Influence of abnormally high leptin levels during pregnancy on metabolic phenotypes in progeny mice

Abstract

Makarova EN, Chepeleva EV, Panchenko PE, Bazhan NM. Influence of abnormally high leptin levels during pregnancy on metabolic phenotypes in progeny mice. Am J Physiol Regul Integr Comp Physiol 305: R1268 -R1280, 2013. First published October 2, 2013; doi:10.1152/ajpregu.00162.2013.-Maternal obesity increases the risk of obesity in offspring, and obesity is accompanied by an increase in blood leptin levels. The "yellow" mutation at the mouse agouti locus (A y ) increases blood leptin levels in C57BL preobese pregnant mice without affecting other metabolic characteristics. We investigated the influence of the A y mutation or leptin injection at the end of pregnancy in C57BL mice on metabolic phenotypes and the susceptibility to diet-induced obesity (DIO) in offspring. In both C57BL-A y and leptin-treated mice, the maternal effect was more pronounced in male offspring. Compared with males born to control mothers, males born to A y mothers displayed equal food intake (FI) but decreased body weight (BW) gain after weaning, equal glucose tolerance, and enhanced FI-to-BW ratios on the standard diet but the same FI and BW on the high-fat diet. Males born to A y mothers were less responsive to the anorectic effect of exogenous leptin and less resistant to fasting (were not hyperphagic and gained less weight during refeeding after food deprivation) compared with males born to control mothers. However, all progeny displayed equal hypothalamic expression of Agouti gene-related protein (AgRP), neuropeptide Y (NPY), and proopiomelanocortin (POMC) and equal plasma leptin and glucose levels after food deprivation. Leptin injections in C57BL mice on day 17 of pregnancy decreased BW in both male and female offspring but inhibited FI and DIO only in male offspring. Our results show that hyperleptinemia during pregnancy has sex-specific long-term effects on energy balance regulation in progeny and does not predispose offspring to developing obesity. leptin; pregnancy; developmental programming; mice; high-fat diet BECAUSE OF THE OBESITY EPIDEMIC, the influence of intrauterine and early postnatal conditions on the metabolic phenotypes of individuals later in life has gained increasing attention. Experimental and clinical investigations have shown that maternal obesity during pregnancy increases the risk of the offspring developing obesity (29,39,42). Obesity is characterized by elevated levels of leptin in both nonpregnant and pregnant females (23,30,33). The adipocyte cytokine leptin plays a key role in energy homeostasis regulation (22), and circulating leptin levels are proportional to the body adipose mass (13).A considerable number of studies have identified leptin as a potential programming factor (48). In experimental animal models, expression of the leptin receptor has been detected in various fetal tissues, including cartilage, bone, lung, brain (16), and pancreas (18). Leptin has been shown to activate the differentiation and proliferation of fetal chondrocytes, osteoblasts (2), and islet cells (18) and to promote the migra...

Sex Dimorphism in the Fgf21 Gene Expression in Liver and Adipose Tissues is Dependent on the Metabolic Condition

“…To induce obesity, mice were fed during 10 weeks with mixed diet, which consisted of standard laboratory chow supplemented with sweet cookies, sunflower seeds and lard -sweet and fat diet. Previously we have shown that this sweet and fat diet rapidly induced obesity in C57Bl mice (Makarova et al, 2013). Mice of control group consumed for 10 weeks standard laboratory chow.…”

Sex‐specific effects of leptin administration to pregnant mice on the placentae and the metabolic phenotypes of offspring

“…On GD12, the females received subcutaneous injections of recombinant murine leptin (4.0 µgÁg À1 BW) dissolved in saline to a final concentration of 500 µgÁmL À1 or were injected with saline (control) at 9 h 00 min. According to our previous research, leptin administered at this dose to mice in late pregnancy did not affect the offspring viability but this administration influenced the offspring phenotype [5]. The leptin-and saline-administered mice were divided into three experimental groups.…”

The Effects of Leptin on Placental Development and Function, and Off05 Behavior in Mice

“…These offspring had decreased weight gain after weaning, were not hyperphagic, and gained less weight after fasting , though they were less responsive to exogenous leptin administration (Makarova et al, 2013). The same study found that offspring from wildtype mouse dams injected with leptin at gestational day 17 had lower body weight, and male offspring had reduced food intake and diet induced obesity (Makarova et al, 2013). In contrast, a previous study from our lab showed that female offspring from mouse dams that were food-restricted and administered leptin during the first half of pregnancy became obese when given a high fat diet .…”

“…Also, both male and female offspring from leptin treated dams had increased energy expenditure when on a high fat diet (Stocker et al, 2007). There is some evidence that mouse dams heterozygous for a mutation at the agouti locus have high leptin without other metabolic alterations at a young age, and their offspring were also resistant to obesity (Makarova et al, 2013). These offspring had decreased weight gain after weaning, were not hyperphagic, and gained less weight after fasting , though they were less responsive to exogenous leptin administration (Makarova et al, 2013).…”

“…There is some evidence that mouse dams heterozygous for a mutation at the agouti locus have high leptin without other metabolic alterations at a young age, and their offspring were also resistant to obesity (Makarova et al, 2013). These offspring had decreased weight gain after weaning, were not hyperphagic, and gained less weight after fasting , though they were less responsive to exogenous leptin administration (Makarova et al, 2013). The same study found that offspring from wildtype mouse dams injected with leptin at gestational day 17 had lower body weight, and male offspring had reduced food intake and diet induced obesity (Makarova et al, 2013).…”