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Gestational diabetes mellitus (GDM) is associated with a high-risk for metabolic complications in offspring. However, exercise is recognized as a non-pharmacological strategy against metabolic disorders and is recommended in GDM treatment. This study aimed to investigate whether gestational exercise (GE) could modulate maternal high-fat high-sucrose (HFHS) diet-related hepatic metabolic and mitochondrial outcomes in female offspring of mothers with HFHS-induced GDM. Female Sprague-Dawley rats were fed with control or HFHS diet and kept sedentary or submitted to GE. Their female offspring were fed with control diet and kept sedentary. Hepatic lipid accumulation, lipid metabolism regulators, mitochondrial biogenesis and dynamics markers, and microRNAs associated to the regulation of these markers were evaluated. Female offspring of GDM mothers showed increased body weight at early age, whereas GE prevented this effect of maternal HFHS-feeding and reduced hepatic lipid accumulation. GE stimulated hepatic mRNA transcription and protein expression of mitochondrial biogenesis markers (peroxisome proliferator-activated receptor-gamma co-activator-1alpha and mitochondrial transcription factor A) and mRNA transcription of mitochondrial dynamics markers (mitofusin-1, mitofusin-2, and dynamin-related protein-1) that were altered by maternal GDM, while mitochondrial dynamics markers protein expression was not affected by maternal diet/GE except for optic atrophy-1. MicroRNAs associated with these processes (miR-122, miR-34a, miR-130b, miR-494), and the expression of auto/mitophagy- and apoptosis-related proteins were not substantially influenced by altered intrauterine environment. Our findings suggest that GE is an important regulator of the intrauterine environment positively affecting liver metabolism and promoting liver mitochondrial biogenesis in female offspring despite eventual effects of maternal HFHS-feeding and related GDM. Highlights: Maternal lifestyle can affect hepatic metabolic status of their female offspring; Female offspring hepatic metabolism is affected by maternal high-fat/sucrose diet; Gestational exercise mitigated maternal diet-related harmful outcomes on offspring liver; Gestational exercise is an important regulator of offspring mitochondrial biogenesis and dynamics; Exercise programs should be encouraged in clinical counseling during pregnancy. This work was supported by the EU's Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie Actions (No.722619, FOIE GRAS; No.734719, mtFOIE GRAS) and by the Por tuguese Foundation for Science and Technology (FCT) (FCT/UID/DTP/00617/2020-base; POCI-01-0145-FEDER-016690-PTDC/DTP-DES/7087/2014; POCI-01-0145-FEDER-016657-PTDC/DTP-DES/1082/2014), to JB (SFRH/BD/129645/2017). info:eu-repo/semantics/publishedVersion

Background Maternal high-caloric nutrition and related gestational diabetes mellitus (GDM) are associated with a high-risk for developing metabolic complications later in life and in their offspring. In contrast, exercise is recognized as a non-pharmacological strategy against metabolic dysfunctions associated to lifestyle disorders. Therefore, we investigated whether gestational exercise delays the development of metabolic alterations in GDM mothers later in life, but also protects 6-week-old male offspring from adverse effects of maternal diet. Methods Female Sprague-Dawley rats were fed with either control (C) or high-fat high-sucrose (HFHS) diet to induce GDM and submitted to gestational exercise during the 3 weeks of pregnancy. Male offspring were sedentary and fed with C-diet. Results Sedentary HFHS-fed dams exhibited increased gestational body weight gain (p

The etiology of nonalcoholic fatty liver disease (NAFLD) has been associated for long with oxidative stress and mitochondrial dysfunction, which are both known to be positively modulated by exercise. The present chapter discusses the role of oxidative stress in disease pathophysiology and the main alterations found in the by-products of lipid, protein, and nucleic acid oxidation. Moreover, physical exercise being one of the first-line therapies for NAFLD, this chapter also addresses the effectiveness of this nonpharmacological intervention in the improvement of liver function through redox remodeling, as well as the possibility of mitigating NAFLD features in the absence of remarkable redox changes.

Mitochondrial membrane lipid composition is a critical factor in non-alcoholic steatohepatitis (NASH). Exercise is the most prescribed therapeutic strategy against NASH and a potential modulator of lipid membrane. Thus, we aimed to analyze whether physical exercise exerted preventive (voluntary physical activity – VPA) and therapeutic (endurance training – ET) effect on NASH-induced mitochondrial membrane changes. Sprague-Dawley rats (n = 36) were divided into standard-diet sedentary (SS, n = 12), standard-diet VPA (SVPA, n = 6), high-fat diet sedentary (HS, n = 12) and high-fat diet VPA (HVPA, n = 6). After 9 weeks of diet-specific feeding, half of SS and HS group were engaged in an ET program for 8 weeks/5 day/week/1 h/day (SET, HET). Liver mitochondria were isolated for oxygen consumption and transmembrane-electric potential (ΔΨ) assays. Mitochondrial phospholipid classes and fatty acids were quantified through thin layer chromatography and gas chromatography, respectively, while cardiolipin (CL), phosphatidylcholine (PC) phosphatidylethanolamine (PE) and phosphatidylinositol (PI) molecular profile was determined by electrospray mass spectrometry. In parallel with histological signs of NASH, high-fat diet decreased PI, CL and PC/PE ratio, whereas PE and phosphatidic acid content increased in sedentary animals (HS vs. SS). Moreover, a decrease in linolelaidic, monounsaturated fatty acids content and an increase in saturated fatty acids (SFAS) were observed. Along with phospholipidomic alterations, HS animals showed a decrease in respiratory control ratio (RCR), ΔΨ and FCCP-induced uncoupling respiration (HS vs. SS). Both phospholipidomic (PC/PE, SFAS) and mitochondrial respiratory alterations were counteracted by exercise interventions. Exercise used as preventive (VPA) or therapeutic (ET) strategies preserved liver mitochondrial phospholipidomic profile and maintained mitochondrial function in a model of NASH.