Correlation of Circulating Irisin and Adipokine Levels Across a Broad Spectrum of Body Mass Index Ranging From Undernourished to Obese and With Insulin Resistance and Risk Factors for the Metabolic Syndrome in Hispanic Children

Background Childhood obesity is one of the most serious global public health challenges of the 21st century (Daniels et al., 2009). Mexico has the highest prevalence of obesity, worldwide; 34.4% of children and 35% of adolescents are overweight or obese (ENSANUT 2012). Among other complications, overweight and obese children are predisposed to develop dyslipidemias, hypertension, the metabolic syndrome (MetS) and non-alcoholic fatty liver disease at a younger age, as well as to become obese as adults (Daniels et al., 2009; Elizondo-Montemayor et al., 2010). On the other hand, undernutrition in children conveys to very detrimental health effects such as stunting, puberty retardation, motor retardation (Roulet et al., 2005), osteoporosis and fractures (Saunders et al., 2011), immunologic deficit, and altered function of every organ and system, such as the heart, lungs, kidneys, gastrointestinal tract and the nervous system, among others (Lecours et al, 2001; Saunders et al., 2011).

A balance between energy intake and energy expenditure is required to sustain a normal body weight. Anything that disrupts this balance may cause individuals to be underweight, overweight or obese. Diverse signals, central and peripheric participate in the regulation of energy balance. Fat has been considered an endocrine organ due to the many peptides and hormones that it secrets that act upon peripheral and central tissues, and their contribution to insulin resistance or sensitivity and body weight regulation among other functions (Elizondo, 2011). Recently, skeletal muscle has been shown to function as a peripheral endocrine organ by releasing myokines, peptide signals, which are implicated in the regulation of metabolic pathways (Pedersen and Febbraio, 2012). Most recently, a new identified hormone secreted by muscle tissue in mouse, irisin, has been discovered. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. In mouse, PGC1alfa expression in muscle stimulates increase in expression of FNDC5, a membrane protein that is cleaved and secreted as this novel hormone, irisin. Irisin is induced with exercise in mice and humans, and medley increased irisin levels in blood cause an increase in energy expenditure in mice with no changes in movement or food intake (Boström et al., 2012).

Irisin was thus, promptly hypothesized as a hormone influencing body weight, obesity and type 2 diabetes mellitus, among other conditions (Sanchis-Gomar et al., 2012). Some studies have indicated that circulating levels of irisin in humans correlate positively with anthropometric parameters such as BMI, fat mass, fat free mass, and are higher as these parameters increase, this is, irisin levels are higher in obese patients compared to lean ones (Stengel et al., 2013; Huh et al., 2012; Roca-Rivada et al., 2013; Crujeiras et al., 2014; Pardo et al., 2014). Studies have shown an association between irisin levels, insulin resistance and the metabolic syndrome (Park et al., 2013; de la Iglesia et al., 2014; Crujeiras et al., 2014; Pardo et al., 2014). However, some others have found a negative correlation with anthropometric parameters, finding lower irisin levels in obese patients (Moreno-Navarrete et al., 2013). Noteworthy, all these studies have been performed in adults in different circumstances or diseased states. To date, there are only two studies evaluating irisin levels in children. One found that a 1-year long lifestyle intervention program was associated with improvement in anthropometric and metabolic parameters and led to an elevation in irisin levels in obese children, although no correlation was found between irisin levels and anthropometric markers (Blüher et al., 2014). The other study investigated normal weight Saudi children and found correlations between circulating irisin and glucose and HDLc, but a negative association with insulin resistance (Al-Daghri et al., 2014).

Besides, associations between irisin levels and adiponectin, leptin and resistin in the set of obesity have been explored. Leptin plays a pivotal role in regulating energy homeostasis, food intake and many neuroendocrine functions, specially triggering puberty in children. Leptin is increased in obese patients, associated with a leptin-resistant state (Blüher and Mantzoros, 2009). Adiponectin is an insulin sensitizing hormone; obese patients have lower levels than normal-weight ones. Circulating adiponectin levels are low in central obesity (Dalamaga et al., 2012), and this low level has been associated with the metabolic syndrome across all ages (Siitonen et al., 2011). Resistin has been associated with insulin resistance, and recently as a proinflamatory adipocytokine (McTernan et al., 2006). Some studies have found a negative correlation between irisin and adiponectin levels (Park et al., 2013), while other have found no association either with leptin or adiponectin (Blüher et al., 2014) here are still conflicting data regarding the association of irisin with anthropometric parameters, obesity and the metabolic syndrome, as well as its 'association with other adipokines, and most important, there is scarce data of these associations in children, the objective of this study will be to correlate the circulating irisin and adipokines levels across a broad spectrum of body mass index ranging from undernourished to obese as well as with insulin resistance and risk factors for the metabolic syndrome in Hispanic children.

There is still conflicting data regarding the association of irisin with anthropometric parameters, obesity and the metabolic syndrome, as well as its 'association with other adipokines, and most important, there is scarce data of these associations in children. Therefore, the objective of this study will be to correlate the circulating irisin and adipokines levels across a broad spectrum of body mass index ranging from undernourished to obese as well as with insulin resistance and risk factors for the metabolic syndrome in Hispanic children.