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Department of Pharmacology (H.-G.J.), German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany and Department of Psychiatry (M.H.T.), Obesity Research Centre and Genome Research Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237
Address all correspondence and requests for reprints to: Dr. Hans-Georg Joost, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany. E-mail: joost{at}mail.dife.de.
Nitric oxide (NO) is a free radical gas that acts as a pleiotropic transmitter in many diverse functions (1). Most importantly, its production by endothelial NO synthase (eNOS) mediates vasodilation and inhibits thrombocyte aggregation. In other cells such as immune cells or neurons, NO is produced by the inducible NO synthase (iNOS) and neuronal NO synthase (nNOS), and mediates an inflammatory response or acts as an atypical neurotransmitter, respectively. Furthermore, it was suggested that NO plays an important role in the regulation of energy balance because administration of the nonspecific NO synthase inhibitor N-nitro-L-arginine-methyl ester (L-NAME) reduced weight gain and food intake in mice (2). In nNOS-knockout mice, the appetite-suppressant activity of leptin was markedly reduced, suggesting that NO is a downstream signal of leptin (3). Because deletion of the iNOS protected mice against high-fat diet-associated insulin resistance (4), it was also suggested that NO ("nitrosative stress") is a player in the pathogenesis of insulin resistance (5). However, such a link between NO and insulin sensitivity is not consistent with studies in eNOS knockout mice, in which deletion of one allele led to reduced insulin sensitivity in response to a high-fat diet (6), and with the concept that endothelial dysfunction is reciprocal to insulin sensitivity (7). Such unresolved inconsistencies may be the reason why NO has not yet made its way into the current textbooks as a major player in the regulation of adiposity and insulin sensitivity or a pathogenetic factor for obesity and diabetes.
The report by Tsuchiya et al. (8) in this issue of Endocrinology readdresses the role of NO in the regulation of energy balance, supports the view that NO synthase is involved in this process, and offers potential mechanistic links with obesity and diabetes. The authors show that a chronic application of the established NO synthase inhibitor L-NAME significantly reduced body weight gain in mice. Intriguingly, this effect was larger in mice on a high-fat diet; here, L-NAME markedly reduced the volume of fat cells as well as triglyceride accumulation. Consistent with this phenomenon, L-NAME reversed the detrimental effects of the high-fat diet on hepatic triglyceride content, glucose tolerance, and in vivo insulin sensitivity. The authors conclude that these effects are due to increased energy dissipation because L-NAME elevated the mRNA levels of uncoupling proteins 1 and 3 in muscle and brown adipose tissue, respectively. Most interestingly, L-NAME also increased the expression of peroxisome proliferator-activated receptor 
in muscle. This transcription factor has recently been shown to be of central importance for fat oxidation in muscle (9). In addition, generation of NO in mitochondria by the mitochondrial NO synthase reduces respiration and oxygen consumption (10). Thus, it appears reasonable to assume that the primary effect of a chronic inhibition of NO production by L-NAME is an enhanced oxidation of fatty acids (Fig. 1
).
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Enzymes whose inhibition reduces high-fat induced adiposity and insulin resistance are potential targets for a pharmacological intervention in obesity. Unfortunately, global inhibition of NO synthesis will lead to undesired cardiovascular and other side effects. In the present study, L-NAME produced a substantial increase of blood pressure, from 112–144 mm Hg, and a compensatory reduction in heart rate. Such side effects would certainly represent a difficult obstacle for a chronic drug therapy of obesity. Thus, without dissociation of the vascular effects from those on energy balance, possibly by a selective and tissue-specific inhibition of iNOS in muscle and/or adipose tissue, it is hard to envision a therapeutic benefit of this approach.
After the discovery of leptin more than 10 yr ago, obesity research has been one of the fastest moving fields, and has provided a large body of knowledge as to the neuroendocrine and hormonal control of hunger, satiety, and energy expenditure (12). Furthermore, a substantial number of genes involved in the regulation of fat storage has been identified through their knockout phenotypes. In contrast, there is much less progress in the search for new therapeutics of obesity, and very few "druggable" targets have been identified so far. The few candidates that made it through large clinical trials, such as cannabinoid receptor antagonists, struggle due to their limited efficacy, potential side effects, and small therapeutic window. However, the report by Tsuchiya et al. (8) reminds us that a large number of unknown or untested antiobesity targets exists, awaiting detailed examination. From genome-wide mutagenesis or knockout screens in Drosophila melanogaster or Caenorhabditis elegans, respectively, we can estimate that the total number of genes involved in the regulation of energy balance is in the hundreds (13, 14). Data from mice are consistent with this estimate. A recent metaanalysis of genome-wide searches for susceptibility loci (quantitative trait loci) indicated that at least 50 chromosomal segments have already been identified that harbor alleles associated with adiposity or leanness (15). Identification of these by positional cloning is difficult and time consuming but appears feasible based on rapidly evolving technology (16). Furthermore, genome-wide association studies in humans carry the potential to lead to new insights into the mechanisms of triglyceride storage; proof of principle has been provided by the recent discovery of the fat mass and obesity associated (FTO) gene (17). Thus, identification and examination of druggable targets of antiobesity therapy remain to be high-hanging fruits. However, in the face of the threat posed by the rapidly increasing incidence of obesity and diabetes, we certainly cannot afford to wait for them to fall into our lap.
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Footnotes |
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Abbreviations: eNOS, Endothelial NO synthase; iNOS, inducible NO synthase; L-NAME, N-nitro-L-arginine-methyl ester; nNOS, neuronal NO synthase; NO, nitric oxide.
Received June 27, 2007.
Accepted for publication July 9, 2007.
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: a dagger in the heart of the metabolic syndrome. J Clin Invest 116:590–597[CrossRef][Medline]This article has been cited by other articles:
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  J. R. Gayen, M. Saberi, S. Schenk, N. Biswas, S. M. Vaingankar, W. W. Cheung, S. M. Najjar, D. T. O'Connor, G. Bandyopadhyay, and S. K. Mahata A Novel Pathway of Insulin Sensitivity in Chromogranin A Null Mice: A CRUCIAL ROLE FOR PANCREASTATIN IN GLUCOSE HOMEOSTASIS J. Biol. Chem., October 16, 2009; 284(42): 28498 - 28509. [Abstract] [Full Text] [PDF]
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