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Maternal antagonism of Glp1 reverses the adverse outcomes of sleeve gastrectomy on mouse offspring
Liron Hefetz, Rachel Ben-Haroush Schyr, Michael Bergel, Yhara Arad, Doron Kleiman, Hadar Israeli, Itia Samuel, Shira Azulai, Arnon Haran, Yovel Levy, Dana Sender, Amihai Rottenstreich, Danny Ben-Zvi
Liron Hefetz, Rachel Ben-Haroush Schyr, Michael Bergel, Yhara Arad, Doron Kleiman, Hadar Israeli, Itia Samuel, Shira Azulai, Arnon Haran, Yovel Levy, Dana Sender, Amihai Rottenstreich, Danny Ben-Zvi
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Research Article Metabolism

Maternal antagonism of Glp1 reverses the adverse outcomes of sleeve gastrectomy on mouse offspring

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Abstract

Mothers that underwent bariatric surgery are at higher risk for delivering a small-for-gestational age (SGA) infant. This phenomenon is attributed to malabsorption and rapid weight loss following surgery. We compared pregnancy outcomes in lean mice that underwent sham surgery or sleeve gastrectomy (SG). SG led to a reduction in glucose levels and an increase in postprandial levels of glucagon-like peptide 1 (Glp1) without affecting mice weight during pregnancy. Pups of SG-operated mice (SG pups) were born SGA. The placenta and pancreas of the pups were not affected by SG, although a high-fat diet caused hepatic steatosis and glucose intolerance in male SG pups. Treatment with a Glp1 receptor antagonist during pregnancy normalized the birth weight of SG pups and diminished the adverse response to a high-fat diet without affecting glucose levels of pregnant mice. The antagonist did not affect the birth weight of pups of sham-operated mice. Our findings link elevated Glp1 signaling, rather than weight loss, to the increased prevalence of SGA births following bariatric surgery with metabolic consequences for the offspring. The long-term effects of bariatric surgery on the metabolic health of offspring of patients require further investigation.

Authors

Liron Hefetz, Rachel Ben-Haroush Schyr, Michael Bergel, Yhara Arad, Doron Kleiman, Hadar Israeli, Itia Samuel, Shira Azulai, Arnon Haran, Yovel Levy, Dana Sender, Amihai Rottenstreich, Danny Ben-Zvi

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Figure 5

Treatment with Exendin 9-39 normalizes the effects of SG on embryo size without affecting maternal glycemia.

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Treatment with Exendin 9-39 normalizes the effects of SG on embryo size ...
(A and B) Oral glucose tolerance test and AUC in pregnant mice (E12.5) that had sham or SG surgery and were treated or not treated with Exendin 9-39 during pregnancy. (C and D) Nonfasting and fasting glucose levels of the 4 groups of mice. (E) Weight at E18.5 of the 4 experimental groups. (F and G) Corrected weight of P1 pups and the average weight of litters in the 4 experimental groups. (H) Fraction of SGA pups in the 4 experimental groups. (I) Scatter plot of birth weight as a function of fasting glycemia in E12.5. (J and K) Weight of male and female offspring of the 4 experimental groups. Blue: sham-operated mice or offspring of sham-operated mice untreated with Exendin 9-39 during pregnancy (full) or treated with Exendin 9-39 (dashed); Red: SG-operated mice or offspring of SG-operated mice untreated with Exendin 9-39 during pregnancy (full) or treated with Exendin 9-39 (dashed). *P < 0.05, **P < 0.01 by 2-way ANOVA with Tukey HSD post hoc test in B–J or by 3-way continuous measures ANOVA in A. In A–D, sham Ex9– n = 14, sham Ex9+ n = 10, SG Ex9– n = 6, SG Ex9+ n = 9; in E, sham Ex9– n = 14, sham Ex9+ n = 10, SG Ex9– n = 6, SG Ex9+ n = 9; in F, sham Ex9– n = 155, sham Ex9+ n = 98, SG Ex9– n =107, SG Ex9+ n = 85; in G, sham Ex9– n = 16, sham Ex9+ n = 10, SG Ex9– n =10, SG Ex9+ n = 8; in I, sham Ex9– n = 13, sham Ex9+ n = 10, SG Ex9– n = 6, SG Ex9+ n = 9; in J, sham Ex9– n = 16, sham Ex9+ n = 16, SG Ex9– n = 25, SG Ex9+ n = 11.

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