Maternal metabolic adaptations are necessary for normal
offspring growth and brain development
Angela M. Ramos-Lobo*, Isadora C. Furigo*, Pryscila D. S. Teixeira, Thais T. Zampieri,
Frederick Wasinski, Daniella C. Buonﬁglio & Jose Donato Jr.
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of S
ao Paulo, S
ao Paulo, SP, Brazil
Energy balance, glucose homeostasis,
hypothalamus, metabolic programming.
Jose Donato Jr., Av. Prof. Lineu Prestes,
ao Paulo, SP 05508-000, Brazil.
This study was supported by the S
Research Foundation (FAPESP, Brazil) via
grants (2015/10992-6) and fellowships
(2012/15517-6, 2014/11752-6, 2016/09679-
4, and 2016/20897-3).
Received: 16 November 2017; Revised: 7
February 2018; Accepted: 12 February 2018
Physiol Rep, 6 (5), 2018, e13643,
*These authors contributed equally to this
study as co-ﬁrst authors.
Several metabolic adaptations emerge during pregnancy and continue through
lactation, including increases in food intake and body weight, as well as insu-
lin and leptin resistance. These maternal adaptations are thought to play a role
in offspring viability and success. Using a model of attenuated maternal meta-
bolic adaptations induced by ablation of the Socs3 gene in leptin receptor
expressing cells (SOCS3 KO mice), our study aimed to investigate whether
maternal metabolic changes are required for normal offspring development,
and if their absence causes metabolic imbalances in adulthood. The litters
were subjected to a cross-fostering experimental design to distinguish the pre-
natal and postnatal effects caused by maternal metabolic adaptations. Males
either born or raised by SOCS3 KO mice showed reduced body weight until
8 weeks of life. Both adult males and females born or raised by SOCS3 KO
mice also had lower body adiposity. Despite that, no signiﬁcant changes in
energy expenditure, glucose tolerance or insulin resistance were observed.
However, males either born or raised by SOCS3 KO mice showed reduced
brain mass in adulthood. Furthermore, animals born from SOCS3 KO mice
also had lower proopiomelanocortin ﬁber density in the paraventricular
nucleus of the hypothalamus. In conclusion, these ﬁndings indicate that the
commonly observed metabolic changes in pregnancy and lactation are neces-
sary for normal offspring growth and brain development.
Pregnancy and lactation are exceptional moments, in
which females not only need to attend their own energetic
demands but also provide energy to their offspring (Lady-
man et al. 2010; Woodside et al. 2012). Several metabolic
adaptations emerge during these periods, helping to sup-
ply the additional energy required. For example, pro-
nounced increases in food intake are observed during
gestation and lactation (Ladyman et al. 2010; Woodside
et al. 2012). Pregnancy also leads to insulin resistance
which is thought to play a role to ensure a high placental
glucose uptake (Catalano 2014). Furthermore, pregnant
animals develop leptin resistance which is perceived by a
reduced anorexigenic response to this hormone and by a
lower leptin’s capacity to recruit STAT3 signaling pathway
in the hypothalamus in comparison to virgin animals
(Ladyman and Grattan 2005, 2016; Ladyman et al. 2009,
2012; Trujillo et al. 2011; Nagaishi et al. 2014).
Leptin resistance has been better characterized in diet-
induced obese animals and this condition is a key feature
of obesity (Balland and Cowley 2015). Some authors sug-
gest that leptin resistance can emerge from defects in the
transduction of leptin receptor (LepR) signaling pathways
(Balland and Cowley 2015). Accordingly, obese animals
show increased hypothalamic expression of regulatory
ª 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of
The Physiological Society and the American Physiological Society.
This is an open access article under the terms of the Creative Commons Attribution License,
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2018 | Vol. 6 | Iss. 5 | e13643
Physiological Reports ISSN 2051-817X