The Role of Selenoprotein Tissue Homeostasis in MetS Programming: Energy Balance and Cardiometabolic Implications

Abstract

Selenium (Se) is an essential trace element mainly known for its antioxidant, anti-inflammatory, and anti-apoptotic properties, as it is part of the catalytic center of 25 different selenoproteins. Some of them are related to insulin resistance (IR) and metabolic syndrome (MetS) generation, modulating reactive oxygen species (ROS), and the energetic sensor AMP-activated protein kinase (AMPK); they can also regulate the nuclear transcription factor kappa-B (NF-kB), leading to changes in inflammation production. Selenoproteins are also necessary for the correct synthesis of insulin and thyroid hormones. They are also involved in endocrine central regulation of appetite and energy homeostasis, affecting growth and development. MetS, a complex metabolic disorder, can appear during gestation and lactation in mothers, leading to energetic and metabolic changes in their offspring that, according to the metabolic programming theory, will produce cardiovascular and metabolic diseases later in life. However, there is a gap concerning Se tissue levels and selenoproteins' implications in MetS generation, which is even greater during MetS programming. This narrative review also provides an overview of the existing evidence, based on experimental research from our laboratory, which strengthens the fact that maternal MetS leads to changes in Se tissue deposits and antioxidant selenoproteins' expression in their offspring. These changes contribute to alterations in tissues' oxidative damage, inflammation, energy balance, and tissue function, mainly in the heart. Se imbalance also could modulate appetite and endocrine energy balance, affecting pups' growth and development. MetS pups present a profile similar to that of diabetes type 1, which also appeared when dams were exposed to low-Se dietary supply. Maternal Se supplementation should be taken into account if, during gestation and/or lactation periods, there are suspicions of endocrine energy imbalance in the offspring, such as MetS. It could be an interesting therapy to induce heart reprogramming. However, more studies are necessary.

Keywords: cardiovascular disease; fetal programming; metabolic syndrome; selenium; selenoprotein.

Figure 1

Selenoproteins’ possible implication in the hepatic insulin signaling pathway. The binding of insulin to the insulin receptor (IR) triggers consecutive phosphorylation (P) of downstream signaling molecules, resulting in activation of Akt. Additionally, NADPH oxidase (NOX)-mediated ROS production is stimulated by insulin. Reduction of H₂O₂ by GPx1 may attenuate insulin signaling, as H₂O₂ is required to inactivate the insulin counter-regulatory phosphatases PTP-1B and PTEN. Moreover, SelP could inhibit adenosine monophosphate-activated protein kinase (AMPK), a metabolic energy sensor, which negatively regulates protein synthesis through the inhibition of the mammalian target of rapamycin (mTOR)-S6 kinase (S6K) pathway, which also modulates IRS phosphorylation. (IRS: insulin receptor substrate; PIP2: phosphatidylinositol 4,5-bisphosphate; PIP3: phosphatidylinositol 3,4,5-trisphosphate; TSC1 and 2: tuberous sclerosis complex 1 and 2).

Figure 2

Schematic representation of endogenous antioxidant enzyme systems, the effect of the selenoprotein GPxs against the formed ROS. MetS implication in ROS generation. SOD: superoxide dismutase; GPx: glutathione peroxidase; CAT: catalase; GR: glutathione reductase; GSH: reduced glutathione; GSSG: oxidized glutathione; MDA: malondialdehyde.

Figure 3

Maternal selenium status and metabolic programming. Effects of maternal Se diet on their offspring: nutritional-morphological parameters and oxidative balance; biochemical parameters; hepatic selenoproteins’ expression and metabolic programming results. SS: selenium supplemented dams (0.5 ppm); SD: selenium deficient dams (0.01 ppm). MI: milk intake, BW: body weight; BMI: body mass index, GR: growth retardation, GPx: glutathione peroxidase, TGs: triglycerides, GLP1: glucagon-like peptide-1, TSH: thyroid-stimulating hormone, Chol: cholesterol, Gluc: glucose, MSI: intestinal mucosa somatic index, PYY: peptide YY, GIP: gastric inhibitory polypeptide, TSI: thyroid somatic index, PTH: parathyroid hormone, OPN: osteopontin, SelP: selenoprotein P, AMPK: AMP-activated protein kinase, IRS-1: insulin receptor substrate 1, HOMA-IR: homeostatic model assessment for insulin resistance, IR: insulin resistance, T2DM: type 2 diabetes mellitus, T1DM: type 1 diabetes mellitus, PSI: pancreas somatic index, ↑: increase, ↓: decrease.

Figure 4

Selenium homeostasis in MetS programming: results in dams and in their offspring. Se intake, excretion, serum concentration, and tissue deposits were analyzed in dams (during gestation process: GP and lactation process: LP) and in their breastfeeding pups (lactating offspring: LO); together with gestational parameters (FFI: female fertility index (nº of pregnancies/nº of mating) × 100, GI: gestational index (nº of successful births/nº of pregnancy rats) × 100) and lactating parameters (LBI: live-born index (nº of pups born alive/nº of pups born) × 10, LSI: lactation survival index (nº of total offspring/nº of dead offspring/nº of total offspring) × 100, and A/T ratio: (abdominal circumference/thoracic circumference) × 100), ↑: increase, ↓: decrease.

Figure 5

MetS programming and selenoprotein expression: pathophysiological implications. Liver, kidney, and heart Se deposits and selenoproteins (GPx1, GPx3, GPx4, and SelP) expression in breastfeeding MetS-exposed pups are affected in a different way, however, in the three tissues, OS was established. These selenoproteins’ imbalance is related to changes in ROS (H₂O₂) generation and OS, in nuclear factor kappa-B (NF-kB) expression and inflammation and fibrosis, and in AMP-activated protein kinase (AMPK) expression and energy cellular balance, in part related to pathophysiological alterations such as insulin resistance (IR) and liver steatosis, low glomerular filtration rate (GFR), hyperaldosteronemia, hypernatremia, high systolic blood pressure (SBP), cardiomegaly, and high heart rate. OS: oxidative stress, SOD: superoxide dismutase, CAT: catalase, GR: glutathione reductase, GPx: glutathione peroxidase, GSH: reduced glutathione, GSSG: oxidized glutathione, ↑: increase, ↓: decrease.

Figure 6

MetS programming and Se in peripheric endocrine signals related to energy balance. MetS exposition provokes changes in anorexigenics (PYY: peptide YY, leptin, and insulin) endocrine signals. Pups present lower milk intake, lower weight gain and length, and higher catabolism, pointing to the leptin resistance process. Hepatic IR process is taking place; however, in serum only triglycerides (TGs) levels are increased. In these processes, Se and selenoproteins (up- or down-regulated) could be implicated, since, in the gastrointestinal tract, pancreas, white adipose tissue (WAT), arcuate nucleus (ARC), and liver, Se and selenoproteins play an important antioxidant role. See text for more information. GIP: gastric inhibitory polypeptide, GLP-1: glucagon-like peptide-1, PSI: pancreas somatic index, BW: body weight, WAT: white adipose tissue, BAT: brown adipose tissue, CCL: cranium–caudal length, Gluc: glucose, Chol: cholesterol, ↑: increase, ↓: decrease.