SOCS3 deficiency in leptin receptor-expressing cells mitigates the development of pregnancy-induced metabolic changes.
OBJECTIVE
During pregnancy, women normally increase their food intake and body fat mass, and exhibit insulin resistance. However, an increasing number of women are developing metabolic imbalances during pregnancy, including excessive gestational weight gain and gestational diabetes mellitus. Despite the negative health impacts of pregnancy-induced metabolic imbalances, their molecular causes remain unclear. Therefore, the present study investigated the molecular mechanisms responsible for orchestrating the metabolic changes observed during pregnancy.


METHODS
Initially, we investigated the hypothalamic expression of key genes that could influence the energy balance and glucose homeostasis during pregnancy. Based on these results, we generated a conditional knockout mouse that lacks the suppressor of cytokine signaling-3 (SOCS3) only in leptin receptor-expressing cells and studied these animals during pregnancy.


RESULTS
Among several genes involved in leptin resistance, only SOCS3 was increased in the hypothalamus of pregnant mice. Remarkably, SOCS3 deletion from leptin receptor-expressing cells prevented pregnancy-induced hyperphagia, body fat accumulation as well as leptin and insulin resistance without affecting the ability of the females to carry their gestation to term. Additionally, we found that SOCS3 conditional deletion protected females against long-term postpartum fat retention and streptozotocin-induced gestational diabetes.


CONCLUSIONS
Our study identified the increased hypothalamic expression of SOCS3 as a key mechanism responsible for triggering pregnancy-induced leptin resistance and metabolic adaptations. These findings not only help to explain a common phenomenon of the mammalian physiology, but it may also aid in the development of approaches to prevent and treat gestational metabolic imbalances.
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, 05508-000, Brazil.
Thais T
TT
Zampieri
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, 05508-000, Brazil.
Angela M
AM
Ramos-Lobo
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, 05508-000, Brazil.
Isadora C
IC
Furigo
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, 05508-000, Brazil.
João A B
JA
Pedroso
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, 05508-000, Brazil.
Daniella C
DC
Buonfiglio
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, 05508-000, Brazil.
Jose
J
Donato
ARH, arcuate nucleus of the hypothalamus; DIO, diet-induced obesity; DMH, dorsomedial nucleus of the hypothalamus; EGWG, excessive gestational weight gain; GDM, gestational diabetes mellitus; GH-V, placental growth hormone; GTT, glucose tolerance test; Gestational diabetes; Hypothalamus; IR, insulin receptor; ITT, insulin tolerance test; LepR, leptin receptor; Leptin; Leptin resistance; Obesity; PKC, protein kinase C; RP, retroperitoneal; SOCS3, suppressor of cytokine signaling-3; STZ, streptozotocin; Suppressor of cytokine signaling; VMH, ventromedial nucleus of the hypothalamus; pSTAT3, phosphorylation of the signal transducer and activator of transcription 3; pSTAT3-ir, pSTAT3-immunoreactive