Ghrelin signalling is dysregulated in male but not female offspring in a rat model of maternal vertical sleeve gastrectomy

Abstract

Bariatric surgery is the most effective and durable means of treating obesity and its comorbidities. Women make up 80% of those receiving weight loss surgery and they experience improvements in fertility. Unfortunately, bariatric surgery in the context of pregnancy is associated with complications, including growth restriction and small‐for‐gestational age offspring (SGA). SGA offspring have a greater risk for obesity in adulthood, although the mechanism for this SGA‐induced obesity is unknown. In a rat model of vertical sleeve gastrectomy (VSG), we previously identified reductions during pregnancy in ghrelin, a stomach‐derived hormone that increases appetite and induces growth hormone secretion. Here, we hypothesise that VSG offspring will have altered ghrelin signalling compared to offspring of Sham dams as a result of reduced in utero ghrelin. At postnatal day (PND)21, male and female offspring of dams that have previously received VSG have an increase in mRNA expression for the ghrelin receptor in the hypothalamus compared to Sham offspring, and the expression of GOAT is lower in females compared to males. Liver expression of endogenous ghrelin antagonist, LEAP2, is elevated at PND60 in VSG offspring. Expression of other genes in the growth hormone system (growth hormone‐releasing hormone and growth hormone) were not altered. Plasma levels of total ghrelin at PND21 are also not different between VSG and Sham pups. In adult pups, 1‐hour chow intake of male but not female VSG offspring given is less than Sham offspring when given 50 µg kg‐1 of exogenous ghrelin by i.p. injection. These results indicate that maternal VSG surgery has an impact on ghrelin signalling in offspring and that, as adults, male VSG offspring may be functionally less responsive to ghrelin than controls.

Altered Estrous Cyclicity and Feeding Neurocircuitry, but Not Cardiovascular Indices in Female Offspring from Dams with Previous Vertical Sleeve Gastrectomy Surgery

“…The current work suggests that maternal VSG alters the normal estrus cycle, producing a dysregulated pattern regardless of whether the female offspring consume chow of HFD during their adult life. These data suggest that in utero exposure to fluctuations in metabolically active hormones [ 23 , 25 , 26 ], variations in nutrient availability [ 22 , 33 ], and immune perturbations [ 27 ] may chronically alter reproduction in VSG offspring.…”

“…Animal care was performed as previously described [ 22 , 25 , 26 , 27 ]. Briefly, animals were maintained on Osmolite OneCal liquid diet (Abbott Laboratories, North Chicago, IL, USA).…”

“…Animals received 5 ml of 0.9% saline daily with buprenorphine and carprofen for pain management for three days. Animals were weight-stabilized for six weeks before mating, as previously described [ 22 , 25 , 26 , 27 ].…”

“…We have described macronutrient and hormone differences in the milk produced by dams with previous VSG surgery compared to controls [ 24 ]. Both ghrelin [ 25 ] and leptin [ 26 ] signaling are dysregulated in the offspring of dams with bariatric surgery prior to pregnancy. Further, VSG offspring exhibit profound changes to their immune systems as a result of being born to dams that have lost weight through bariatric means [ 27 ].…”

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

“…The clinical observations of SGA births following bariatric surgery prompted us to hypothesize that bariatric surgery affects embryonic development and long-term offspring metabolic health independent of maternal weight loss (49)(50)(51)(52). To test this hypothesis, we performed SG or sham surgery in lean female mice and mated them with lean male mice.…”