Intrauterine Growth Restriction Programs the Hypothalamus of Adult Male Rats: Integrated Analysis of Proteomic and Metabolomic Data.
Programming of hypothalamic functions regulating energy homeostasis may play a role in intrauterine growth restriction (IUGR)-induced adulthood obesity. The present study investigated the effects of IUGR on the hypothalamus proteome and metabolome of adult rats submitted to 50% protein-energy restriction throughout pregnancy. Proteomic and metabolomic analyzes were performed by data independent acquisition mass spectrometry and multiple reaction monitoring, respectively. At age 4 months, the restricted rats showed elevated adiposity, increased leptin and signs of insulin resistance. 1356 proteins were identified and 348 quantified while 127 metabolites were quantified. The restricted hypothalamus showed down-regulation of 36 proteins and 5 metabolites and up-regulation of 21 proteins and 9 metabolites. Integrated pathway analysis of the proteomics and metabolomics data indicated impairment of hypothalamic glucose metabolism, increased flux through the hexosamine pathway, deregulation of TCA cycle and the respiratory chain, and alterations in glutathione metabolism. The data suggest IUGR modulation of energy metabolism and redox homeostasis in the hypothalamus of male adult rats. The present results indicated deleterious consequences of IUGR on hypothalamic pathways involved in pivotal physiological functions. These results provide guidance for future mechanistic studies assessing the role of intrauterine malnutrition in the development of metabolic diseases later in life.
Department of Physiology, Universidade Federal de São Paulo UNIFESP , São Paulo, SP 04021-001, Brazil.
Amanda P
0000-0001-7088-0187
AP
Pedroso
Department of Physiology, Universidade Federal de São Paulo UNIFESP , São Paulo, SP 04021-001, Brazil.
Adriana P
AP
Souza
Department of Physiology, Universidade Federal de São Paulo UNIFESP , São Paulo, SP 04021-001, Brazil.
Ana P S
AP
Dornellas
Department of Physiology, Universidade Federal de São Paulo UNIFESP , São Paulo, SP 04021-001, Brazil.
Lila M
LM
Oyama
Department of Physiology, Universidade Federal de São Paulo UNIFESP , São Paulo, SP 04021-001, Brazil.
Cláudia M O
CM
Nascimento
Division of Applied Statistics, Universidade Federal de São Paulo UNIFESP , São Paulo, SP 04021-001, Brazil.
Gianni M S
GM
Santos
Protein Chemistry Center, Department of Molecular and Cell Biology, Ribeirão Preto Medical School, Universidade de São Paulo , Ribeirão Preto, SP 03178-200, Brazil.
José C
JC
Rosa
Department of Surgery, Universidade Federal de São Paulo UNIFESP , São Paulo, SP 04021-001, Brazil.
Ricardo P
RP
Bertolla
iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado Denver , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
Jelena
J
Klawitter
iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado Denver , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
Uwe
U
Christians
Department of Biochemistry, Universidade Federal de São Paulo UNIFESP , São Paulo, SP 04021-001, Brazil.
Alexandre K
AK
Tashima
Department of Physiology, Universidade Federal de São Paulo UNIFESP , São Paulo, SP 04021-001, Brazil.
Eliane B
EB
Ribeiro
D000818:Animals; D000831:Animals, Newborn; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism; D055432:Metabolomics; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics*; D040901:Proteomics; D051381:Rats
energy metabolism; hypothalamus; label-free proteomics; low birth weight; metabolic programming; metabolomics; obesity; protein-energy restriction; redox homeostasis