Perinatal exposure to isocaloric diet with moderate-fat promotes pancreatic islets insulin hypersecretion and susceptibility to islets exhaustion in response to fructose intake in adult male rat offspring.

AIMS: Perinatal maternal hypercaloric diets increase the susceptibility to metabolic disorders in the offspring. We hypothesized that maternal intake of an isocaloric moderate-fat diet (mMFD) would disturb the glucose homeostasis and favor the ß-cell failure in response to fructose overload in adult male offspring. METHODS: Female Wistar rats received an isocaloric diet (3.9 kcal/g) containing 29 % (mMFD) or 9 % as fat (mSTD) prior mating and throughout gestation and lactation. After weaning, male offspring received standard chow and fructose-drinking water (15 %) between 120 and 150 days old. KEY FINDINGS: mMFD offspring had higher body weight, visceral adiposity and, fasting glycemia, with normal insulinemia. Fructose increased glycemia at 15 min from oral glucose administration, but only mMFD had returned to basal glucose levels at 120 min. Fructose increased HOMA-IR index regardless diet, but only mMFD exhibited hyperinsulinemia and a higher HOMA-ß index. mMFD pancreatic islets showed increased area and insulin immunostaining density, suggesting ß-cell hypertrophy. Fructose induced the expected compensatory hypertrophy in mSTD islets, while the opposite occurred in mMFD islets, associated with reduced insulin immunostaining, suggesting lower insulin storage. Pancreatic islets isolated from mMFD offspring exhibited higher glucose-stimulated insulin release at physiological concentrations. However, at higher glucose concentrations, the islets from fructose-treated mMFD reduced dramatically their insulin release, suggesting exhaustion. SIGNIFICANCE: Isocaloric mMFD induced adaptive mechanism in the offspring allowing insulin hypersecretion, but under metabolic challenge with fructose, ß-cell compensation shifts to exhaustion, favoring dysfunction. Therefore, a maternal MFD may contribute to developing diabetes under fructose overload in the adult offspring.

Maternal Isocaloric High-Fat Diet Induces Liver Mitochondria Maladaptations and Homeostatic Disturbances Intensifying Mitochondria Damage in Response to Fructose Intake in Adult Male Rat Offspring.

SCOPE: Perinatal maternal obesity and excessive fructose consumption have been associated with liver metabolic diseases. The study investigates whether moderate maternal high-fat diet affects the liver mitochondria responses to fructose intake in adult offspring. METHODS AND RESULTS: Wistar female rats have received a standard diet (mSTD) or high-fat diet (mHFD) (9% and 28.6% fat, respectively), before mating until the end of lactation. Male offspring were fed standard diet from weaning to adulthood and received water or fructose-drinking water (15%) from 120 to 150 days old. Fructose induces liver mitochondrial ultrastructural alterations with higher intensity in mHFD offspring, accompanied by reduced autophagy markers. Isolated mitochondria respirometry shows unaltered ATP-coupled oxygen consumption with increased Atp5f1b mRNA only in mHFD offspring. Fructose increases basal respiration and encoding complex I-III mRNA, only in mSTD offspring. Uncoupled respiration is lower in mHFD mitochondria that are unable to exhibit fructose-induced increase Ucp2 mRNA. Fructose decreases antioxidative defense markers, increases unfolded protein response and insulin resistance only in mHFD offspring without fructose-induced hepatic lipid accumulation. CONCLUSION: Mitochondrial dysfunction and homeostatic disturbances in response to fructose are early events evidencing the higher risk of fructose damage in the liver of adult offspring from dams fed an isocaloric moderate high-fat diet.

Differentiated Hepatic Response to Fructose Intake during Adolescence Reveals the Increased Susceptibility to Non-Alcoholic Fatty Liver Disease of Maternal High-Fat Diet Male Rat Offspring.

SCOPE: Non-alcoholic fatty liver disease (NAFLD) among adolescents has been related to fructose intake. Additionally, maternal high-fat diet (mHFD) increases the offspring susceptibility to NAFLD at adulthood. Here, it is hypothesized that mHFD may exacerbate the fructose impact in adolescent male rat offspring, by changing the response of contributing mechanisms to liver injury. METHODS AND RESULTS: Female Wistar rats receive standard (mSTD: 9% fat) or high-fat diet (mHFD: 29% fat) prior mating throughout pregnancy and lactation. After weaning, offspring receive standard chow and, from the 25th to 45th day, receive water or fructose-drinking water (15%). At 46 days old, fructose groups show increased adiposity, increased serum and hepatic triglycerides, regardless of maternal diet. Fructose aggravates the hepatic imbalance of redox state already exhibited by mHFD offspring. The hepatic activation of cellular repair pathways by fructose, such as unfolded protein response and macroautophagy, is disrupted only in mHFD offspring. Fructose does not change the liver morphology of mSTD offspring. However, it intensifies the liver injury already present in mHFD offspring. CONCLUSION: Fructose intake during adolescence accelerates the emergence of NAFLD observed previously at the adult life of mHFD offspring, and reveals a differentiated hepatic response to metabolic insult, depending on the maternal diet.

Fish oil supplementation during adolescence attenuates metabolic programming of perinatal maternal high-fat diet in adult offspring.

Perinatal maternal high-fat diet (HFD) increases susceptibility to obesity and fatty liver diseases in adult offspring, which can be attenuated by the potent hypolipidaemic action of fish oil (FO), an n-3 PUFA source, during adult life. Previously, we described that adolescent HFD offspring showed resistance to FO hypolipidaemic effects, although FO promoted hepatic molecular changes suggestive of reduced lipid accumulation. Here, we investigated whether this FO intervention only during the adolescence period could affect offspring metabolism in adulthood. Then, female Wistar rats received isoenergetic, standard (STD: 9 % fat) or high-fat (HFD: 28·6 % fat) diet before mating, and throughout pregnancy and lactation. After weaning, male offspring received the standard diet; and from 25 to 45 d old they received oral administration of soyabean oil or FO. At 150 d old, serum and hepatic metabolic parameters were evaluated. Maternal HFD adult offspring showed increased body weight, visceral adiposity, hyperleptinaemia and decreased hepatic pSTAT3/STAT3 ratio, suggestive of hepatic leptin resistance. FO intake only during the adolescence period reduced visceral adiposity and serum leptin, regardless of maternal diet. Maternal HFD promoted dyslipidaemia and hepatic TAG accumulation, which was correlated with reduced hepatic carnitine palmitoyl transferase-1a content, suggesting lipid oxidation impairment. FO intake did not change serum lipids; however, it restored hepatic TAG content and hepatic markers of lipid oxidation to STD offspring levels. Therefore, we concluded that FO intake exclusively during adolescence programmed STD offspring and reprogrammed HFD offspring male rats to a healthier metabolic phenotype in adult life, reducing visceral adiposity, serum leptin and hepatic TAG content in offspring adulthood.

Perinatal maternal high-fat diet promotes alterations in hepatic lipid metabolism and resistance to the hypolipidemic effect of fish oil in adolescent rat offspring.

SCOPE: Maternal high-fat diet (HFD) promotes obesity and metabolic disturbances in offspring at weaning and adult life. We investigated metabolic consequences of maternal HFD in adolescent rat offspring and the potential benefic effects of fish oil (FO) (n-3 polyunsaturated fatty acid source). METHODS AND RESULTS: Female rats received isocaloric, standard diet (STD: 9% fat) or HFD (28.6%) before mating, and throughout pregnancy and lactation. After weaning, male offspring received standard diet and, from 25th to 45th day, received oral administration of soybean oil (SO) or FO. HFD offspring showed higher body weight and adiposity, which was not attenuated by FO. In STD offspring, FO reduced serum triglyceride and cholesterol, as expected, but not in HFD offspring. Liver of HFD offspring groups showed increased free cholesterol and FO-treated HFD group showed lower expression of Abcg8, suggesting decreased cholesterol biliary excretion. HFD offspring presented higher hepatic expression of lipogenic markers, Srebf1 mRNA and acetyl CoA carboxylase (ACC). Serum n-3 PUFA were decreased in FO-treated HFD compared to FO-treated STD offspring, which may explain the reduced hypolipidemic FO effect. CONCLUSION: Maternal HFD impaired the ability of FO to reduce adiposity and serum lipids in adolescent offspring, suggesting a potential predisposition to future development of metabolic disorders.

ω-3 polyunsaturated fatty acid supplementation does not influence body composition, insulin resistance, and lipemia in women with type 2 diabetes and obesity.

To evaluate the influence of ω-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation on body composition, insulin resistance, and lipemia of women with type 2 diabetes, the authors evaluated 41 women (60.64 ± 7.82 years) with high blood pressure and diabetes mellitus in a randomized and single-blind longitudinal intervention study. The women were divided into 3 groups: GA (2.5 g/d fish oil), GB (1.5 g/d fish oil), and GC (control). The capsules with the supplement contained 21.9% of eicosapentaenoic acid and 14.1% of docosapentaenoic acid. Biochemical (glucose, glycated hemoglobin, total and fractional cholesterol, triglycerides, and insulin) and anthropometric (body mass, stature, waist circumference [WC], and body composition) evaluations were performed before and after the 30 days of intervention. Homeostasis model assessment-insulin resistance and the Quantitative Insulin Sensitivity Check Index were used to evaluate the insulin resistance and insulin sensitivity (IS), respectively. GB presented a greater loss of body mass and WC (P < .05), greater frequency of glycemic and total cholesterol reduction, and an increase of high-density lipoprotein cholesterol compared with GA. Thus, a high dose of ω-3 PUFA can reduce IS. A lower dose of ω-3 PUFA positively influenced body composition and lipid metabolism.