Enhancing hepatic fatty acid oxidation as a strategy for reversing metabolic disorders programmed by maternal undernutrition during gestation.
OBJECTIVE
Moderate maternal calorie-restriction during gestation programmes offspring for a major propensity to develop metabolic alterations in adulthood. We aimed to assess whether increased hepatic fatty-acid oxidation (FAO), at early ages, by gene transfer of Cpt1am (active mutant of carnitine palmitoyltransferase-1a), may be a strategy for reversing metabolic disturbances associated to maternal calorie-restriction during gestation in rats.


METHODS
AAV-Gfp (control) and AAV-Cpt1am vectors were administered by tail vein injection in 18-day-old control-pups and the offspring of 20% calorie-restricted rats during gestation (CR). After weaning, animals were fed with normal-fat diet. At the age of 4 months, they were moved to HF-diet and sacrificed at the age of 6 months to collect tissues. Locomotive activity, energy expenditure and blood pressure were measured.


RESULTS
Under HF-diet, CR-animals showed higher HOMA-IR, adipocyte diameter and hepatic triglyceride accumulation than controls; these alterations were reverted in Cpt1am-injected animals. In liver, this treatment ameliorated inflammatory state, decreased expression of lipogenesis-related genes and partially restored the decreased expression of leptin-receptor occurring in CR-animals. Treatment also reverted the decreased energy expenditure and the increased blood pressure of CR-animals.


CONCLUSIONS
Increasing hepatic FAO through AAV-Cpt1am injection at juvenile ages prevents some metabolic disorders associated to gestational maternal calorie-restriction.
Laboratory of Molecular Biology, Nutrition, and Biotechnology (Nutrigenomics), University of the Balearic Islands and CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Palma de Mallorca, Balearic Islands.
Juana María
JM
Torrens
Josep M
JM
Orellana-Gavaldà
Mariona
M
Palou
Juana
J
Sánchez
Laura
L
Herrero
Catalina
C
Picó
Dolors
D
Serra
Andreu
A
Palou
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D044342:Malnutrition / Q000378:metabolism*; D008659:Metabolic Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D010084:Oxidation-Reduction; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism*; D011270:Pregnancy, Animal; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar
D005227:Fatty Acids; D002334:Carnitine O-Palmitoyltransferase