Chronic tumor necrosis factor-alpha infusion in gravid C57BL6/J mice accelerates adipose tissue development in female offspring

OBJECTIVE: Tumor necrosis factor (TNF)-alpha is thought to mediate, in part, the link between obesity and insulin resistance, and women with gestational diabetes mellitus (GDM) have raised serum TNF-alpha concentrations. Our objective was to investigate whether systemic TNF-alpha administration into gravid C57BL6/J mice causes a GDM-like syndrome and affects growth and adipose tissue (AT) development in the offspring. METHODS: We assessed glucose tolerance and reproductive outcome in mice infused with saline, or 2 mug or 4 mug recombinant mouse (rm)TNF-alpha by subcutaneous mini-osmotic pumps between days (d)11.5 and 18.5 of gestation. Subsequently, we studied the effects of the 2-mug dose on maternal AT metabolism. Finally, the growth of offspring exposed to 2 mug rmTNF-alpha in utero was followed until 8 weeks postnatal age. At 8 weeks, we assessed AT accumulation, as well as adipocyte area in white AT and insulin sensitivity in males, and adipokine mRNA levels in various AT depots in females. RESULTS: The peak glucose response to an intraperitoneal glucose stimulus in late-gravid mice and fetal weight were higher with 2 mug but not 4 mug rmTNF-alpha compared with saline; however, 2 mug TNF-alpha did not affect AT parameters. The female but not male offspring of these mice showed accelerated growth, hyperadiposity, robustly increased leptin expression in all AT depots, and raised fasting blood glucose. CONCLUSIONS: TNF-alpha infusion (2 mug for 7 days) in gravid mice resulted in a mild GDM syndrome and accelerated AT development in the offspring in a sex-specific manner. The data suggest that TNF-alpha mediates in part the effects of GDM on fetal growth and postnatal adiposity, and constitutes a potential mediator of intrauterine programming.status: publishe