Exposure to chronic early-life stress lastingly alters the adipose tissue, the leptin system and changes the vulnerability to western-style diet later in life in mice

Abstract

Early-life stress (ES) increases the vulnerability to develop psychopathologies and cognitive decline in adulthood. Interestingly, this is often comorbid with metabolic disorders, such as obesity. However, it is unclear whether ES leads to lasting metabolic changes and to what extent this is associated with the ES-induced cognitive impairments. Here, we used an established chronic ES mouse model (from postnatal day (P) 2 to P9) to investigate the short- and long-term effects of ES exposure on parameters of the adipose tissue and the leptin system (i.e. circulating levels and gene expression of leptin and its receptor) in both sexes. Immediately following ES, the offspring exhibited reductions in white adipose tissue (WAT) mass, plasma leptin levels and in leptin mRNA expression in WAT. Furthermore, ES exposure led to increased brown adipose tissue and browning of WAT, which was evident by a drastic increase in uncoupling protein 1 mRNA expression in the inguinal WAT at P9. Notably, the ES-induced reductions in WAT mass, plasma leptin and leptin expression in WAT were sustained into adulthood and were accompanied by changes in body fat distribution, such as a higher ratio between mesenteric WAT and other WATs. Interestingly, while ES exposure increased leptin receptor mRNA expression in the choroid plexus, it was unaltered in the hippocampus. This suggests an adaptation to maintain central leptin homeostasis following ES exposure. In addition, chronic ES exposure resulted in the well-established cognitive impairment in object recognition performance during adulthood, which correlated positively with reductions in WAT mass observed in male, but not in female mice. Finally, to assess if ES leads to a different metabolic phenotype in a moderate obesogenic environment, we measured body fat accumulation of control and ES-exposed mice in response to a moderate western-style diet (WSD) that was provided during adulthood. ES-exposed mice subjected to WSD exhibit a higher increase in adiposity when compared to controls, suggesting that ES exposure might result in a higher vulnerability to develop obesity in a moderate obesogenic environment. To conclude, chronic ES exposure alters parameters of the adipose tissue, leads to central adaptations in leptin regulation and results in higher fat accumulations when exposed to a WSD challenge later in life. A better understanding of these metabolic effects induced by ES might open up new avenues for therapeutic (e.g. nutritional) interventions.

Food for thought: how nutrition impacts cognition and emotion

“…White adipose mass (WAT), plasma leptin (the adipokine released from the WAT) and leptin mRNA expression in WAT are persistently reduced in ES-exposed offspring. 39 In addition, exposure of ES mice to an unhealthy western style diet, leads to a higher increase in adiposity in these mice when compared to controls. These findings suggest that ES exposure leads to metabolic dysregulation and a greater vulnerability to develop obesity in a moderately obesogenic environment.…”

Social Origins of Developmental Risk for Mental and Physical Illness

“…To address this, an alternative limited-bedding paradigm was initially developed in rats (Gilles et al, 1996), obviating the requirement for overt separation of pups and dams typically used in rodent ELS models . This paradigm induces inconsistent and fragmented maternal care (Heun-Johnson and Levitt, 2016), which has since been validated and adopted for use with mice by multiple laboratories Wang et al, 2011Wang et al, , 2013Gunn et al, 2013;Malter Cohen et al, 2013;Liao et al, 2014;Kohl et al, 2015;Naninck et al, 2015;Yang et al, 2015;Arp et al, 2016;Bath et al, 2016Bath et al, , 2017Liu et al, 2016;McIlwrick et al, 2016McIlwrick et al, , 2017Yam et al, 2017). The paradigm provides an ethologically relevant framework for addressing heritability of risk-, sex-, and developmentally dependent influences that determine outcomes following ELS.…”

“…Recent studies indicate that, even in the absence of placental effects, the early postnatal period represents a distinct developmental window for sex-dependent responses to early life stressors (Kawakami et al, 2007;Coutellier and Würbel, 2009;Kikusui and Mori, 2009;Gross et al, 2012;Kawakami et al, 2013;Naninck et al, 2015;Arp et al, 2016;Fuentes et al, 2016;Lerch et al, 2016;Bath et al, 2017;de Azeredo et al, 2017;Yam et al, 2017). For the most part, the mechanisms underlying sex-dependent outcomes in response to exposure to stressors during this later period are poorly understood.…”

Hormonal and nutritional regulation of postnatal hypothalamic development

“…The effects of 196 early life stress on ghrelin are sex-dependent, suggesting that ghrelin does not influence 197 feeding, metabolic, or stress circuitry in this model, since other effects of early life stress on 198 this circuitry are similar between the sexes (Yam et al, 2017b). However, early life stress 199 does lead to a suppression of leptin that may be responsible for some of these long-term 200 weight regulatory effects (Yam et al, 2017a). anything, in an obese phenotype.…”

“…Chronic early life stress is 193 associated with an early reduction in weight gain (P2-P9) followed by a later weight 194 acceleration (P14 onwards) such that the stressed pups have normal weight as adults, but 195 accumulate more adipose when consuming a high fat diet (Yam et al, 2017a). The effects of 196 early life stress on ghrelin are sex-dependent, suggesting that ghrelin does not influence 197 feeding, metabolic, or stress circuitry in this model, since other effects of early life stress on 198 this circuitry are similar between the sexes (Yam et al, 2017b).…”