Integrated stress response activation by sleep fragmentation during late gestation in mice leads to emergence of adverse metabolic phenotype in offspring.

BACKGROUND: Late gestational sleep fragmentation (SF) is highly prevalent particularly in obese women, and induces metabolic dysfunction in adult offspring mice. SF induces activation of the integrated stress response (ISR), which might be involved in metabolic disorders. We hypothesized that adult offspring of double mutant mice (DM) involving the critical ISR genes CHOP and GADD34 would be protected from developing obesity and insulin resistance following SF.

METHODS: Time-pregnant CHOP/GADD34 DM and wild type (WT) mice were randomly assigned to sleep control (SC) or SF conditions during the last 5days of gestation. At 24-weeks of age, body weight, fat mass, and HOMA-IR were assessed in the offspring. Tregs lymphocytes, Lyc6chigh , M1 and M2 macrophages were examined in visceral white adipose tissues (vWAT) using flow cytometry. The effects of plasma exosomes on adipocyte cell line proliferation, differentiation and insulin sensitivity were also evaluated.

RESULTS: SF-WT male showed significant increases in body weight, vWAT mass and HOMA-IR compared to SC-WT mice, while SF had no effect in SF-DM mice. Inflammatory macrophages (Ly-6chigh ) and the ratio of M1/M2 macrophages were increased while FoxP3+ Tregs counts were decreased in SF-WT but not in SF-DM mice. Exosomes from SF-WT, but not from the SF-DM offspring increased pre-adipocyte proliferation and differentiation, and decreased in vitro adipocyte insulin sensitivity.

CONCLUSION: Activation of the ISR during late gestation, as induced by late gestational SF, appears to underlie some of the transgenerational modifications in metabolic genes ultimately contributing to a metabolic syndrome phenotype in adult offspring.