This present case- control study demonstrated that the normal birth weight had preventive role on up-regulated expression level of MTNR1B, NTRK2, PCSK1, and PTEN genes, while the expression level of PPAR-a gene was significantly down regulated in the LBW infants compared to the infants with normal birth weight. LBW infants are at higher risk for obesity, neurodevelopment failure, cardiovascular disease, and other metabolic disorders [20]. Birth weight is considered as a suitable indicator for the quality of fetal growth and a predictor of health throughout life [20, 21]. To best our knowledge, this current study was evaluated the association between birth weight and obesity and diabetes gene expression in healthy infants.
Our findings indicated that the birth weight was associated with up-regulated the expression level of MTNR1B. Holzapfel et al. [22] observed that the MTNR1B was associated with diabetes in children and adolescents. Another study by Lianget al. [23] showed that maternal MTNR1B genotype involved in the etiology of childhood obesity. Recently, the MTNR1B has been shown to increase the risk of obesity and type 2 diabetes [22, 24]. It is also highly expressed in retinal cells, pancreas and especially pancreatic islet cells. Melatonin is a neurohormone secreted by pineal gland which can adjust the circadian rhythm and the circadian rhythm regulates the insulin level. However, melatonin secretion is impaired in diabetics [24].
We also indicated up-regulated the expression level of the NTRK2 with increasing of the birth weight. In study by Metrustry et al. variants in the NTRK2 gene and birth weight were examined. This study was showed that this gene was highly expressed in LBW twins [25]. NTRK2 is located on 9q21.33. NTRK2 encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family that is a membrane-bound receptor for BDNF and regulates energy balance downstream of MC4R. Also it involved (involves) in MAPK pathway and cell differentiation [26]. Mutations of NTRK2 have been associated with obesity and eating behavior [25, 27].
In current study the expression level of the PCSK1 was up-regulated in the LBW infants. Ruiz-Narváez et al. showed that LBW plays a role the expression level of the PCSK1 by disrupting central nervous system mechanisms and increases obesity in adulthood [28]. PCSK1 which is located on 5q15 encodes a prohormone convertase 1/3 (PC 1/3) that involved in pro-insulin processing under influencing of TCF7L2 [29]. As well as PCSK1 is involved in the processing of pro-opiomelanocortin, proglucagon, proGnRH and proTRH. In addition, PCSK1 variants are associated with extreme obesity, impaired glucose tolerance, and poly cystic ovarian syndrome. Rare mutations in PCSK1 cause childhood obesity, impaired prohormone processing and abnormal glucose homeostasis with increasing proinsulin concentrations [28, 30].
In present study, another up-regulated the expression level of gene was related to the PTEN gene. In study by Li et al. [31] the high expression level of gene PTEN was associated with increase of insulin resistance. Although the gene was first identified as a tumor suppressor, it has recently been shown to be important with its antagonistic function in the insulin signaling cascade and is involved in glucose metabolism [32]. PTEN is a phosphatase which plays role in signaling pathway and suppression of tumor in which is able to suppress phosphatidylinositol 3-kinase (PI3K) signaling [10, 11, 13]. Since activation of PI3K is essential for insulin performance, PTEN is known to be effective in development of insulin resistance by reducing PI3K [33].
On the other hand, we observed that the expression level of PPAR-a gene was significantly down regulated in the LBW infants. Laleh et al. [34] demonstrated that the high expression level of PPAR-a suppressed appetite in obesity. Priego et al. [35] showed that the higher expression level of PPAR-α gene in infants is associated with a lower risk of overweight. PPAR-a is a group of legend activated nuclear receptors that are mainly expressed in tissues that are vital for fatty acid metabolism, such as the liver, kidney, and heart, where they play an important role in regulating transcription of fatty acid metabolism, lipid homeostasis, and regulation of obesity [36]. During times of starvation and energy depletion, the PPAR-α increases fatty acids beta-oxidation. Animal study showed that PPAR-a deficiency was related with obesity and dyslipidemia [18].
Limitations
This current study was the first case- control study on birth weight and obesity and diabetes gene expression in healthy infants. However, it suffered from some limitations. The sample size was small due to economic constraints. Second, although we controlled many infants and maternal factors between the two groups, there was difference between the two groups because many infants in the control group were preterm in term of pregnancy weight gain and current weight infants.