{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/394221"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/394221","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Placental (Mal)Adaptation in Maternal Obesity: Immune-Mediated Regulation of Placental Nutrient Partitioning and Fetal Growth","abstract":"Global rates of obesity continue to rise, leading to increased numbers of women entering pregnancy obese. Maternal obesity is an established risk factor for metabolic complications during pregnancy and can programme the offspring for elevated risk of non-communicable diseases. Obesity is also linked with chronic low-grade inflammation. The placenta plays a central role in mediating metabolic and inflammatory effects of the gestational environment on fetal growth and serves as a critical determinant of long-term offspring health. This project aims to investigate how maternal obesity, and inflammation may disrupt placental nutrient partitioning potentially leading to fetal growth restriction. To address this, both murine and in vitro models were employed. Mice were fed a high-fat high-sugar (HFHS) diet 9-weeks prior to and throughout pregnancy to create a diet-induced obesity model. HFHS pregnancies presented with increased maternal plasma, gonadal fat, liver, and spleen gene and protein expression of pro-inflammatory cytokines (including IL1, IL6, TNFα). The pro-inflammatory profile in HFHS dams were mirrored by inflammation in the placental nutrient transport zone (labyrinth zone) and a reduction in growth factors and nutrient transporters for lipids, glucose, and amino acids. HFHS dams also exhibited fetal and placental growth restriction. Using primary cultures of term placental syncytiotrophoblasts, the individual and combined acute effects of high glucose, palmitic acid (a representative saturated fat), and pro-inflammatory cytokines (IL1, IL6, TNFα) on nutrient uptake were investigated. These experiments revealed that cytokines exposure, whether alone or in combination with glucose, fat, or both (HFHS), generally increased glucose and fatty acid uptake compared to control conditions. However, a smaller subset of samples showed decreased nutrient uptake under the same treatments. This variability was partially reflected in molecular analyses. For instance, samples with increased nutrient uptake showed increased phosphorylation of the inflammatory marker nuclear factor kappa B (NFkB) in response to treatment. Additional differences were observed in the expression of nutrient transporters, growth signalling pathways, and other inflammatory markers. Further experiments using a first-trimester human trophoblast stem cell line (hTSCs), assessed in both undifferentiated and differentiated syncytiotrophoblast states, demonstrated that acute treatment with high glucose, high fat and cytokines increased glucose uptake and inflammatory responses, but decreased fatty acid uptake. In summary, these results underscore the complex interplay between inflammation, metabolic stress, and nutrient handling in the human and mouse placenta. They also highlight important differences between acute human in vitro responses and chronic in vivo outcomes observed in mouse models of maternal obesity during pregnancy.","abstract_html":"Global rates of obesity continue to rise, leading to increased numbers of women entering pregnancy obese. Maternal obesity is an established risk factor for metabolic complications during pregnancy and can programme the offspring for elevated risk of non-communicable diseases. Obesity is also linked with chronic low-grade inflammation. The placenta plays a central role in mediating metabolic and inflammatory effects of the gestational environment on fetal growth and serves as a critical determinant of long-term offspring health. This project aims to investigate how maternal obesity, and inflammation may disrupt placental nutrient partitioning potentially leading to fetal growth restriction. To address this, both murine and in vitro models were employed. Mice were fed a high-fat high-sugar (HFHS) diet 9-weeks prior to and throughout pregnancy to create a diet-induced obesity model. HFHS pregnancies presented with increased maternal plasma, gonadal fat, liver, and spleen gene and protein expression of pro-inflammatory cytokines (including IL1, IL6, TNFα). The pro-inflammatory profile in HFHS dams were mirrored by inflammation in the placental nutrient transport zone (labyrinth zone) and a reduction in growth factors and nutrient transporters for lipids, glucose, and amino acids. HFHS dams also exhibited fetal and placental growth restriction. Using primary cultures of term placental syncytiotrophoblasts, the individual and combined acute effects of high glucose, palmitic acid (a representative saturated fat), and pro-inflammatory cytokines (IL1, IL6, TNFα) on nutrient uptake were investigated. These experiments revealed that cytokines exposure, whether alone or in combination with glucose, fat, or both (HFHS), generally increased glucose and fatty acid uptake compared to control conditions. However, a smaller subset of samples showed decreased nutrient uptake under the same treatments. This variability was partially reflected in molecular analyses. For instance, samples with increased nutrient uptake showed increased phosphorylation of the inflammatory marker nuclear factor kappa B (NFkB) in response to treatment. Additional differences were observed in the expression of nutrient transporters, growth signalling pathways, and other inflammatory markers. Further experiments using a first-trimester human trophoblast stem cell line (hTSCs), assessed in both undifferentiated and differentiated syncytiotrophoblast states, demonstrated that acute treatment with high glucose, high fat and cytokines increased glucose uptake and inflammatory responses, but decreased fatty acid uptake. In summary, these results underscore the complex interplay between inflammation, metabolic stress, and nutrient handling in the human and mouse placenta. They also highlight important differences between acute human in vitro responses and chronic in vivo outcomes observed in mouse models of maternal obesity during pregnancy.","abstract_has_math":false,"creators":["Zhang, Xin Wen"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Sferruzzi-Perri, Amanda"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-07-31","date_published":"2025-07-31","updated_at":"2026-07-22T22:24:31Z","subjects":["Obesity","Placenta","Maternal-Fetal Health","Fetal Growth Restriction","Inflammation"],"languages":["eng"],"rights":[],"rights_urls":["https://www.repository.cam.ac.uk/bitstreams/2e755bd1-2411-4aa5-9402-de796293a4f8/download","http://purl.org/NET/rdflicense/allrightsreserved"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.124270","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Sferruzzi-Perri, Amanda"]},{"key":"dc:creator","label":"Author","values":["Zhang, Xin Wen"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2025-07-31"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/394221"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Obesity","Placenta","Maternal-Fetal Health","Fetal Growth Restriction","Inflammation"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://www.repository.cam.ac.uk/bitstreams/2e755bd1-2411-4aa5-9402-de796293a4f8/download","http://purl.org/NET/rdflicense/allrightsreserved"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2026-12-19"]},{"key":"dc:rights.embargotype","label":"Dc Rights Embargotype","values":["embargo"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.124270"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://www.repository.cam.ac.uk/bitstreams/1cdbfca4-c744-404e-9715-18e4fd097bf3/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Global rates of obesity continue to rise, leading to increased numbers of women entering pregnancy obese. Maternal obesity is an established risk factor for metabolic complications during pregnancy and can programme the offspring for elevated risk of non-communicable diseases. Obesity is also linked with chronic low-grade inflammation. The placenta plays a central role in mediating metabolic and inflammatory effects of the gestational environment on fetal growth and serves as a critical determinant of long-term offspring health. This project aims to investigate how maternal obesity, and inflammation may disrupt placental nutrient partitioning potentially leading to fetal growth restriction. To address this, both murine and in vitro models were employed. Mice were fed a high-fat high-sugar (HFHS) diet 9-weeks prior to and throughout pregnancy to create a diet-induced obesity model. HFHS pregnancies presented with increased maternal plasma, gonadal fat, liver, and spleen gene and protein expression of pro-inflammatory cytokines (including IL1, IL6, TNFα). The pro-inflammatory profile in HFHS dams were mirrored by inflammation in the placental nutrient transport zone (labyrinth zone) and a reduction in growth factors and nutrient transporters for lipids, glucose, and amino acids. HFHS dams also exhibited fetal and placental growth restriction. Using primary cultures of term placental syncytiotrophoblasts, the individual and combined acute effects of high glucose, palmitic acid (a representative saturated fat), and pro-inflammatory cytokines (IL1, IL6, TNFα) on nutrient uptake were investigated. These experiments revealed that cytokines exposure, whether alone or in combination with glucose, fat, or both (HFHS), generally increased glucose and fatty acid uptake compared to control conditions. However, a smaller subset of samples showed decreased nutrient uptake under the same treatments. This variability was partially reflected in molecular analyses. For instance, samples with increased nutrient uptake showed increased phosphorylation of the inflammatory marker nuclear factor kappa B (NFkB) in response to treatment. Additional differences were observed in the expression of nutrient transporters, growth signalling pathways, and other inflammatory markers. Further experiments using a first-trimester human trophoblast stem cell line (hTSCs), assessed in both undifferentiated and differentiated syncytiotrophoblast states, demonstrated that acute treatment with high glucose, high fat and cytokines increased glucose uptake and inflammatory responses, but decreased fatty acid uptake. In summary, these results underscore the complex interplay between inflammation, metabolic stress, and nutrient handling in the human and mouse placenta. They also highlight important differences between acute human in vitro responses and chronic in vivo outcomes observed in mouse models of maternal obesity during pregnancy."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["a2c9f00506d9f75b898e6317af234777","87eda9de84448d1f82354d60eee3eb5f"]},{"key":"dc:title","label":"Title","values":["Placental (Mal)Adaptation in Maternal Obesity: Immune-Mediated Regulation of Placental Nutrient Partitioning and Fetal Growth"]}]}],"canonical_facts":{"dc:contributor.advisor":["Sferruzzi-Perri, Amanda"],"dc:creator":["Zhang, Xin Wen"],"dc:date.issued":["2025-07-31"],"dc:description.abstract":["Global rates of obesity continue to rise, leading to increased numbers of women entering pregnancy obese. Maternal obesity is an established risk factor for metabolic complications during pregnancy and can programme the offspring for elevated risk of non-communicable diseases. Obesity is also linked with chronic low-grade inflammation. The placenta plays a central role in mediating metabolic and inflammatory effects of the gestational environment on fetal growth and serves as a critical determinant of long-term offspring health. This project aims to investigate how maternal obesity, and inflammation may disrupt placental nutrient partitioning potentially leading to fetal growth restriction. To address this, both murine and in vitro models were employed. Mice were fed a high-fat high-sugar (HFHS) diet 9-weeks prior to and throughout pregnancy to create a diet-induced obesity model. HFHS pregnancies presented with increased maternal plasma, gonadal fat, liver, and spleen gene and protein expression of pro-inflammatory cytokines (including IL1, IL6, TNFα). The pro-inflammatory profile in HFHS dams were mirrored by inflammation in the placental nutrient transport zone (labyrinth zone) and a reduction in growth factors and nutrient transporters for lipids, glucose, and amino acids. HFHS dams also exhibited fetal and placental growth restriction. Using primary cultures of term placental syncytiotrophoblasts, the individual and combined acute effects of high glucose, palmitic acid (a representative saturated fat), and pro-inflammatory cytokines (IL1, IL6, TNFα) on nutrient uptake were investigated. These experiments revealed that cytokines exposure, whether alone or in combination with glucose, fat, or both (HFHS), generally increased glucose and fatty acid uptake compared to control conditions. However, a smaller subset of samples showed decreased nutrient uptake under the same treatments. This variability was partially reflected in molecular analyses. For instance, samples with increased nutrient uptake showed increased phosphorylation of the inflammatory marker nuclear factor kappa B (NFkB) in response to treatment. Additional differences were observed in the expression of nutrient transporters, growth signalling pathways, and other inflammatory markers. Further experiments using a first-trimester human trophoblast stem cell line (hTSCs), assessed in both undifferentiated and differentiated syncytiotrophoblast states, demonstrated that acute treatment with high glucose, high fat and cytokines increased glucose uptake and inflammatory responses, but decreased fatty acid uptake. In summary, these results underscore the complex interplay between inflammation, metabolic stress, and nutrient handling in the human and mouse placenta. They also highlight important differences between acute human in vitro responses and chronic in vivo outcomes observed in mouse models of maternal obesity during pregnancy."],"dc:format.checksum.md5":["a2c9f00506d9f75b898e6317af234777","87eda9de84448d1f82354d60eee3eb5f"],"dc:identifier.doi":["https://doi.org/10.17863/CAM.124270"],"dc:identifier.uri":["https://www.repository.cam.ac.uk/bitstreams/1cdbfca4-c744-404e-9715-18e4fd097bf3/download"],"dc:language":["eng"],"dc:publisher.institution":["University of Cambridge"],"dc:relation.isreferencedby.uri":["https://www.repository.cam.ac.uk/handle/1810/394221"],"dc:rights":["https://www.repository.cam.ac.uk/bitstreams/2e755bd1-2411-4aa5-9402-de796293a4f8/download","http://purl.org/NET/rdflicense/allrightsreserved"],"dc:rights.embargodate":["2026-12-19"],"dc:rights.embargotype":["embargo"],"dc:subject":["Obesity","Placenta","Maternal-Fetal Health","Fetal Growth Restriction","Inflammation"],"dc:title":["Placental (Mal)Adaptation in Maternal Obesity: Immune-Mediated Regulation of Placental Nutrient Partitioning and Fetal Growth"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-22T22:24:31Z"}