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Inhibition of the swallowing reflex by nesfatin-1 2 47 Abstract 48 49 Nesfatin-1, an 82-amino acid peptide encoded by the secreted precursor nucleobinin-2 50 (NUCB2), exerts potent anorexigenic action independently of leptin signaling. This propensity has 51 propelled this peptide and its analogues as potential anti-obesity drug candidates. However, a more 52 extensive comprehension of its biological actions is needed prior to envisaging its potential use in the 53 treatment of metabolic diseases. Swallowing is an essential motor component of ingestive behavior, 54 which induces the propulsion of the alimentary bolus from the mouth to the esophagus. The dorsal 55 swallowing group (DSG) which constitutes a part of the central pattern generator of swallowing 56 (SwCPG) is located within the solitary tract nucleus (STN), a region reported to contain nesfatin-57 1/NUCB2 expressing neurons. In this context, we investigate here the possible effects of nesfatin-1 58 on swallowing discharge. Nesfatin-1 dose-dependently inhibited swallowing reflex and activated 59 neurons located in the DSG region. In addition, we provide evidences that strongly suggest that this 60 nesfatin-1 inhibitory effect involved an oxytocinergic relay. Indeed, oxytocin (OT) injection at the 61 brainstem level inhibited swallowing reflex and OT receptor antagonist prevented nesfatin-1 62 inhibitory action. Altogether, these data constitute the first demonstration that nesfatin-1 modulates 63 swallowing reflex by acting at the brainstem level via an oxytocinergic relay. 64

Fe deficiency is relatively common in pregnancy and has both short- and long-term consequences. However, little is known about the effect on the metabolism of other micronutrients. A total of fifty-four female rats were fed control (50 mg Fe/kg) or Fe-deficient diets (7·5 mg/kg) before and during pregnancy. Maternal liver, placenta and fetal liver were collected at day 21 of pregnancy for Cu and Zn analysis and to measure expression of the major genes of Cu and Zn metabolism. Cu levels increased in the maternal liver (P=0·002) and placenta (P=0·018) of Fe-deficient rats. Zn increased (P<0·0001) and Cu decreased (P=0·006) in the fetal liver. Hepatic expression of the Cu chaperones antioxidant 1 Cu chaperone (P=0·042) and cytochrome c oxidase Cu chaperone (COX17, P=0·020) decreased in the Fe-deficient dams, while the expression of the genes of Zn metabolism was unaltered. In the placenta, Fe deficiency reduced the expression of the chaperone for superoxide dismutase 1, Cu chaperone for superoxide dismutase (P=0·030), ceruloplasmin (P=0·042) and Zn transport genes, ZRT/IRT-like protein 4 (ZIP4, P=0·047) and Zn transporter 1 (ZnT1, P=0·012). In fetal liver, Fe deficiency increased COX17 (P=0·020), ZRT/IRT-like protein 14 (P=0·036) and ZnT1 (P=0·0003) and decreased ZIP4 (P=0·004). The results demonstrate that Fe deficiency during pregnancy has opposite effects on Cu and Zn levels in the fetal liver. This may, in turn, alter metabolism of these nutrients, with consequences for development in the fetus and the neonate.

Iron is a key trace element, involved in different processes of metabolism such as respiration, energy production, DNA synthesis and cell proliferation. However, given its capacity for changing valency, it also has potential for toxicity at excessive levels. Consequently, a tight regulation of absorption and excretion has evolved.Many studies have examined the way other nutrients and micronutrients interact with iron metabolism. These interactions can be both direct and indirect. For example, vitamin C or cysteine and histidine can bind iron atoms, increasing bioavailability and increasing iron absorption [1][2][3]. Alternatively, copper deficiency can negatively impact iron flux from the liver by decreasing the expression of ceruloplasmin, required for iron incorporation into transferrin [4]. Nutrients that alter expression of some of the iron regulatory pathways can also modify iron metabolism [5]. These compounds have proved particularly valuable in elucidating the regulation of iron.Dietary iron is found in two forms; haem iron and non-haem (inorganic) iron. These two forms of iron have separate absorption mechanisms across the gut [6-8]. Haem iron is transported either by a haem AbstractIron (Fe) metabolism is modified by many nutritional factors. Amino acids (AA) play a central role in various biological processes, such as protein synthesis and energy supply. However, the influence of AA status on iron metabolism has not been investigated. Here, we test whether AA alters iron metabolism in an intestinal cell model. Both Fe uptake and transfer across the cell monolayer were significantly increased by non-essential AA deficiency (both p < 0.001) while only Fe transfer was increased by essential AA deficiency (p < 0.0001). Both essential and non-essential AA deficiency decreased DMT1 (±IRE) exon1A mRNA expression (respectively p = 0.0007 and p = 0.006) and increased expression of ferritin heavy chain. DMT1 + IRE (also expressing exon1A or 1B) mRNA levels were decreased by essential AA deficiency (p = 0.012). The mRNA levels of total DMT1 were also decreased by essential, but not non-essential, AA deficiency (p = 0.006). Hepcidin levels were increased significantly by non-essential amino acid deprivation (p = 0.047). Protein levels of ferroportin and/or ferritin heavy chain were not altered by AA deficiency, suggesting that they had no effect on Fe efflux or storage in the cell, though iron content of ferritin could be increased. Our data demonstrate, for the first time, that AA status affects iron transport and the expression of genes related to iron metabolism in Caco-2 cells, although the changes observed are not sufficient to explain the alteration in iron transport. We hypothesise that the effect on Fe transfer is mediated through an increased movement across the cell layer, rather than transfer across the cell membranes.

Iron deficiency is the most prevalent micronutrient deficiency worldwide and is believed to affect nearly 15 percent of pregnant women in the UK. Metabolic crossroads between iron and copper, another trace element that is essential for fetal growth, have been established for decades (1) but the effect of iron deficiency on copper metabolism during pregnancy is not fully understood. 54 Rowett Hooded female rats were fed control (50 mg iron/ kg, n = 30) or iron deficient diets (7.5 mg iron / kg, n = 24) for 4 weeks prior to mating and during pregnancy. Maternal liver, placenta and fetal liver were collected at day 21 of pregnancy for the measurement of copper levels and the gene expression of the main proteins involved in copper metabolism (Figure 1). Copper levels increased in the maternal liver (p = 0.002) and placenta (p = 0.018) of iron deficient rats while they decreased in the fetal liver (p = 0.006). Iron deficiency decreased the expression of the chaperone ATOX1 by −10.5% (p = 0.042) and cytochrome c oxidase chaperone (COX17) by −13.8% (p = 0.020) in the maternal liver, while COX17 was increased by 15.0% (p = 0.020) in the fetal liver. In iron deficient placenta, the copper chaperone for copper/zinc superoxide dismutase complex (CCS) decreased by −9.5% (p = 0.030) and ceruloplasmin (CP) by −15.0% (p = 0.042) compared to control (Table 1).