Maternal bitter melon supplementation reduces the risk for metabolic defects later in life: effects on lipidhandling, oxidative stress and inflammation in offspring born to damsfed a high fructose diet

Abstract

The relationship between fructose consumption and metabolic

diseases has drawn substantial attention in recent years. Dietary fructose

consumption has climbed dramatically in the past 40 years, and this trend

coincides with the prevalence of obesity and diabetes worldwide. In

rodents, maternal obesogenic diets are associated with higher risks of

metabolic derangement later in life whereas bitter melon (BM)

supplementation has been shown to improve blood glucose and lipid

profiles. The overall objective of this thesis was to test the hypothesis that

through developmental programming metabolic derangement in offspring

born to rat dams fed a high-fructose (F) diet could be offset by the addition

of BM to the maternal diet.

Virgin female rats received a control (C), F (60%) or BM-supplemented

F (FBM,1%) diet 8 weeks before conception and throughout gestation and

lactation. Weaned male offspring consumed C diet (C/C,F/C,FBM/C) for 11

weeks. The concentrations of serum insulin, triglyceride, free fatty acid

(FFA), and hepatic lipids in FBM/C offspring matched that in C/C offspring

and were significantly lower than F/C offspring. These phenotypic changes

were accompanied with suppressed hepatic lipogenic gene expression but

enhanced expression of lipid oxidation-related genes.

In the second experiment, we extended the earlier findings by

examining whether adding BM to F-fed dams would still benefit offspring if

they continued to consume the F diet postweaning. This simulates the

scenario in affluent societies where fructose overconsumption may occur in

two consecutive generations. The dose-response effect of BM at doses of

0.85% (FBM1) and 1% (FBM2) was also examined. Male offspring born to

dams fed the C, F, FBM1 or FBM2 diet were weaned to C or F diet

(C/C,C/F,F/F,FBM1/F,FBM2/F) for 20 weeks. BM normalized the serum

FFA elevation observed in F/F offspring, although hyperinsulinemia

remained in FBM1/F and FBM2/F offspring. The altered liver lipid profile

and its molecular changes observed in F/F offspring were ameliorated by

maternal BM supplementation. Lower adipose expression of

mesoderm-specific transcript, hormone sensitive lipase, sterol regulatory

element-binding transcription factor 1, and peroxisome

proliferator-activated receptor-gamma (PPARγ) and PPARγ-target genes in

FBM1/F and FBM2/F offspring indicated that BM could reduce adipocyte

size as well as lower lipolysis and lipogenesis.

Since FFA stimulates reactive oxygen species generation that

enhances cellular stress, oxidative stress and inflammation in offspring of

two-generation F exposure with or without maternal BM supplementation

were examined. FBM1/F and FBM2/F offspring showed reduced lipid

peroxidation but enhanced antioxidant capacity in the liver. BM suppressed

the expression of proinflammatory genes and phosphorylation of c-Jun

amino terminal kinase1, as well as promoted insulin receptor substrate 1

protein expression. These BM-mediated antioxidant and anti-inflammatory

effects may be associated with a reduction of circulating FFA.

Taken together, the data support the concept of developmental

programming as maternal fructose clearly induced dyslipidemia, adipocyte

dysfunction, oxidative stress and inflammation in offspring. That these

abnormalities were largely reversed by adding BM to the maternal diet

suggests that perinatal BFC supplementation could alter the course of

maternal malnutrition-induced metabolic defects later in life.