Maternal fructose boosts the effects of a Western-type diet increasing SARS-COV-2 cell entry factors in male offspring

Abstract

Fructose-rich beverages and foods consumption correlates with the epidemic rise in cardiovascular disease, diabetes and obesity. Severity of COVID-19 has been related to these metabolic diseases. Fructose-rich foods could place people at an increased risk for severe COVID-19. We investigated whether maternal fructose intake in offspring affects hepatic and ileal gene expression of proteins that permit SARS-CoV2 entry to the cell. Carbohydrates were supplied to pregnant rats in drinking water. Adult and young male descendants subjected to water, liquid fructose alone or as a part of a Western diet, were studied. Maternal fructose reduced hepatic SARS-CoV2 entry factors expression in older offspring. On the contrary, maternal fructose boosted the Western diet-induced increase in viral entry factors expression in ileum of young descendants. Maternal fructose intake produced a fetal programming that increases hepatic viral protection and, in contrast, exacerbates fructose plus cholesterol-induced diminution in SARS-CoV2 protection in small intestine of progeny.

Keywords: ACE2, angiotensin-converting enzyme 2; ADAM17, ADAM metallopeptidase domain 17; Cholesterol; Fetal programming; Fructose; HDL, high-density lipoprotein; HFCS, high fructose corn syrup; Ileum; Liver; MetS, metabolic syndrome; NAFLD, non-alcoholic fatty liver disease; SARS-CoV-2; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; SRB1, HDL-scavenger receptor B type 1; SSB, sugar-sweetened beverages; T2DM, type 2 diabetes; TMPRSS2, transmembrane protease serine 2.

Graphical abstract

Fig. 1

Cell surface receptors and cofactors facilitating SARS-CoV-2 entry. Canonical pathway occurs by binding to the cell surface receptor angiotensin-converting enzyme 2 (ACE2) and then, the transmembrane protease serine 2 (TMPRSS2) cleaves the viral spike protein, allowing fusion of cellular and viral membranes. Non-canonical pathways would involve other proteases: Cathepsin L, ADAM metallopeptidase domain 17 (ADAM17) or furin; and receptors: neuropilin-1 or HDL-scavenger receptor B type 1 (SRB1). SRB1 alone or in collaboration with HDL augments SARS-CoV-2 attachment and then, host cell entry is completed through ACE2 interaction. The neuropilin and furin collaboration would be an alternative entry to SARS-CoV-2 to that made by the ACE2 and TMPRSS2 cooperation. ADAM17 does cleave ACE2, and releases a soluble form of ACE2 that can interact with SARS-CoV-2 and mediate its entry to the cell. This image has been created using Servier Medical Art (https://smart.servier.com).

Fig. 2

Fructose in pregnancy affects hepatic cell surface receptors and cofactors facilitating SARS-CoV-2 entry in adult male progeny. (A) Experimental design. Hepatic levels of specific mRNA for (B) TMPRSS2, (C) neuropilin-1, (D) furin, (E) ADAM17, (F) cathepsin L, and (G) SRB1 genes of 261-day-old male progeny from control (empty bar), fructose-fed (black bar) and glucose-fed (grey bar) pregnant rats. Relative target gene mRNA levels were measured by Real Time PCR as explained in Materials and Methods, normalized to Rps29 levels and expressed in arbitrary units (a.u.). Data are means ± S.E. from 5 to 6 litters. Values not sharing a common letter are significantly different (P < 0.05). TMPRSS2: transmembrane protease serine 2; ADAM17: ADAM metallopeptidase domain 17; SRB1: HDL-scavenger receptor B type 1. E: embryonic/fetal days (E21: delivery); P: postnatal days.

Fig. 3

Liquid fructose in gestation exacerbates fructose-induced augmentation of hepatic TMPRSS2 expression in adult male progeny. (A) Experimental design. Hepatic levels of specific mRNA for (B) TMPRSS2, (C) neuropilin-1, (D) furin, (E) ADAM17, (F) cathepsin L, and (G) SRB1 genes. Liver (mRNA) expression of fructose-fed male adult progeny from control (C/F, light grey bar), fructose- (F/F, black bar), and glucose-supplemented (G/F, dark grey bar) mothers. C/C: Control 261-day-old male offspring from control pregnant rats (empty bar, C/C). Relative target gene mRNA levels were measured by Real Time PCR as explained in Materials and Methods, normalized to Rps29 levels and expressed in arbitrary units (a.u.). Data are means ± S.E. from 5 to 6 litters. Values not sharing a common letter are significantly different (P < 0.05). TMPRSS2: transmembrane protease serine 2; ADAM17: ADAM metallopeptidase domain 17; SRB1: HDL-scavenger receptor B type 1. E: embryonic/fetal days (E21: delivery); P: postnatal days.

Fig. 4

Fructose and fructose plus cholesterol affect hepatic cell surface receptors and cofactors facilitating SARS-CoV-2 entry in young male progeny. (A) Experimental design. Hepatic levels of specific mRNA for (B) TMPRSS2, (C) neuropilin-1, (D) furin, (E) ADAM17, (F) cathepsin L, and (G) SRB1 genes. Liver (mRNA) expression from control (C, empty bar), fructose- (F, light grey bar), and fructose plus cholesterol-supplemented (FCho, dark grey bar) young male progeny from Control (left panel) or Fructose-fed (right panel) mothers. Relative target gene mRNA levels were measured by Real Time PCR as explained in Materials and Methods, normalized to Rps29 levels and expressed in arbitrary units (a.u.). Data are means ± S.E. from 7 to 8 litters. Asterisks denote a significant difference (*, P < 0.05; **, P < 0.01; ***, P < 0.001) between the groups under the crossbar (groups with a different diet but the same motheŕs diet). Hash symbols denote a significant difference (#, P < 0.05; ##, P < 0.01; ###, P < 0.001) as compared to the Control mothers (groups with the same diet but different motheŕs diet). TMPRSS2: transmembrane protease serine 2; ADAM17: ADAM metallopeptidase domain 17; SRB1: HDL-scavenger receptor B type 1. E: embryonic/fetal days (E21: delivery); P: postnatal days.

Fig. 5

Maternal fructose exacerbates Western-type diet-induced increase of SARS-CoV-2 cell entry factors in ileum of young male offspring. Experimental design shown in Fig. 4. Ileal levels of specific mRNA for (A) ACE2, (B) TMPRSS2, (C) neuropilin-1, (D) furin, (E) ADAM17, (F) cathepsin L, and (G) SRB1 genes. Ileum (mRNA) expression from control (C, empty bar), fructose- (F, light grey bar), and fructose plus cholesterol-supplemented (FCho, dark grey bar) young male progeny from Control (left panel) or Fructose-fed (right panel) mothers. Relative target gene mRNA levels were measured by Real Time PCR as explained in Materials and Methods, normalized to Rps29 levels and expressed in arbitrary units (a.u.). Data are means ± S.E. from 7 to 8 litters. Asterisks denote a significant difference (*, P < 0.05; **, P < 0.01; ***, P < 0.001) between the groups under the crossbar (groups with a different diet but the same motheŕs diet). Hash symbols denote a significant difference (#, P < 0.05; ##, P < 0.01; ###, P < 0.001) as compared to the Control mothers (groups with the same diet but different motheŕs diet). ACE2: angiotensin-converting enzyme 2; TMPRSS2: transmembrane protease serine 2; ADAM17: ADAM metallopeptidase domain 17; SRB1: HDL-scavenger receptor B type 1.

Fig. 6

Tagatose affects hepatic cell surface receptors and cofactors facilitating SARS-CoV-2 entry in liver of young male progeny. (A) Experimental design. Hepatic levels of specific mRNA for (B) TMPRSS2, (C) neuropilin-1, (D) furin, (E) ADAM17, (F) cathepsin L, and (G) SRB1 genes. Liver (mRNA) expression from control (C, empty bar), fructose- (F, light grey bar), and tagatose-supplemented (T, dark bar) young male progeny from Control (left panel) or Fructose-fed (right panel) mothers. Relative target gene mRNA levels were measured by Real Time PCR as explained in Materials and Methods, normalized to Rps29 levels and expressed in arbitrary units (a.u.). Data are means ± S.E. from 7 to 8 litters. Asterisks denote a significant difference (*, P < 0.05; **, P < 0.01; ***, P < 0.001) between the groups under the crossbar (groups with a different diet but the same motheŕs diet). Hash symbols denote a significant difference (#, P < 0.05; ##, P < 0.01; ###, P < 0.001) as compared to the Control mothers (groups with the same diet but different motheŕs diet). TMPRSS2: transmembrane protease serine 2; ADAM17: ADAM metallopeptidase domain 17; SRB1: HDL-scavenger receptor B type 1. E: embryonic/fetal days (E21: delivery); P: postnatal days.

Fig. 7

Maternal fructose modulates how the sweetener tagatose affects SARS-CoV-2 cell entry factors in ileum of young male offspring. Experimental design shown in Fig. 6. Ileal levels of specific mRNA for (A) ACE2, (B) TMPRSS2, (C) neuropilin-1, (D) furin, (E) ADAM17 (F) cathepsin L and (G) SRB1 genes. Ileum (mRNA) expression from control (C, empty bar), fructose- (F, light grey bar), and tagatose-supplemented (T, dark bar) young male progeny from Control (left panel) or Fructose-fed (right panel) mothers. Relative target gene mRNA levels were measured by Real Time PCR as explained in Materials and Methods, normalized to Rps29 levels and expressed in arbitrary units (a.u.). Data are means ± S.E. from 7 to 8 litters. Asterisks denote a significant difference (*, P < 0.05; **, P < 0.01; ***, P < 0.001) between the groups under the crossbar (groups with a different diet but the same motheŕs diet). Hash symbols denote a significant difference (#, P < 0.05; ##, P < 0.01; ###, P < 0.001) as compared to the Control mothers (groups with the same diet but different motheŕs diet). ACE2: angiotensin-converting enzyme 2; TMPRSS2: transmembrane protease serine 2; ADAM17: ADAM metallopeptidase domain 17; SRB1: HDL-scavenger receptor B type 1.