Insulin sensitivity, leptin, adiponectin, resistin, and testosterone in adult male and female rats after maternal-neonatal separation and environmental stress

Abstract

Care of premature infants often requires parental and caregiver separation, particularly during hypoxic and hypothermic episodes. We have established a neonatal rat model of human prematurity involving maternal-neonatal separation and hypoxia with spontaneous hypothermia prevented by external heat. Adults previously exposed to these neonatal stressors show a sex difference in the insulin and glucose response to arginine stimulation suggesting a state of insulin resistance. The current study used this cohort of adult rats to evaluate insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], plasma adipokines (reflecting insulin resistance states), and testosterone. The major findings were that daily maternal-neonatal separation led to an increase in body weight and HOMA-IR in adult male and female rats and increased plasma leptin in adult male rats only; neither prior neonatal hypoxia (without or with body temperature control) nor neonatal hypothermia altered subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia; male-female differences in resistin were lost in the adults that were exposed to hypoxia and spontaneous hypothermia as neonates. Exposure of neonates to daily hypoxia without spontaneous hypothermia led to a decrease in plasma testosterone in adult male rats. We conclude that neonatal stressors result in subsequent adult sex-dependent increases in insulin resistance and adipokines and that our rat model of prematurity with hypoxia without hypothermia alters adult testosterone dynamics.

The effects of flutamide on the neonatal rat hypothalamic–pituitary–adrenal and gonadal axes in response to hypoxia

“…Interestingly, acute hypoxia did not stimulate neonatal testosterone production which does not agree with previous studies (Boksa & Zhang, 2008;Liu & Du, 2002). One possible explanation for this is the prior use of relatively nonspecific immunoassays for testosterone whereas we used a more specific and sophisticated LC-MS/MS method validated for the use in rat plasma (Raff et al, 2018). Regardless, we showed that flutamide has effects in the nonstressed male neonate confirming that an increase in testosterone is not required to exert important physiological effects (Gray et al, 2006;McCormick, Furey, Child, Sawyer, & Donohue, 1998…”

“…The main motivation for this study was our previous findings that neonatal stressors program the control of HPA axis, insulin and glucose, and other metabolic biomarkers in the adult rat in a sexually dimorphic manner (Gehrand et al, 2018(Gehrand et al, , 2016Raff et al, 2018). Based on the literature, we thought that stress-induced testosterone responses in the neonatal male rat could be responsible for this longterm programming (Boksa & Zhang, 2008;Brunton, 2015;Clarkson & Herbison, 2016;Jopek et al, 2017;Kasprzak & Lesniewska, 1986;Liu & Du, 2002;Slob, Ooms, & Vreeburg, 1980;Vega Matuszczyk, Silverin, & Larsson, 1990;Ward, Ward, Denning, French, & Hendricks, 2002).…”

“…Male LH samples were not subject to statistical analysis since most of the results were below the limit of detection. Plasma testosterone levels in male pups were measured by LC-MS/ MS as described previously (Raff et al, 2018). Plasma estradiol levels in female pups were measured via a validated ELISA (Calbiotech #ES180S-100) as described previously (Haisenleder, Schoenfelder, Marcinko, Geddis, & Marshall, 2011).…”

Sex Dimorphic Responses of the Hypothalamus–Pituitary–Thyroid Axis to Maternal Separation and Palatable Diet

“…An HFC feeding increased serum insulin concentration in MS males but reduced that of corticosterone, consistent with previous data (5). MS-induced insulinemia is prevented by mechanical and tactical stimulation of the pups (56), supporting the role of neonatal stress shown to alter the pancreatic beta-cell function and insulin sensitivity in rats, with males being more sensitive than females (58, 59).…”

Electroacupuncture Ameliorates Cognitive Deficit and Improves Hippocampal Synaptic Plasticity in Adult Rat with Neonatal Maternal Separation

“…This result agreed with previous studies examining maternal separation on rats during PND2–9 or PND10–17 [ 39 ]. Some previous studies showed that repeated maternal separation altered body weight in offspring [ 40 , 41 ], which may be related to variation of MS protocol (longer versus shorter time separation), species of animals, or the different postnatal periods of MS [ 42 ]. Moreover, EA stimulation in young adulthood does not affect the weight gain of rats with MS, compared to the MS or control group ( Figure 1(b) ).…”