly greater than the weight loss observed in the placebo groups (1.8 and 1.5 kg reductions) for the intent-to-treat population.14, 15 This does not include the approximate 2 kg lost by each treatment group during the diet run-in period that preceded randomization.14, 15 In both the RIO-Europe and RIO-Lipids trials, a clear divergence in the body weights of the rimonabant 20 mg and placebo groups was observed as early as the fourth week of treatment (Figure 4).14, 15

Overall, these large randomized, placebo-controlled clinical trials provide compelling evidence of the benefits of CB1 receptor blockade in the treatment of obesity. In these trials, weight loss with rimonabant was accompanied by improvements in cardiovascular risk parameters such as waist circumference, high-density lipoprotein cholesterol, triglycerides, and insulin resistance.14, 15 Thus, in obese individuals, weight loss mediated by rimonabant treatment may represent an important step toward global risk factor reduction.

Figures

Figure 1. Plasma levels of AEA (anandamide) (A) and 2-AG (B) in healthy women and in women with anorexia nervosa (AN), bulimia nervosa (BN), or binge eating disorder (BED). The mean body mass index (BMI kg/m2, expressed as mean ± SD) for the 4 groups of women was as follows: healthy women, BMI 22.2 ± 2.3; AN, 15.9 ± 1.6; BN, 21.1 ± 2.9; BED, 31.2 ± 6.2. Horizontal bars indicate mean values. From Monteleone et al.11

Figure 2. Plasma levels of AEA (anand­amide) and 2-AG in lean and obese postmenopausal women. *P <0.05 vs lean women. From Engeli.16

Figure 3. Endocannabinoid levels in the visceral adipose tissue of normoweight and overweight/obese subjects and in the subcutaneous fat of obese subjects. **, P ≤0.01 versus visceral fat from normoweight volunteers; ##, P < 0.01 versus visceral fat from subjects as assessed by the Kuskal-Wallis nonparametric test. From Matias et al.12

Figure 4. Effect of rimonabant 20 mg on body weight at 1 year. From Van Gaal LF et al14 and Després J-P et al.15

References

  1. NHLBI Obesity Education Initiative Expert Panel on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults-the evidence report. National Institutes of Health. Obes Res. 1998;6(Suppl 2):51S-209S. [Published erratum appears in Obes Res. 1998;6:464.]
  2. Fricke O, Lehmkuhl G, Pfaff DW. Cybernetic principles in the systematic concept of hypothalamic feeding control. Eur J Endocrinol. 2006;154:167-173.
  3. Aja S, Moran TH. Recent advances in obesity: adiposity signaling and fat metabolism in energy homeostasis. Adv Psychosom Med. 2006;27:1-23.
  4. Wiley JL, Burston JJ, Leggett DC et al. CB1 cannabinoid receptor-mediated modulation of food intake in mice. Br J Pharmacol. 2005;145:293-300.
  5. Cota D, Woods SC. The role of the endocannabinoid system in the regulation of energy homeostasis. Curr Opin Endocrinol Diabetes. 2005;12:338-351.
  6. Bensaid M, Gary-Bobo M, Esclangon A et al. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Molec Pharmacol. 2003;63:908-914.
  7. Fulton S, Richard D, Woodside B, Shizgal P. Interaction of CRH and energy balance in the modulation of brain stimulation reward. Behav Neurosci. 2002;116:651-659.
  8. Cvetkovic V, Brischoux F, Griffond B et al. Evidence of melanin-concentrating hormone-containing neurons supplying both cortical and neuroendocrine projections. Neuroscience. 2003;116:31-35.
  9. Fadel J, Deutch AY. Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience. 2002;111:379-387.
  10. Liu YL, Connoley IP, Wilson CA, Stock MJ. Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lepob/Lepob mice. Int J Obesity. 2005;29:183-187.
  11. Monteleone P, Matias I, Martiadis V, De Petrocellis L, Maj M, Di Marzo V. Blood levels of the endocannabinoid anandamide are increased in anorexia nervosa and in binge-eating disorder, but not in bulimia nervosa. Neuropsychopharmacology. Jun 2005;30(6):1216-1221.
  12. Matias I, Gonthier M-P, Orlando P et al. Regulation, function and dysregulation of endocannabinoids in models of adipose and β-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrin Metab. 2006;(e-pub):1-27.
  13. Sipe JC, Waalen J, Gerber A, Beutler E. Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH). Int J Obesity. 2005;29:755-759.
  14. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S, for the RIO-Europe Study Group. Effects of cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005;365:1389-1397.
  15. Després J-P, Golay A, Sjöström, for the Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353:2121-2134.
  16. Engeli S, Böhnke J, Feldpausch M et al. Activation of the peripheral endocannabinoid system in human obesity. Diabetes. 2005;54:2838-2843.
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