Hyperleptinemia During Pregnancy Decreases Adult Weight of Offspring and Is Associated With Increased Offspring Locomotor Activity in Mice

Abstract

Pregnant women who are obese or have gestational diabetes mellitus have elevated leptin levels and their children have an increased risk for child and adult obesity. The goals of this study were to determine whether offspring weights are altered by maternal hyperleptinemia, and whether this occurs via behavioral changes that influence energy balance. We used 2 hyperleptinemic mouse models. The first was females heterozygous for a leptin receptor mutation (DB/+), which were severely hyperleptinemic, and that were compared with wild-type females. The second model was wild-type females infused with leptin (LEP), which were moderately hyperleptinemic, and were compared with wild-type females infused with saline (SAL). Total food consumption, food preference, locomotor activity, coordinated motor skills, and anxiety-like behaviors were assessed in wild-type offspring from each maternal group at 3 postnatal ages: 4-6, 11-13, and 19-21 weeks. Half the offspring from each group were then placed on a high-fat diet, and behaviors were reassessed. Adult offspring from both groups of hyperleptinemic dams weighed less than their respective controls beginning at 23 weeks of age, independent of diet or sex. Weight differences were not explained by food consumption or preference, because female offspring from hyperleptinemic dams tended to consume more food and had reduced preference for palatable, high-fat and sugar, food compared with controls. Offspring from DB/+ dams were more active than offspring of controls, as were female offspring of LEP dams. Maternal hyperleptinemia during pregnancy did not predispose offspring to obesity, and in fact, reduced weight gain.

GENDER-SPECIFIC INFLUENCE OF Aу MUTATION ON PROGENY METABOLIC PHENOTYPE, FETAL GROWTH AND PLACENTAL GENE EXPRESSION IN MICE

“…Ранее нами установлено, что однократное введение лептина в конце беременности снижает массу тела у потомства на стандартной диете (Makarova et al, 2013). В исследованиях других авторов тоже обнаружено, и в генетической модели, и при введении лептина, что гиперлептинемия при беременности сопровождается меньшей массой у потомства, причем у крыс масса была снижена только у женского потомства (Nilsson et al, 2003), а у мышей -вне зависимости от пола (Pollock et al, 2015). Меньшая масса тела у мужского потомства А у /а самок по сравнению с потомством а/а самок наблюдалась при одинаковом потреблении пищи, что предполагает более интенсивный расход энергии у этих животных.…”

Absence of a gestational diabetes phenotype in the LepRdb/+ mouse is independent of control strain, diet, misty allele, or parity

“…Similarly, Pollock et al . (2015) reported improved glucose tolerance in db/+ mice compared to WT mice, despite significant hyperleptinemia in the former33. Recently, we studied a potential new treatment for GDM in db/+ mice; however, we similarly did not observe glucose intolerance in the model.…”

“…These animals typically present with glucose intolerance, insulin resistance, hyperglycemia, increased food intake, and increased weight gain during, but not prior to, pregnancy2223242526273031. However, several recent studies using the model, including our own, have been unable to reproduce this phenotype323337. The current study aimed to investigate potential reasons for the loss of a GDM phenotype in some colonies.…”

“…Most early studies in db/+ mice (in which a GDM phenotype was observed) used C57BL/6J mice as control animals212638. However, some of the more recent db/+ studies, including our own, used WT littermates as controls2933. This is likely due to current recommendations that knockout studies use WT offspring of the same parentage as experimental animals as controls, in order to account for epigenetic effects in utero 3940.…”

Investigating impacts of altered central metabolism on ovarian function

“…Heterozygous individuals were originally considered phenotypically and morphologically indistinguishable from the wild type mice, however, this has since been shown to not be the case. Significant elevation in the levels of circulating leptin are characteristic of the heterozygous phenotype, potentially as a compensatory response to leptin resistance induced by the heterozygous loss of function in the leptin receptor [131]. In addition to its influence on circulating levels of gonadotropins, leptin also directly regulates ovarian function.…”