Pioglitazone therapy in mouse offspring exposed to maternal obesity

Abstract

Objective Pioglitazone (PIO), an antidiabetic drug of the thiazolidinedione family, improves glucose and lipid metabolism in muscle, adipose, and liver tissues via peroxisome proliferator-activated receptor gamma (PPARγ) activation. We hypothesize that PIO therapy will improve the metabolic status of offspring exposed to maternal obesity in a mouse model developmentally programmed for metabolic syndrome (MetS). Study Design CD-1 female mice were fed a high-fat diet for 3 months prior to breeding and throughout pregnancy and lactation. The pups were weaned to a standard-fat diet. Offspring were randomly assigned to receive 40 mg/kg of PIO in 0.5% of methyl cellulose or 0.5% methyl cellulose by daily oral gavage for 2 weeks. The pre- and post-treatment total body weights of the pups were recorded. Visceral (VAT) and subcutaneous (SAT) adipose tissue were evaluated using micro-computed tomography. Serum analytes were measured. Post-treatment, minimally invasive microendoscopic fluorescence confocal imaging and intraperitoneal glucose tolerance tests were performed. The data were analyzed using appropriate statistical tests (significance, P<0.05). Results PIO therapy resulted in lower total body weight and lower VAT gain, and increased SAT. PIO significantly lowered triglyceride, insulin levels, and HOMA-IR in males, and fasting glucose in females. There was a trend toward larger adipocyte size. Conclusion Short-term PIO therapy in the offspring of obese mothers attenuates metabolic changes associated with the developmental programming of metabolic syndrome. These novel data suggest a potential role for drugs that activate PPARγ receptors to prevent MetS in the adult offspring at risk to develop metabolic alterations.

SIRT1 overexpression attenuates offspring metabolic and liver disorders as a result of maternal high‐fat feeding

“…) and MHF mouse offspring treated with pioglitazone, a PPARγ agonist, have reduced body weight, reduced visceral WAT gain, increased s.c. WAT mass in association with lower levels of fasting glucose and insulin resistance (Kalanderian et al . ). In the present study, IPGTT was reduced and QUICKI was improved in MHF‐Tg offspring, suggesting the positive effect of SIRT1 overexpression on systemic insulin sensitivity and glucose homeostasis.…”

“…It has been shown that the expression of PPARγ and SREBP-1c in S.C. WAT is suppressed in obese patients with insulin resistance (Kolehmainen et al 2001;Dubois et al 2006). Thus, PPARγ agonists are used clinically as insulin sensitizers (Lebovitz et al 2001;Ahmadian et al 2013) and MHF mouse offspring treated with pioglitazone, a PPARγ agonist, have reduced body weight, reduced visceral WAT gain, increased S.C. WAT mass in association with lower levels of fasting glucose and insulin resistance (Kalanderian et al 2013). In the present study, IPGTT was reduced and QUICKI was improved in MHF-Tg offspring, suggesting the positive effect of SIRT1 overexpression on systemic insulin sensitivity and glucose homeostasis.…”

Maternal High-Fat Diet Modulates Hepatic Glucose, Lipid Homeostasis and Gene Expression in the PPAR Pathway in the Early Life of Offspring

“…A previous study in rats also demonstrated that maternal malnutrition leads to alterations in PPAR gene expression (PPARα and PPARγ) in the offspring at 18 months of age [ 27 ]. Another study indicated that short-term Pioglitazone (a potential role for drugs that activate PPARγ receptors) therapy in the offspring of obese mothers attenuates metabolic changes associated with the developmental programming of metabolic syndrome [ 28 ]. A recent study demonstrated that maternal diet induced obesity contributed to metabolism disorder, hepatic lipotoxicity, and liver steatosis in the offspring, and Bezafibrate, which targets PPAR, had beneficial effects in ameliorating these disorders, predominately through the PPARγ activation and the increased PPARα/PPARγ ratio in the liver [ 29 ].…”

Nutritional programming of insulin resistance: causes and consequences

“…A limited number of intervention studies in rodents with different approaches, such as increased physical activity [116], dietary modulation [117], or pharmacologic interventions [118][119][120], are starting to emerge. For example, IUGR rodents exposed to postnatal CR show increased metabolic flexibility and leanness compared to those fed ad libitum postnatally [117].…”