title: Maternal overweight programs insulin and adiponectin signaling in the offspring.
abstract: Gestational exposure to maternal overweight (OW) influences the risk of obesity in adult life. Male offspring from OW dams gain greater body weight and fat mass and develop insulin resistance when fed high-fat diets (45% fat). In this report, we identify molecular targets of maternal OW-induced programming at postnatal d 21 before challenge with the high-fat diet. We conducted global transcriptome profiling, gene/protein expression analyses, and characterization of downstream signaling of insulin and adiponectin pathways in conjunction with endocrine and biochemical characterization. Offspring born to OW dams displayed increased serum insulin, leptin, and resistin levels (P < 0.05) at postnatal d 21 preceding changes in body composition. A lipogenic transcriptome signature in the liver, before development of obesity, was evident in OW-dam offspring. A coordinated locus of 20 sterol regulatory element-binding protein-1-regulated target genes was induced by maternal OW. Increased nuclear levels of sterol regulatory element-binding protein-1 and recruitment to the fatty acid synthase promoter were confirmed via ELISA and chromatin immunoprecipitation analyses, respectively. Higher fatty acid synthase and acetyl coenzyme A carboxylase protein and pAKT (Thr(308)) and phospho-insulin receptor-beta were confirmed via immunoblotting. Maternal OW also attenuated AMP kinase/peroxisome proliferator-activated receptor-alpha signaling in the offspring liver, including transcriptional down-regulation of several peroxisome proliferator-activated receptor-alpha-regulated genes. Hepatic mRNA and circulating fibroblast growth factor-21 levels were significantly lower in OW-dam offspring. Furthermore, serum levels of high-molecular-weight adiponectin (P < 0.05) were decreased in OW-dam offspring. Phosphorylation of hepatic AMP-kinase (Thr(172)) was significantly decreased in OW-dam offspring, along with lower AdipoR1 mRNA. Our results strongly suggest that gestational exposure to maternal obesity programs multiple aspects of energy-balance regulation in the offspring.
authors.affiliation: Arkansas Children's Nutrition Center, 15 Children's Way, Slot 512-20B, Little Rock, Arkansas 72202, USA. ShankarKartik@uams.edu
authors.forename: Kartik
authors.initials: K
authors.lastname: Shankar
authors.forename: Ping
authors.initials: P
authors.lastname: Kang
authors.forename: Amanda
authors.initials: A
authors.lastname: Harrell
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhong
authors.forename: John C
authors.initials: JC
authors.lastname: Marecki
authors.forename: Martin J J
authors.initials: MJ
authors.lastname: Ronis
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Badger
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D064429:Fatty Acid Synthases / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D020738:Leptin / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000503:physiopathology; D050177:Overweight / Q000503:physiopathology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D052243:Resistin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D052242:Adiponectin; D007328:Insulin; D020738:Leptin; D052243:Resistin; D005346:Fibroblast Growth Factors; D064429:Fatty Acid Synthases; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase