**1. Introduction**

Perilipins are proteins that coat intracellular lipid droplets [1,2] and play a central role in lipid storage and mobilization. Non-phosphorylated perilipin protects the lipid core from the activity of lipases, such as hormone-sensitive lipase (HSL), which hydrolyze triglycerides into glycerol and fatty acids, preventing basal lipolysis and promoting cellular triglyceride storage by limiting lipase access to triglyceride stores [3–5]. Once phosphorylated, however, perilipin allows lipases to access lipid droplets and, hence, causes active lipolysis. Thus, the activity of perilipin may play a role in body weight and lipid metabolism by regulating adipocyte metabolism, fat storage, and lipolysis [6].

The most widely studied member of the family, perilipin 1 (PLIN1), is the most abundant protein on the surface of adipocyte lipid droplets and the major substrate for the cAMP-dependent protein kinase [7]. The human *PLIN1* gene is found at chromosomal location 15q26.1 [8]. It has been shown to be a susceptibility locus for obesity and hypertriglyceridemia [9]. In fact, some studies have shown that common polymorphisms in the *PLIN1* gene are associated with obesity risk and obesity-related phenotypes [10–12].

**Citation:** Vales-Villamarín, C.; Lumpuy-Castillo, J.; Gavela-Pérez, T.; de Dios, O.; Pérez-Nadador, I.; Soriano-Guillén, L.; Garcés, C. Sex-Dependent Mediation of Leptin in the Association of Perilipin Polymorphisms with BMI and Plasma Lipid Levels in Children. *Nutrients* **2022**, *14*, 3072. https:// doi.org/10.3390/nu14153072

Academic Editor: Carlos Diéguez González

Received: 1 June 2022 Accepted: 22 July 2022 Published: 26 July 2022

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Furthermore, *PLIN1* single-nucleotide polymorphisms (SNPs) have also been related to variability in weight loss [12–15]. However, several analyses of the associations between these polymorphisms and body weight and BMI have reported divergent results [16]. A polymorphism in *PLIN2*, another member of the family involved in the formation of lipid droplets, has also been shown to affect the structure and function of the protein. A substitution of serine by proline at the 251 position results in an altered protein structure and a reduction in lipolysis and plasma triglycerides [17,18].

To our knowledge, no studies have investigated the association of the *PLIN* SNPs in a general population of children. A couple of studies in children have focused on specific populations, such as obese children or children in a weight loss intervention [19,20]. Thus, limited evidence is available for Caucasian pre-pubertal children regarding the possible association of these SNPs with obesity-related alterations.

Significant gene–diet interactions involving these *PLIN* SNPs have been reported [21–24], suggesting that nutritional status may modify the association of *PLIN* polymorphisms with these traits. Leptin levels can be considered a good indicator of nutritional status [25].

Leptin, a hormone consistently related to obesity and obesity-related alterations [26], has been shown to exert direct and indirect effects on adipocyte metabolism [27]. As adipocytes express leptin receptors, leptin may influence adipocyte metabolism directly, triggering lipolysis via a lipolytic pathway mediated by cAMP, protein kinase A, perilipin, and HSL. Indeed, cAMP activates the protein kinase A, which is then able to phosphorylate cellular proteins, such as perilipin and HSL. Phosphorylated perilipin may activate HSL function, hydrolyzing triglycerides into glycerol and fatty acids [28,29].

In our study, we aimed to investigate, the association of body mass index (BMI) and plasma lipid levels with several *PLIN1* SNPs (11482G > A (rs894160), 13041A > G (rs2304795), and 14995A > T (rs1052700)) and with the *PLIN2* SNP Ser251Pro (rs35568725) in a large, population-based cohort of Spanish prepubertal children aged between 6 and 8 years. The SNPs selected have been associated with obesity-related phenotypes in adults, but they have not been previously studied in a cohort of children. In addition, we aimed to explore whether leptin modulates the effect of these polymorphisms.

### **2. Materials and Methods**
