"Mens sana in corpore sano": exercise and hypothalamic ER stress

Abstract

A novel mechanism explains how exercise exerts its beneficial effects on energy balance through an effect at the level of the hypothalamus.

Figure 1. Altered energy balance leads to obesity and metabolic disorders.

(A) When the quantity of energy absorbed by an animal (i.e., food intake) equals its energy expenditure (i.e., physical activity/exercise), the result is a neutral energy balance that permits body weight stability. In this situation lipids are stored in white adipose tissue (WAT). (B) An imbalance in either food intake or energy expenditure leads to increased body weight and obesity. In this context, the storage capacity of WAT may become saturated, which redirect lipids to be accumulated in peripheral organs such as liver, muscle, and pancreas. In a first step, these lipids are accumulated as triacylglycerols (TGs). When the storage capacity of these tissues is also saturated, excess of lipids, enters in alternative non-oxidative pathways that results in production of toxic reactive lipid species (such as diacylglycerols and ceramides) leading to tissue-specific damage, a process known as lipotoxicity.

Figure 2. ER stress and UPR signaling pathway.

Under optimal nutrient surplus of nutrients, the chaperone BiP remains associated to the luminal surface of ER with three UPR transducer proteins (ER stress sensors: IRE1, PERK, and ATF6), maintaining them inactive. Overnutrition and lipid excess (as well as other insults, such as hypoxia, radiation, oxidative stress, viral infections, etc.) lead to impairment of normal protein folding in the ER, resulting in accumulation of unfolded proteins. In this situation, BiP preferentially binds the misfolded proteins, liberating the ER stress sensors. Dimerization and auto-phosphorylation of IRE1 triggers its endoribonuclease activity to induce cleavage of XBP1 mRNA to its spliced form XBP1s, which upregulates genes encoding chaperones and genes encoding for proteosome machinery, controlling ER-associated degradation (ERAD). PERK is activated by homodimerization and auto-phosphorylation leading to phosphorylation eIF2α, which results in attenuation of general protein translation and increased transcription of ATF4, which will induce transcription of pro-apoptotic genes such as CHOP10. ATF6 released from BiP is translocated to Golgi complex where it is cleaved by S1P/S2P proteases, releasing the 50 KDa domain, that acts as a transcription factor of gene-encoding chaperones including BiP. The overall effect of these events is an adaptive program comprising four different sequential responses, depending on the grade and persistence of the stimulated ER stress cell: (1) a transcriptional and translational attenuation, which reduces synthesis of new proteins preventing further accumulation of misfolded proteins; (2) upregulation of genes encoding ER chaperones to increase protein folding in the ER and prevent aggregation of unfolded proteins; (3) if stimuli persists, proteosome machinery is increased by transcription induction of its genes improving ERAD; and (4) if all of its processes do not rescue the cell from the ER stress and if ER stress inducers persist, genes encoding cell death and apoptosis of the cell will be induced. ATF4 and 6: activating transcription factor 4 and 6; BiP: binding immunoglobulin protein, also known as GRP78, glucose regulated protein 78 KDa; CHOP10: C/EBP homologous protein, also known as DDIT3, DNA-damage inducible transcript 3; eIF2α: eukaryotic initiation factor 2α subunit; IRE1: inositol requiring enzyme 1; PERK: PKR-like ER kinase, also known as dsRNA-dependent protein kinase like ER kinase; S1P/S2P: site-1, site-2 proteases; XBP1: X-box binding protein 1; XBP1s: X-box binding protein 1, spliced.

Figure 3. Exercise and ER stress in hypothalamus.

Overnutrition increases hypothalamic activation of IKKβ/NF-κB and ER stress (they enhance each other), which leads to insulin and leptin resistance in the hypothalamus, hyperphagia, and obesity. Exercise reduces hypothalamic IKKβ/NF-κB activation and ER stress through a mechanism involving IL-6 and IL-10. As a result of this effect, insulin and leptin sensitivity, and consequently food intake, are restored. Whether hypothalamic lipotoxicity contributes to increased activation of IKKβ/NF-κB and ER stress will require further investigation. 3V: third ventricle; ARC: arcuate nucleus of the hypothalamus; DMH: dorsomedial nucleus of the hypothalamus; IKKβ/NF-κB: inhibitor of nuclear factor kappa-B kinase subunit beta/nuclear transcription factor kappa-B; LHA: lateral hypothalamic area; PVH: paraventricular nucleus of the hypothalamus; VMH: ventromedial nucleus of the hypothalamus.