Prenatal exposure to a low-protein diet programs disordered regulation of lipid metabolism in the aging rat.
The nutritional environment encountered during fetal life is strongly implicated as a determinant of lifelong metabolic capacity and risk of disease. Pregnant rats were fed a control or low-protein (LP) diet, targeted to early (LPE), mid-(LPM), or late (LPL) pregnancy, or throughout gestation (LPA). The offspring were studied at 1, 9, and 18 mo of age. All LP-exposed groups had similar plasma triglyceride, cholesterol, glucose, and insulin concentrations to those of controls at 1 and 9 mo of age, but by 18 mo there was evidence of LP-programmed hypertriglyceridemia and insulin resistance. All LP-exposed groups exhibited histological evidence of hepatic steatosis and were found to have two- to threefold more hepatic triglyceride than control animals. These phenotypic changes were accompanied by age-related changes in mRNA and protein expression of the transcription factors SREBP-1c, ChREBP, PPARgamma, and PPARalpha and their respective downstream target genes ACC1, FAS, L-PK, and MCAD. At 9 mo of age, the LP groups exhibited suppression of the SREBP-1c-related lipogenic pathway but between 9 and 18 mo underwent a switch to increased lipogenic capacity with a lower expression of PPARgamma and MCAD, consistent with reduced lipid oxidation. The findings indicate that prenatal protein restriction programs development of a metabolic syndrome-like phenotype that develops only with senescence. The data implicate altered expression of SREBP-1c and ChREBP as key mediators of the programmed phenotype, but the basis of the switch in metabolic status that occurred between 9 and 18 mo of age is, as yet, unidentified.
Erhuma
Aml
A
School of Biosciences, University of Nottingham, Queens Medical Centre, Nottingham, UK.
Salter
Andrew M
AM
Sculley
Dean V
DV
Langley-Evans
Simon C
SC
Bennett
Andrew J
AJ
D000273:Adipose Tissue / Q000378:metabolism; D000375:Aging / Q000097:blood / Q000378:metabolism*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D001835:Body Weight; D018753:Diet, Protein-Restricted; D005234:Fatty Liver / Q000209:etiology; D005260:Female; D015228:Hypertriglyceridemia / Q000209:etiology; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009929:Organ Size; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C442825:Mlxipl protein, rat; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides