Chronic Tumor Necrosis Factor-α Infusion in Gravid C57BL6/J Mice Accelerates Adipose Tissue Development in Female Offspring

Objective: Tumor necrosis facto (TNF)-α is thought to mediate, in part, the link between obesity and insulin resistance, and women with gestational diabetes mellitus (GDM) have raised serum TNF-α concentrations. Our objective was to investigate whether systemic TNF-α 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 μg or 4 μg recombinant mouse (rm)TNF-α by subcutaneous mini-osmotic pumps between days (d)11.5 and 18.5 of gestation. Subsequently, we studied the effects of the 2-μg dose on maternal AT metabolism. Finally, the growth of offspring exposed to 2 μg rmTNF-α 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 intraperiotneal glucose in late-gravid mice and fetal weight were higher with 2 μg but not 4 μg rmTNF-α compared with saline; however, 2 μg TNF-α 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-α infusion (2 μg 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-α mediates in part the effects of GDM on fetal growth and postnatal adiposity, and constitutes a potential mediator of intrauterine programming.