Prenatal caffeine exposure induces high susceptibility to metabolic syndrome in offspring adult female rats and possible mechanism / 中国药理学与毒理学杂志

ABSTRACT

OBJECTIVE To observe the increased susceptibility to metabolic syndrome (MS) in offspring adult female rats which experienced prenatal caffeine exposure (PCE) and underwent early postnatal catch-up growth and late chronic stress, and to explore the underlying mechanism. METHODS Starting from gestational day 11, pregnant Wistar rats were intragastrically administered with caffeine at the dose of 120 mg·kg-1 per day until delivery. The female offspring rats were fed a high-fat diet from postnatal week 4 (PW4) to PW24, and then exposed to two weeks of unpredictable chronic stress at PW38-PW40. Blood glucose and serum adrenocorticotropic hormone, corticosterone, insulin, triglycer? ides, total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) levels were detected. Meanwhile, the mRNA expression of adrenal steroidogenic acute regulatory protein, P450 side- chain cleavage enzyme, 3β- hydroxysteroid dehydrogenase, steroid 11β- hydroxy? lase, steroid 21β- hydroxylase, hepatic insulin receptor, insulin receptor substrate 2 and glucose trans? porter 2 (GLUT2) were examined by real- time quantitative PCR. The morphological changes of the adrenal gland, pancreas and liver were observed using hematoxylin-eosin staining. RESULTS Compared with control group〔(13.9±2.8) g〕, the body mass of the PCE offspring female rats at PW1〔(10.5±1.0) g〕 was significantly lower (P<0.01), which lasted until PW40 (P<0.05, P<0.01). However, the gain rate of body mass was higher in the PCE group at PW4- PW16 (P<0.05, P<0.01). Levels of blood glucose〔(5.9±0.3) mmol·L- 1〕and serum insulin〔(100±31) mU·L-1〕, the insulin resistance index (26.3±5.7), LDL-C〔(0.55±0.05) mmol·L-1〕level and LDL-C/HDL-C ratio (0.87±0.11) were increased compared with (4.3±0.3) mmol·L-1, (45±4) mU·L-1, 8.3±0.9, (0.38±0.04) mmol·L-1 and 0.66±0.07 in the control group, respectively (P<0.05, P<0.01). The mRNA expression of hepatic GLUT2 in the PCE group was lower than in the control group (P<0.05). Furthermore, the thicknesses of the adrenal zona fasciculata was re?duced and the area of pancreatic islets became smaller, but there was no significant change in liver morphology. CONCLUSION PCE offspring adult female rats display high susceptibility to MS, which is mainly manifested as insulin resistance, characterized by hyperglycemia and hyperinsulinemia, lipid metabolism disorder and structural and functional abnormalities of multiple organs. The mechanism is possibly related to the disorder of hypothalamic-pituitary-adrenal axis-associated neuroendocrine meta? bolic programming.