SOCS3 deficiency in leptin receptor-expressing cells mitigates the development of pregnancy-induced metabolic changes

Abstract

ObjectiveDuring 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.MethodsInitially, 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.ResultsAmong 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.ConclusionsOur 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.

Neuronal STAT5 signaling is required for maintaining lactation but not for postpartum maternal behaviors in mice

“…In mice exposed to high-fat diets, increased hypothalamic expression of SOCS3 decreases leptin sensitivity, increases the food intake and favors the development of diet-induced obesity (Briancon et al, 2010; Mori et al, 2004; Pedroso et al, 2014). In addition, our group recently showed that SOCS3 deficiency in leptin receptor-expressing cells blunts the increased food intake typically observed during pregnancy and lactation (Zampieri et al, 2015). Since leptin inhibits food intake in part by reducing the activity of NPY/AgRP neurons (Morton et al, 2014), the reduced hypothalamic SOCS3 expression may have favored the anorexigenic effects of leptin during lactation resulting in lower expression of NPY and AgRP which, in turn, led to the decreased food consumption.…”

Interactions between prolactin and kisspeptin to control reproduction

“…Indeed, several populations of leptin receptorexpressing neurons in mice are directly responsive to prolactin (37). Furthermore, inactivation of the Socs3 gene in leptin receptor-expressing cells improves leptin sensitivity in pregnant mice and mitigates major gestational metabolic adaptions (38). Altogether, these findings suggest that changes in prolactin levels during pregnancy lead to leptin resistance, which, in turn, is responsible for orchestrating many metabolic adaptations commonly observed in pregnant animals.…”

Leptin receptor-positive and leptin receptor-negative proopiomelanocortin neurons innervate an identical set of brain structures

“…Leptin-responsive neurons were determined by assessing cells that expressed pSTAT3 after an acute leptin stimulus, as previously described (Donato Jr. et al, 2010;Nagaishi et al, 2014;Zampieri et al, 2015). Mice were fasted for 5 h and received a subcutaneous injection of mouse recombinant leptin (5 µg/g).…”