Hypothalamic redox balance and leptin signaling - Emerging role of selenoproteins

Abstract

The hypothalamus is the central neural site governing food intake and energy expenditure. During the past 25 years, understanding of the hypothalamic cell types, hormones, and circuitry involved in the regulation of energy metabolism has dramatically increased. It is now well established that the adipocyte-derived hormone, leptin, acts upon two distinct groups of hypothalamic neurons that comprise opposing arms of the central melanocortin system. These two cell populations are anorexigenic neurons expressing proopiomelanocortin (POMC) and orexigenic neurons that express agouti-related peptide (AGRP). Several important studies have demonstrated that reactive oxygen species and endoplasmic reticulum stress significantly impact these hypothalamic neuronal populations that regulate global energy metabolism. Reactive oxygen species and redox homeostasis are influenced by selenoproteins, an essential class of proteins that incorporate selenium co-translationally in the form of the 21st amino acid, selenocysteine. Levels of these proteins are regulated by dietary selenium intake and they are widely expressed in the brain. Of additional relevance, selenium supplementation has been linked to metabolic alterations in both animal and human studies. Recent evidence also indicates that hypothalamic selenoproteins are significant modulators of energy metabolism in both neurons and tanycytes, a population of glial-like cells lining the floor of the 3rd ventricle within the hypothalamus. This review article will summarize current understanding of the regulatory influence of redox status on hypothalamic nutrient sensing and highlight recent work revealing the importance of selenoproteins in the hypothalamus.

Keywords: Endoplasmic reticulum stress; Energy metabolism; Hypothalamus; Leptin; Obesity; Selenoprotein.

Figure 1. Overview of Selenium Metabolism and Transport in the Brain

SELENOP is transported across the blood-brain barrier upon binding to LRP2 or LRP8. Evidence suggests that a small molecule form of Se, presumably selenosugar, can also enter the brain. Within the brain, SELENOP is produced by astrocytes and these cells provide Se to adjacent neurons by secreting SELENOP. LRP8-mediated uptake of SELENOP is the principal route of Se supply to neurons, although alternative pathways exist. The Sec residues present in SELENOP are decomposed into selenide by SCLY. Selenide can then be reutilized for additional selenoprotein synthesis. Also shown are the selenoproteins most widely expressed in neurons, along with their subcellular localization.

Figure 2. Influence of Leptin on the Central Melanocortin System

Circulating leptin enters the median eminence (ME) via the fenestrated capillaries, is transported into the CSF by ObR-expressing tanycytes, and then acts upon AGRP and POMC neurons in the ARC. The effect of leptin upon POMC neurons is stimulatory, whereas it inhibits AGRP neurons. Activation of POMC neurons stimulates release of α-MSH in PVN, which in turn, acts upon the MC4R. The MC4R promotes anorexigenic responses, such as activation of downstream brain stem regions and secretion of CRH and TRH into the ME.

Figure 3. Summary of Leptin Signaling Pathways

Upon leptin (Ob) binding to the leptin receptor (ObR), JAK2 is phosphorylated. In turn, JAK2 phosphorylates two key tyrosine residues on the ObR that serve as docking sites for SHP2 (Tyr985) and STAT3 (Tyr1138), which leads to activation of the ERK and STAT3 pathways. Moreover, JAK2 also activates a parallel pathway involving IRS, PI3K, and AKT. When phosphorylated, STAT3 dimerizes and translocates to the nucleus, where it upregulates specific target genes, such as POMC and SOCS3. SOCS3 exerts negative feedback on leptin signaling by binding to Tyr985 of the ObR. Also shown is PTP1B, another negative regulator of leptin signaling that dephosphorylates JAK2.

Figure 4. TXNIP is a Focal Point for Crosstalk between ER Stress Signaling and the Thioredoxin System

ER stress-mediated activation of IRE1 and PERK leads to increased TXNIP mRNA levels. TXNIP promotes activation of the NLRP3 inflammasome and downstream secretion of IL1β. In parallel, TXNIP negatively regulates TXN and thereby promotes activation of an ASK1-JNK-c-Jun pro-apoptotic pathway. Also shown are TXNRD and NADPH, which are essential components of the TXN system that regenerate reduced TXN from its oxidized form.