Diet‐induced obesity and renal dysfunction is enhanced in female rats exposed to chronic stress during early life
Authors: Murphy Margaret , Wills Caleb , Gilbert Lucas , Cohn Dianne , Loria Analia 
Published: November 2023

Studies in humans and animal models have shown a positive correlation between early life stress (ELS) and the development of cardiovascular disease and type 2 diabetes later in life, but few of them have addressed the sex‐specific disparities.Previously, we have shown that MatSep, a model of ELS in rodents, does not change body weight, glucose tolerance or renal function in male rats fed a 20‐week HFD following weaning. However, we reported that a mouse model of MatSep exaggerated several risk factors for cardiometabolic disease more in female than male mice.Therefore, the goal of this study was to determine whether female rats exposed to MatSep display increased susceptibility to develop cardiometabolic disease in response to a HFD challenge. MatSep was performed in WKY rats by separation (3 hr/day) from the dam during the first two weeks of life (day 2 to 14). Non‐disturbed littermates were used as controls. MatSep and control rats (n=6–8) were placed on a HFD (60% kcal from fat) upon weaning for 10 weeks. At week 9, an oral glucose tolerance test (OGTT) was performed and 3 days before the end of the study, rats were placed in metabolic cages for urine collection. A subset of rats (n=4) was used for the determination of the transcutaneous glomerular filtration rate (GFR). Plasma was collected under anesthesia for metabolite analysis. MatSep exaggerated body weight gain (253±3.9 vs. 234±2.75 g, p<0.05), gonadal fat pad (6.4±0.6 vs. 4.1±0.3 g, p<0.05) and subcutaneous fat pad weights (2.1±0.1 vs. 1.59±0.12 g, p<0.05). Spleen, liver, kidney, left ventricle and adrenal gland weight were similar between groups. MatSep increased plasma leptin levels compared to controls (2113±446 vs. 1548±371 pg/ml) and aldosterone (491±99 vs. 231±30 pg/ml). OGTT was impaired in MatSep rats showing a greater AUC compared to control rats (25776±339 vs. 22491±982 A.U., p<0.05). Transcutaneous GFR was increased in obese MatSep rats compared to control rats (1.1±0.3 vs. 0.78±0.5 ml/min/100g, p<0.05), with elevated urine excretion (18±2 vs. 13±0.7 ml/day, p<0.05) although proteinuria was not different between groups (2.3±0.4 vs. 1.9±0.1 mg/day). MatSep rats also showed increased water intake (25.2±1.7 vs. 21.0±0.5 ml/day, p<0.05) but not food intake (14.6±0.8 vs. 13.5±0.4 g/day). Taken together, these data indicate that MatSep combined with HFD induces obesity, glucose intolerance and alterations in metabolic function comparable to a pre‐diabetic state, including renal hyperfiltration, polydipsia and polyuria in female rats. These factors could increase the risk to develop type 2 diabetes and cardiovascular disease later in life. Thus, we have shown that the metabolic function in female rats and mice exposed to ELS are sensitized in response to a secondary dietary stressor such as a HFD. These data show similar predispositions across species, although the molecular mechanisms may not be identical. These results propose the combination of MatSep with HFD challenge at weaning as a novel paradigm to mimic the higher comorbidities for psychosocial stress and cardiovascular diseases observed in women.Support or Funding InformationNIH R00 HL111354; COBRE P20 GM103527‐06