Obesity programmed by prenatal dexamethasone and postnatal high-fat diet leads to distinct alterations in nutrition sensory signals and circadian-clock genes in visceral adipose tissue

Abstract

Background: Prenatal dexamethasone treatment has been shown to enhance the susceptibility of offspring to postnatal high-fat (HF) diet-induced programmed obesity. We investigated the metabolic phenotypes, nutrient-sensing signal and circadian-clock genes in adipose tissue that are programmed by prenatal dexamethasone exposure and postnatal HF diet.

Methods: Male offspring of Sprague-Dawley rats were divided into four experimental groups: normal diet, prenatal dexamethasone exposure, postnatal HF diet, and prenatal dexamethasone plus postnatal HF diet. Postnatal HF diet was prescribed from weaning to 6 months of age.

Results: Prenatal dexamethasone and postnatal HF diet exerted synergistic effects on body weight and visceral adiposity, whereas prenatal dexamethasone and postnatal HF diet altered the metabolic profile and caused leptin dysregulation. Prenatal dexamethasone and postnatal HF diet distinctly influenced nutrient-sensing molecules and circadian-clock genes in adipose tissue. The mRNA expression of mTOR, AMPK-α2, PPAR-α, and PPAR-γ was suppressed by prenatal dexamethasone but enhanced by postnatal HF diet.

Conclusion: Prenatal dexamethasone and postnatal HF treatment cause dysregulation of nutrient-sensing molecules and circadian-clock genes in visceral adipose tissue. Characterizing altered nutrient-sensing molecules and circadian-clock genes has potential therapeutic relevance with respect to the pathogenesis and treatment of prenatal stress and postnatal HF diet-related metabolic disorders.

Keywords: Adipose tissue; Circadian-clock; Nutrition sensory signals; Postnatal high-fat diet; Prenatal dexamethasone.

Fig. 1

Blood glucose levels in post-stimulation tests. (a) Intraperitoneal glucose tolerance test (IPGTT); (b) Glucose area under the curve (AUC) of IPGTT; (c) plasma insulin level; (d) insulin tolerance test (ITT); and (e) AUC of ITT in the four experimental groups. Results were analyzed using two-way ANOVA (prenatal dexamethasone exposure × postnatal HF diet). All values are presented as the mean ± standard error (n = 8). *P < 0.05. VEH, normal diet; DEX, prenatal dexamethasone exposure; VHF, postnatal HF diet; DHF, prenatal dexamethasone plus postnatal HF diet

Fig. 2

Hit 1/Hit 2 (H1/H2) induced chronic inflammation and leptin dysregulation in visceral adipose tissue. Fold change in the mRNA expression of (a) TNF-receptor 1 (TNF-R1), (b) TNF-R2, and (c) leptin in retroperitoneal adipose tissue was decreased by prenatal dexamethasone exposure and increased by postnatal high-fat (HF) diet. Results were analyzed using two-way ANOVA (prenatal dexamethasone exposure × postnatal HF diet). All values are presented as the mean ± standard error (n = 8). *P < 0.05. VEH, normal diet; DEX, prenatal dexamethasone exposure; VHF, postnatal HF diet; DHF, prenatal dexamethasone plus postnatal HF diet

Fig. 3

Results of western blotting analysis of SIRT1 in the four experimental groups. SIRT1 abundance is shown after normalization with ponceau S abundance. The abundance of SIRT1 protein was decreased by postnatal high-fat (HF) diet exposure. VEH, normal diet; DEX, prenatal dexamethasone exposure; VHF, postnatal HF diet; DHF, prenatal dexamethasone plus postnatal HF diet

Fig. 4

Hit 1/Hit 2 (H1/H2) caused alteration in nutrition sensory signaling. Fold change in the mRNA expression of nutrition sensory signals in retroperitoneal adipose tissue as determined by qRT-PCR: (a) PGC1-α, (b) mTOR, (c) AMPK-α2, (d) PPAR-γ, (e) PPAR-α, and (f) GLUT4. Results were analyzed using two-way ANOVA (prenatal dexamethasone exposure × postnatal HF diet). All values are presented as the mean ± standard error (n = 8). *P < 0.05. VEH, normal diet; DEX, prenatal dexamethasone exposure; VHF, postnatal HF diet; DHF, prenatal dexamethasone plus postnatal HF diet

Fig. 5

H1/H2 altered the expression of circadian-clock genes in visceral adipose tissue. The effects of prenatal dexamethasone and postnatal HF diet on the expression of the circadian-clock genes (a) Bmal-1, (b) Per1, (c) Per2, (d) Cry1, (e) Cry2, (f) CLOCK, (g) Ck1e, and (h) Rev-erbα. Results were analyzed using two-way ANOVA (prenatal dexamethasone exposure × postnatal HF diet). All values are presented as the mean ± standard error (n = 8). *P < 0.05. VEH, normal diet; DEX, prenatal dexamethasone exposure; VHF; postnatal HF diet; DHF, prenatal dexamethasone plus postnatal HF diet