Maternal Fat-1 Transgene Protects Offspring from Excess Weight Gain, Oxidative Stress, and Reduced Fatty Acid Oxidation in Response to High-Fat Diet

Abstract

Overweight and obesity accompanies up to 70% of pregnancies and is a strong risk factor for offspring metabolic disease. Maternal obesity-associated inflammation and lipid profile are hypothesized as important contributors to excess offspring liver and skeletal muscle lipid deposition and oxidative stress. Here, we tested whether dams expressing the fat-1 transgene, which endogenously converts omega-6 (n-6) to omega-3 (n-3) polyunsaturated fatty acid, could protect wild-type (WT) offspring against high-fat diet induced weight gain, oxidative stress, and disrupted mitochondrial fatty acid oxidation. Despite similar body mass at weaning, offspring from fat-1 high-fat-fed dams gained less weight compared with offspring from WT high-fat-fed dams. In particular, WT males from fat-1 high-fat-fed dams were protected from post-weaning high-fat diet induced weight gain, reduced fatty acid oxidation, or excess oxidative stress compared with offspring of WT high-fat-fed dams. Adult offspring of WT high-fat-fed dams exhibited greater skeletal muscle triglycerides and reduced skeletal muscle antioxidant defense and redox balance compared with offspring of WT dams on control diet. Fat-1 offspring were protected from the reduced fatty acid oxidation and excess oxidative stress observed in offspring of WT high-fat-fed dams. These results indicate that a maternal fat-1 transgene has protective effects against offspring liver and skeletal muscle lipotoxicity resulting from a maternal high-fat diet, particularly in males. Altering maternal fatty acid composition, without changing maternal dietary composition or weight gain with high-fat feeding, may highlight important strategies for n-3-based prevention of developmental programming of obesity and its complications.

Keywords: fatty acid oxidation; maternal obesity; metabolism; omega-3.

Figure 1

Study Design.

Figure 2

Maternal fat-1 transgene alters aconitase activity and complete fatty acid oxidation in fetal liver. Aconitase activity (a) and total fatty acid oxidation (b) were measured in fetal liver samples from WT dams fed a control diet (WT-CD), or offspring of WT or fat-1 hemizygous dams fed a high-fat diet (WT-HF and FAT-HF, respectively) throughout pregnancy, with sample collection at day E18.5. Total fatty acid oxidation is the sum of complete fatty acid oxidation to CO₂ (c) and partially oxidized fatty acids (d). All data are presented as mean ± SD. Different letters above bars denote statistically significant differences between those bars at p < 0.05 significance level.

Figure 3

Maternal fat-1 transgene partially protects offspring from excess weight gain. Weight was measured from weaning to 20 wks in offspring of WT dams fed a control diet (WT-CD), or offspring of WT or fat-1 hemizygous dams fed a high-fat diet (WT-HF and FAT-HF, respectively) throughout pregnancy and lactation. All offspring were WT and were weaned to control or high-fat diet for male (a–c) or female (d–f) offspring. For males, n ≥ 10 per group. For females, n ≥ 5 per group. All data are presented as mean ± SD. * p < 0.05 for difference between WT-CD and WT-HF. ^ p < 0.05 for difference between WT-CD and FAT-HF. # p < 0.05 for difference between WT-HF and FAT-HF. Different letters above bars denote statistically significant differences between those bars at p < 0.05 significance level.

Figure 4

Maternal fat-1 transgene partially protects offspring from insulin resistance. Blood glucose levels were measured following bolus insulin injection (insulin tolerance test) in offspring of WT dams fed a control diet (WT-CD), or offspring of WT or fat-1 hemizygous dams fed a high-fat diet (WT-HF and FAT-HF, respectively) throughout pregnancy and lactation. All offspring were WT and were weaned to control or high-fat diet for male (a–c) or female (d–f) offspring. For c, f, data are the area fall from baseline over 30 minutes with baseline represented as fasting glucose levels. For males, n ≥ 9 per group. For females, n ≥ 5 per group. All data are presented as mean ± SD. * p < 0.05 for difference between WT-CD and WT-HF. Different letters above bars denote statistically significant differences between those bars at p < 0.05 significance level.

Figure 5

Maternal fat-1 transgene improves offspring liver fatty acid oxidation rates. Liver total fatty acid oxidation (b), complete fatty acid oxidation (b) and incomplete fatty acid oxidation (c) were measured at 20 wks in offspring of WT dams fed a control diet (WT-CD), or offspring of WT or fat-1 hemizygous dams fed a high-fat diet (WT-HF and FAT-HF, respectively) throughout pregnancy and lactation. All offspring were WT males (circles) and WT females (triangles) and were weaned to control or high-fat diet (post-weaning diet). Data are presented as mean ± SD. Different letters above bars denote statistically significant differences between those bars at p < 0.05 significance level.

Figure 6

Maternal fat-1 transgene protects offspring from excess intramuscular triglyceride and lower fatty acid oxidation. Skeletal muscle triglyceride content (a), and total (b), complete (c), and incomplete (d) fatty acid oxidation were measured in offspring of WT dams fed a control diet (WT-CD), or offspring of WT or fat-1 hemizygous dams fed a high-fat diet (WT-HF and FAT-HF, respectively) throughout pregnancy and lactation. All offspring were WT males (circles) and WT females (triangles) and were weaned to control or high-fat diet (post-weaning diet). Data are presented as mean ± SD. Different letters above bars denote statistically significant differences between those bars at p < 0.05 significance level.

Figure 7

Maternal fat-1 transgene partially protects from perturbations in antioxidant defense and redox balance. Skeletal muscle aconitase enzyme activity (a), oxidized:reduced glutathione ratio (b), and SIRT3 (c) and MnSOD (d) protein content were measured in offspring of WT dams fed a control diet (WT-CD), or offspring of WT or fat-1 hemizygous dams fed a high-fat diet (WT-HF and FAT-HF, respectively) throughout pregnancy and lactation. All offspring were WT males (circles) and WT females (triangles) and were weaned to control or high-fat diet (post-weaning diet). Data are presented as mean ± SD. Different letters above bars denote statistically significant differences between those bars at p < 0.05 significance level.