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Abstract
AimThe aim of the present study was to evaluate whether activation of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma by Bezafibrate (BZ) could attenuate hepatic and white adipose tissue (WAT) abnormalities in male offspring from diet-induced obese dams.Materials and MethodsC57BL/6 female mice were fed a standard chow (SC; 10% lipids) diet or a high-fat (HF; 49% lipids) diet for 8 weeks before mating and during gestation and lactation periods. Male offspring received SC diet at weaning and were subdivided into four groups: SC, SC/BZ, HF and HF/BZ. Treatment with BZ (100 mg/Kg diet) started at 12 weeks of age and was maintained for three weeks.ResultsThe HF diet resulted in an overweight phenotype and an increase in oral glucose intolerance and fasting glucose of dams. The HF offspring showed increased body mass, higher levels of plasmatic and hepatic triglycerides, higher levels of pro-inflammatory and lower levels of anti-inflammatory adipokines, impairment of glucose metabolism, abnormal fat pad mass distribution, higher number of larger adipocytes, hepatic steatosis, higher expression of lipogenic proteins concomitant to decreased expression of PPARalpha and carnitine palmitoyltransferase I (CPT-1) in liver, and diminished expression of PPARgamma and adiponectin in WAT. Treatment with BZ ameliorated the hepatic and WAT abnormalities generated by diet-induced maternal obesity, with improvements observed in the structural, biochemical and molecular characteristics of the animals' livers and epididymal fat.ConclusionDiet-induced maternal obesity lead to alterations in metabolism, hepatic lipotoxicity and adverse liver and WAT remodeling in the offspring. Targeting PPAR with Bezafibrate has beneficial effects reducing the alterations, mainly through reduction of WAT inflammatory state through PPARgamma activation and enhanced hepatic beta-oxidation due to increased PPARalpha/PPARgamma ratio in liver.
Highlights
Obesity and comorbidities is due to environmental factors and to maternal nutrition [1]
The high-fat diet (HF) diet resulted in an overweight phenotype and an increase in oral glucose intolerance and fasting glucose of dams
Treatment with BZ ameliorated the hepatic and white adipose tissue (WAT) abnormalities generated by diet-induced maternal obesity, with improvements observed in the structural, biochemical and molecular characteristics of the animals’ livers and epididymal fat
Summary
Obesity and comorbidities (metabolic syndrome, MS, leading to type 2 diabetes mellitus, DM2, cardiovascular disease, CVD, and non-alcoholic fatty liver disease, NAFLD) is due to environmental factors and to maternal nutrition [1]. According to the Developmental Overnutrition Hypothesis, maternal overnutrition leads to permanent alterations in appetite control, neuroendocrine behavior and/or energetic metabolism in offspring during development, leading to obesity in adulthood even in the absence of excessive energy intake [2,3]. Visceral fat accumulation is a cornerstone for the development of obesity-related pathologies, such as NAFLD, in contrast with subcutaneous WAT [6,7]. NAFLD evolves to non alcoholic steatohepatitis (NASH) because of continuous inflammation and the peroxidation of lipids. Maternal diet during gestation and lactation can induce IR and NAFLD in offspring [3,12]
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