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Interleukin-15, IL-15 Receptor-Alpha, and Obesity: Concordance of Laboratory Animal and Human Genetic Studies

DOI: 10.1155/2011/456347

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Interleukin-15 (IL-15) is a cytokine which inhibits lipid deposition in cultured adipocytes and decreases adipose tissue deposition in laboratory rodents. In human subjects, negative correlations between circulating IL-15 levels and both total and abdominal fat have been demonstrated. Deletions of IL15 in humans and mice are associated with obesity, while gain-of-function IL-15 overexpressing mice are resistant to diet-induced obesity. IL-15 is highly (but not exclusively) expressed at the mRNA level in skeletal muscle tissue, and the regulation of IL-15 translation and secretion is complex. Conflicting evidence exists concerning whether circulating IL-15 is released from skeletal muscle tissue in response to exercise or other physiological stimuli. The IL-15 receptor-alpha (IL-15Rα) subunit has a complex biochemistry, encoding both membrane-bound and soluble forms which can modulate IL-15 secretion and bioactivity. The gene encoding this receptor, IL15RA, resides on human chromosome 10p, a location linked to obesity and type-2 diabetes. Several single-nucleotide polymorphisms (SNPs) in human IL15RA and IL15 correlate with adiposity and markers of the metabolic syndrome. Genetic variation in IL15RA may modulate IL-15 bioavailability, which in turn regulates adiposity. Thus, IL-15 and the IL-15Rα may be novel targets for pharmacologic control of obesity in the human population. 1. Introduction The increased incidence of obesity in both developed and developing nations is a major public health problem [1]. Altered energy balance resulting in obesity is believed to be causal in the development of the metabolic syndrome and type-2 diabetes mellitus, conditions whose incidence is also rising at alarming rates [2, 3]. The economic burden of obesity and diabetes in the U.S. is currently in excess of $200 billion annually, and it is expected to rise [1]. Diet and lifestyle modifications are often unsuccessful in reducing obesity [4–6], and presently available pharmacologic treatments are problematic due to serious adverse effects [7]. Therefore, research involving novel pathways to control adiposity is warranted. Here, evidence that interleukin-15 (IL-15) can inhibit adipose tissue deposition in both laboratory animals and human subjects will be reviewed. Additionally, the complex regulation of IL-15 expression and secretion will be summarized. The specific receptor for IL-15, IL-15 receptor-alpha (IL-15Rα), appears to regulate IL-15 secretion, stability, and activity [8, 9]. Several single-nucleotide polymorphisms (SNPs) in human IL15 and IL15RA have been

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