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Induced by overfeeding, hepatic steatosis is a process exploited for the “foie gras” production in mule ducks. To better understand the mechanisms underlying its development, the physiological responses of mule ducks overfed with corn for a duration of 11 days were analyzed. A kinetic analysis of glucose and lipid metabolism and cell protection mechanisms was performed on 96 male mule ducks during overfeeding with three sampling times (after the 4th, the 12th, and the 22nd meal). Gene expression and protein analysis realized on the liver, muscle, and abdominal fat showed an activation of a cholesterol biosynthetic pathway during the complete overfeeding period mainly in livers with significant correlations between its weight and its cholesterolemia ( r = 0.88; P < 0.0001) and between the liver weight and the hmgcr and soat1 expression ( r = 0.4, P < 0.0001 and r = 0.67; P < 0.0001, respectively). Results also revealed an activation of insulin and amino acid cells signaling a pathway suggesting that ducks boost insulin sensitivity to raise glucose uptake and use via glycolysis and lipogenesis. Cellular stress analysis revealed an upregulation of key autophagy-related gene expression atg8 and sqstm1( P < 0.0001) during the complete overfeeding period, mainly in the liver, in contrast to an induction of cyp2e1( P < 0.0001), suggesting that autophagy could be suppressed during steatosis development. This study has highlighted different mechanisms enabling mule ducks to efficiently handle the starch overload by keeping its liver in a nonpathological state. Moreover, it has revealed potential biomarker candidates of hepatic steatosis as plasma cholesterol for the liver weight.

Embryonic thermal programming has been shown to improve foie gras production in overfed mule ducks. However, the mechanisms at the origin of this programming have not yet been characterized. In this study, we investigated the effect of embryonic thermal manipulation (+1°C, 16 h/24 h from embryonic (E) day 13 to E27) on the hepatic expression of genes involved in lipid and carbohydrate metabolisms, stress, cell proliferation and thyroid hormone pathways at the end of thermal manipulation and before and after overfeeding (OF) in mule ducks. Gene expression analyses were performed by classic or high throughput real-time qPCR. First, we confirmed well-known results with strong impact of OF on the expression of genes involved in lipid and carbohydrates metabolisms. Then we observed an impact of OF on the hepatic expression of genes involved in the thyroid pathway, stress and cell proliferation. Only a small number of genes showed modulation of expression related to thermal programming at the time of OF, and only one was also impacted at the end of the thermal manipulation. For the first time, we explored the molecular mechanisms of embryonic thermal programming from the end of heat treatment to the programmed adult phenotype with optimized liver metabolism.

Kinetic study of the expression of genes related to hepatic steatosis, global intermediate 1 metabolism and cellular stress during overfeeding in mule ducks 2 3 ABSTRACT 24 25 Induced by overfeeding, hepatic steatosis is a reversible process exploited for "foie gras" 26 production. To better understand the mechanisms underlying this non-pathological 27 phenomenon, we analysed the physiological responses of the mule duck to cope with 22 28 carbohydrate meals. A kinetic analysis of intermediate metabolism and cell protection 29 mechanisms was performed during overfeeding. As expected, dietary carbohydrates are up 30 taken mainly by the liver (chrebp, glut1/2/8) and converted into lipids (acox, scd1, acsl1, fas, 31 dgat2). Our study showed an activation of cholesterol biosynthetic pathway with significant 32 correlations between plasma cholesterol, expression of key genes (hmgcr, soat1) and liver 33 weight. Results revealed an activation of insulin and amino acid cell signalling pathway 34 suggesting that ducks boost insulin sensitivity to raise glucose uptake and use via glycolysis 35 and lipogenesis. Expression of cpt1a, acad, hadh suggested an induction of beta-oxidation 36 probably to remove part of newly synthesized lipids and avoid lipotoxicity. Cellular stress 37 analysis revealed an upregulation of autophagy-related gene expression (atg8, atg9, sqstm1) in 38 contrast with an induction of cyp2e1 suggesting that autophagy could be suppressed. Lamp2a 39 and plin2 enhanced, conflicting with the idea of an inhibition of lipophagy. Hsbp1 40 overexpression indicated that mechanisms are carried out during overfeeding to limit cellular 41 stress and apoptosis to prevent the switch to pathological state. Atf4 and asns overexpression 42 reflects the nutritional imbalance during overfeeding. These results permitted to highlight the 43 mechanisms enabling mule ducks to efficiently handle the huge starch overload and reveal 44 potential biomarker candidates of hepatic steatosis as plasma cholesterol for liver weight. 45