Maternal High-Fat Diet Multigenerationally Programs HPA Function and Behaviors in Male Rat Offspring.

Maternal environmental factors have been demonstrated to exert significant influences on the health of offspring. The hypothalamic-pituitary-adrenal (HPA) axis is an important neuroendocrine stress system that can be influenced by early life challenges. Our previous research has revealed that the consumption of a high-fat diet (HFD) by pregnant and lactating rats leads to the programming of HPA axis activity in male offspring of the first generation (referred to as F1HFD/C). The present study aimed to investigate whether the observed remodeling of the HPA axis could be inherited by second-generation male offspring (referred to as F2HFD/C), following maternal HFD exposure. The results showed that F2HFD/C rats exhibited enhanced basal HPA axis activity, similar to their F1HFD/C ancestors. Moreover, F2HFD/C rats displayed exacerbated corticosterone responses to restraint and lipopolysaccharide-induced stress, but not to insulin-induced hypoglycemia stress. Furthermore, maternal HFD exposure significantly aggravated depression-like behavior in the F2 generation subjected to chronic unpredictable mild stress. To investigate the role of central calcitonin gene-related peptide (CGRP) signaling in maternal diet-induced programming of the HPA axis across generations, we conducted central infusion of αCGRP8-37, a CGRP receptor antagonist, in F2HFD/C rats. The results demonstrated that αCGRP8-37 attenuated depression-like behaviors and reduced the hyperresponsiveness of the HPA axis to restraint stress in these rats. Therefore, central CGRP signaling may contribute to maternal diet-induced programming of HPA axis across generations. In conclusion, our study provides evidence that maternal HFD consumption can lead to multigenerational programming of the HPA axis and behaviors in adult male descendants.

Lin C ，Lei Q ，Yu M ，Lin Y ，Lu H ，Huang Y ，Wang H ，Xu H ，Lin Y ... -  《-》

Maternal high fat diet programs hypothalamic-pituitary-adrenal function in adult rat offspring.

Maternal environmental factors such as diet have profound effects on offspring development and later health. The hypothalamic-pituitary-adrenal (HPA) axis is an important stress neuroendocrine system that is subject to programming by early life challenges. The present study was further to investigate whether maternal high fat diet (HFD) exposure during rat pregnancy and lactation can alter the HPA axis activity in adult male offspring. We observed that maternal HFD consumption exerted long-term effects on the basal activity of the HPA axis in adult offspring, with increased mean plasma corticosterone levels that result from elevated steroid pulse frequence and pulse amplitude. More importantly, maternal HFD offspring displayed enhanced corticosterone responses to restraint (1 h) and lipopolysaccharide (25 μg/kg, iv) but not insulin-induced hypoglycemia (0.3U/kg, iv) stress, suggesting a stressor-specific effect of maternal diet on the hyperresponsiveness of the HPA axis to stress. Additionally, maternal HFD exposure markedly attenuated the habituation of HPA responses to repeated restraint stress. These findings demonstrate that perinatal HFD exposure has a potent and long-lasting influence on development of neuroendocrine regulatory mechanisms. Maternal HFD consumption significantly increased basal corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus; nevertheless, similar increments in CRF mRNA levels following restraint were observed between maternal HFD offspring and control rats. Furthermore, the medial and central nuclei of amygdala played a pivotal role in maternal HFD-induced sensitization of the HPA response to psychological and systemic stress, respectively, suggesting that different neural pathways may mediate maternal HFD-induced HPA hyperresponsivity to different types of stressors. Take together, the long-term effects of maternal HFD challenge on the central regulation of the HPA axis, therefore, expose the adult offspring to greater HPA function throughout lifespan, in stressor-specific and region-specific manner.

Niu X ，Wu X ，Ying A ，Shao B ，Li X ，Zhang W ，Lin C ，Lin Y ... -  《-》

Maternal high fat diet programs stress-induced behavioral disorder in adult offspring.

Early life exposure to specific environmental factors can contribute to development of behavioral disorders in adulthood. Although maternal high fat diet (HFD) consumption during the perinatal period has been reported to program offspring behavior, the underlying mechanisms remain to be elucidated. The present study was designed to evaluate the influence of maternal HFD on offspring behavior under nonstressed and stressful conditions, using male Sprague-Dawley offspring, which mothers were fed with HFD or normal diet (ND), receiving chronic unpredictable mild stress (CUMS) in the adulthood. We found that although the detrimental effects of maternal HFD consumption on offspring depressive behavior did not persist into adulthood, it markedly aggravated the behavioral disorder response to stressful challenge in adult offspring. Moreover, calcitonin gene-related peptide (CGRP) concentration in CSF and hippocampus were increased in the HFD+CUMS rats, compared to the ND+CUMS subjects. Another separate groups were fitted with intracerebroventricular (icv) cannulae. Central infusion of αCGRP8-37, a CGRP antagonist, produced antidepressant effects in HFD+CUMS rats, implying that the programming of maternal HFD on offspring behavior responses to stress may be mediated partially by endogenous central CGRP signaling. Moreover, we found that maternal HFD significantly exacerbated HPA profile response to acute restraint stress and attenuated the habituation of HPA responses to repeated restraint stress, suggesting that maternal HFD may program the changes of HPA-regulatory mechanisms. Overall, our findings suggest that maternal HFD influence adult depressive disorder response to stressful challenge, through the modulation of endogenous central CGRP signaling and HPA-regulatory components.

Lin C ，Shao B ，Huang H ，Zhou Y ，Lin Y ... -  《-》

Perinatal high fat diet induces early activation of endocrine stress responsivity and anxiety-like behavior in neonates.

The maternal environment has a profound effect on the development of offspring, including responses to stress mediated by the hypothalamic-pituitary-adrenal (HPA) axis. In rodents, perinatal high fat diet (HFD) has been shown to program the HPA axis in a manner that persists throughout adulthood, however the effects of perinatal HFD on stress-related behaviors and physiology in neonates are limited. The first two weeks of life in rodents are known as the stress hyporesponsive period, during which animals do not respond to stressors that are otherwise known to elicit behavioral and physiological responses in mature animals. As neonates emerge from the hyporesponsive period, the maturing neural systems mediating the HPA axis leads to the suppression of ultrasonic vocalizations (USVs) and movement in the presence of threatening stimuli, such as male adult rat odor. In this study, we investigated the effects of perinatal HFD exposure, spanning the maternal pregestation, gestation and lactation period, on stress-related behaviors and physiology in neonatal rat offspring throughout the stress hyporesponsive period. During the stress hyporesponsive period, postnatal day (PND) 7, HFD pups had higher corticosterone levels in response to the presence of male odor, produced fewer USVs, and had an increase in basal corticotropin releasing hormone (Crh) transcript levels in the paraventricular nucleus of the hypothalamus. As pup emerged from the stress hyporesponsive period, PND 13, HFD offspring exhibited higher adrenocorticotropic hormone (ACTH) levels in response to male odor, increased anxiety-like behaviors as shown by increased USVs and immobility, and lower glucocorticoid receptor (Nr3c1) transcript abundance in the ventral hippocampus. These results indicate an alteration in the typical physiological and behavioral responses to stress during the hyporesponsive period of the HPA axis as a function of perinatal HFD exposure, which involves changes in the regulation of key genes mediating the HPA axis.

Abuaish S ，Spinieli RL ，McGowan PO 《-》

Prenatal stress programs neuroendocrine stress responses and affective behaviors in second generation rats in a sex-dependent manner.

An adverse environment in early life is often associated with dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis and higher rates of mood disorders in adulthood. In rats, exposure to social stress during pregnancy results in hyperactive HPA axis responses to stress in the adult offspring and heightened anxiety behavior in the males, but not the females. Here we tested whether, without further intervention, the effects of prenatal stress (PNS) in the first filial generation (F1) are transmitted to the F2 generation via the maternal line. F1 control and PNS female rats were mated with control males and housed under non-stress conditions throughout pregnancy. HPA axis responses to acute stress, anxiety- and depressive-like behavior were assessed in the adult F2 offspring. ACTH and corticosterone responses to an acute stressor were markedly enhanced in F2 PNS females compared with controls. This was associated with greater corticotropin releasing hormone (Crh) mRNA expression in the paraventricular nucleus and reduced hippocampal glucocorticoid (Gr) and mineralocorticoid receptor (Mr) mRNA expression. Conversely, in the F2 PNS males, HPA axis responses to acute stress were attenuated and hippocampal Gr mRNA expression was greater compared with controls. F2 PNS males exhibited heightened anxiety-like behavior (light-dark box and elevated plus maze) compared with F2 control males. Anxiety-like behavior did not differ between F2 control and PNS females during metestrus/diestrus, however at proestrus/estrus, F2 control females displayed a reduction in anxiety-like behavior, but this effect was not observed in the F2 PNS females. Heightened anxiety in the F2 PNS males was associated with greater Crh mRNA expression in the central nucleus of the amygdala compared with controls. Moreover, Crh receptor-1 (Crhr1) mRNA expression was significantly increased, whereas Crhr2 mRNA was significantly decreased in discrete regions of the amygdala in F2 PNS males compared with controls, with no differences in the F2 females. No differences in depressive-like behavior (sucrose preference or forced swim test) were observed in either sex. In conclusion, the effects of maternal stress during pregnancy on HPA axis regulation and anxiety-like behavior can be transmitted to future generations in a sex-dependent manner. These data have implications for human neuropsychiatric disorders with developmental origins.

Grundwald NJ ，Brunton PJ 《-》