Short term exendin-4 treatment reduces markers of metabolic disorders in female offspring of obese rat dams.
OBJECTIVE
Maternal obesity imposes significant health risks in the offspring including diabetes and dyslipidemia. We previously showed that the hypoglycaemic agent exendin-4 (Ex-4) administered from weaning can reverse the maternal impact of 'transmitted disorders' in such offspring. However daily injection for six-weeks was required and the beneficial effect may lapse upon drug withdrawal. This study aimed to investigate whether short term Ex-4 treatment during suckling period in a rodent model can reverse transmitted metabolic disorders due to maternal obesity.


METHODS
Maternal obesity was induced in female Sprague Dawley rats by high-fat diet feeding for 6 weeks, throughout gestation and lactation. Female offspring were treated with Ex-4 (5μg/kg/day) between postnatal day (P) 4 and 14. Female offspring were harvested at weaning (P20). Lipid and glucose metabolic markers were measured in the liver and fat. Appetite regulators were measured in the plasma and hypothalamus.


RESULTS
Maternal obesity significantly increased body weight, fat mass, and liver weight in the offspring. There was an associated inhibition of peroxisomal proliferator activated receptor gamma coactivator 1α (PGC1α), increased fatty acid synthase (FASN) expression in the liver, and reduced adipocyte triglyceride lipase (ATGL) expression. It also increased the plasma gut hormone ghrelin and reduced glucagon-like peptide-1. Ex-4 treatment partially reversed the maternal impact on adiposity and impaired lipid metabolism in the offspring, with increased liver PGC1α and inhibition of FASN mRNA expression. Ex-4 treatment also increased the expression of a novel fat depletion gene a2-zinc-glycoprotein 1 in the fat tissue.


CONCLUSIONS
Short term Ex-4 treatment during the suckling period significantly improved the metabolic profile in the offspring from the obese mothers at weaning. Long-term studies are needed to follow such offspring to adulthood to examine the sustained effects of Ex-4 in preventing the development of metabolic disease.
School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia.
Yik Lung
YL
Chan
School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia; Department of Medicine, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW 2065, Australia.
Sonia
S
Saad
Inflammation and Infection Research, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
David
D
Simar
School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia.
Brian
B
Oliver
School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia.
Kristine
K
McGrath
School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia.
David van
Dv
Reyk
School of Medical Sciences, RMIT University, VIC, 3001, Australia.
Paul P
PP
Bertrand
School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia.
Cathy
C
Gorrie
Department of Medicine, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW 2065, Australia.
Carol
C
Pollock
School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia. Electronic address: Hui.chen-1@uts.edu.au.
Hui
H
Chen
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D000077270:Exenatide; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D020738:Leptin / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D008659:Metabolic Diseases / Q000188:drug therapy* / Q000209:etiology; D009765:Obesity / Q000209:etiology / Q000503:physiopathology; D010455:Peptides / Q000627:therapeutic use*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014688:Venoms / Q000627:therapeutic use*
D015415:Biomarkers; D007004:Hypoglycemic Agents; D020738:Leptin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide
AZGP1; Adiposity; Leptin sensitivity; Lipid metabolism; PGC-1α