This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Desai, M. Articles by Ross, M. G. Search for Related Content PubMed PubMed Citation Social Bookmarking                   What's this?

Programmed Hyperphagia Due to Reduced Anorexigenic Mechanisms in Intrauterine Growth-Restricted Offspring

Perinatal Research Laboratories, Department of Obstetrics and Gynecology, David-Geffen School of Medicine at University of California Los Angeles (UCLA), and Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, mdesai{at}obgyn.humc.edu

Dave Gayle, PhD

Perinatal Research Laboratories, Department of Obstetrics and Gynecology, David-Geffen School of Medicine at University of California Los Angeles (UCLA), and Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California

Guang Han, MD

Perinatal Research Laboratories, Department of Obstetrics and Gynecology, David-Geffen School of Medicine at University of California Los Angeles (UCLA), and Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California

Michael G. Ross, MD, MPH

Perinatal Research Laboratories, Department of Obstetrics and Gynecology, David-Geffen School of Medicine at University of California Los Angeles (UCLA), and Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California

Maternal food restriction during pregnancy results in intrauterine growth-restricted (IUGR) newborns with significantly decreased plasma leptin levels. When nursed by ad libitum—fed controls, IUGR offspring exhibit hyperphagia with adult obesity, marked by increased percentage body fat and plasma leptin, suggesting altered anorexigenic pathways. The authors examined leptin signaling pathways and food intake responses to 2 putative anorexic effectors (leptin and sibutramine, a serotonin reuptake inhibitor) in IUGR offspring. From 10 days to term gestation and through lactation, control pregnant rats received ad libitum food, whereas study rats were 50% food restricted. Following birth, litter size was standardized, and all offspring were nursed by control dams. At 3 weeks of age, offspring were weaned to ad libitum laboratory chow. At ages 1 day and 3 weeks, hypothalamic leptin receptor (Ob-Rb) mRNA and total STAT3 protein expression were determined. In addition, phosphorylated STAT3 was measured in 1-day-old offspring administered peripheral leptin. In prepubescent and adult offspring, anorexic effects of leptin and sibutramine were determined. At 1 day of age, IUGR pups showed increased hypothalamic Ob-Rb mRNA and total STAT3 protein expression though reduced leptin activated phosphorylated STAT3. At 3 weeks of age, IUGR offspring had decreased hypothalamic Ob-Rb mRNA expression, although with continued elevated STAT3 protein levels. The IUGR offspring demonstrated resistance to anorexigenic agents, leptin (6 weeks and 6 months), and sibutramine (8 months), as evidenced by less reduction in food intake and less body weight loss than controls. The IUGR offspring demonstrate suppressed leptin-induced STAT3 phosphorylation and impaired anorexigenic response to 2 factors in the central satiety pathway. This reduced anorexigenic function, together with normal or perhaps enhanced orexigenic function, contributes to the development of programmed obesity in IUGR rat offspring.

Key Words: Obesity • leptin,sibutramine • STAT3 • hypothalamus.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?