Dissertation/Thesis Abstract

The effects of maternal low protein diet during pregnancy and lactation on the status of lipid homeostasis and mitochondrial function in adult rat offspring
by Browne, Veron P., Ph.D., University of the Sciences in Philadelphia, 2014, 211; 3586938
Abstract (Summary)

We previously found that maternal protein restriction throughout pregnancy and lactation reduced liver triglyceride (TAG) content selectively in the rat adult male offspring. The mechanism mediating the reduction of liver TAG content is unknown. We hypothesize that the decrease in hepatic TAG content is due to increased mitochondrial fatty acid β-oxidation (FAO). The first objective of the current study was to examine the status of FAO in the liver, skeletal muscle and heart and to determine their contribution to the decrease in liver TAG content observed in male low protein (LP) offspring. Pregnant Sprague-Dawley rats received either a control or a LP diet throughout gestation and lactation. On day 28, pups from both groups were weaned onto regular laboratory chow. Rats were sacrificed on day 65 and liver, muscle and heart harvested and stored at -80°C, pending analysis. Carnitine palmitoyltransferase-1 (CPT-1) is the rate limiting enzyme in FAO that mediates the transport of long chain fatty acids from the cytosol to the mitochondria. Medium chain acyl-CoA dehydrogenase (MCAD) is another critical V enzyme that works independently from CPT-1, and catalyzes the initial oxidation step in mitochondrial fatty-acid metabolism. The activity of these enzymes are regulated through the action of metabolic nuclear transcription factor, peroxisome proliferator activated receptor alpha (PPAR-α). Male, but not female, LP offspring tended to exhibit higher liver CPT-1 activity suggesting increased fatty acid transport into the mitochondrial matrix. The MCAD activity in the liver was similar between LP offspring and their controls. Additionally, the expression of PPAR-α expression in liver demonstrated no differences between the two groups. CPT-1 and MCAD activity in skeletal muscle and heart were similar between control and LP offspring. These results demonstrate that triglyceride utilization via FAO cannot account for the reduction in liver triglyceride content in male LP offspring. Also, our studies have shown that maternal LP diet throughout pregnancy and lactation increases core body temperature (CBT) and sympathetic drive in the adult offspring. Skeletal muscle is an important thermogenic tissue and thermogenesis is mediated, in part, through sympathetic nervous system (SNS) mediated alterations in mitochondrial status. We therefore, hypothesize that maternal low protein diet during pregnancy and lactation will increase mitochondrial biogenesis and function within skeletal muscle in the adult offspring. The second objective of the study was to determine the contributions of mitochondrial biogenesis and function in gastrocnemius muscle to the elevated CBT in LP offspring. Mitochondrial biogenesis was assessed by measuring the expression of peroxisome proliferator activated receptor γ coactivator-1α (PGC1α), mitochondrial transcription factor A (TFAM), and nuclear respiratory factor-1 (NRF-1). Mitochondrial DNA (mtDNA) content was quantitated by measuring the expression of displacement loop (DLoop), NADH dehydrogenase subunit 1 (ND1), ribosomal RNA (12s) and tRNA-Leucine 1 (tRNA) and normalizing the expression of these mitochondrial target genes to the expression of the nuclear gene, beta-2 microglobulin (β2M). Mitochondrial function was assessed by measuring the VI expression of select genes in the complexes including NADH dehydrogenase subunits 1 and 5, and ATP synthase subunits 6 and 8. There was no difference in NRF-1 expression or mtDNA content between control and LP offspring. However, expression of PGC1α and TFAM were decreased in LP offspring. Expression of genes involved in mitochondrial complexes were similar in control and LP offspring. Overall these results suggest that elevated CBT in LP offspring is not mediated by altered mitochondrial status in gastrocnemius muscle

Indexing (document details)
Advisor: D'mello, Anil P.
Commitee:
School: University of the Sciences in Philadelphia
School Location: United States -- Pennsylvania
Source: DAI-B 75/07(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Toxicology, Surgery, Pharmacology
Keywords: Carnitine palmitoyltransferase, Lactation, Lipid homeostasis, Low-protein diet, Pregnancy, Triglycerides
Publication Number: 3586938
ISBN: 9781303852398
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