Maternal Obesity in Sheep Increases Fatty Acid Synthesis, Upregulates Nutrient Transporters, and Increases Adiposity in Adult Male Offspring after a Feeding Challenge

<div><p>Maternal obesity in women is increasing worldwide. The objective of this study was to evaluate differences in adipose tissue metabolism and function in adult male offspring from obese and control fed mothers subjected to an <i>ad libitum</i> feeding challenge. We developed a model in which obese ewes were fed 150% of feed provided for controls from 60 days before mating to term. All ewes were fed to requirements during lactation. After weaning, F1 male offspring were fed only to maintenance requirements until adulthood (control = 7, obese = 6), when they were fed <i>ad libitum</i> for 12 weeks with intake monitored. At the end of the feeding challenge offspring were given an intravenous glucose tolerance test (IVGTT), necropsied, and adipose tissue collected. During the feeding trial F1obese males consumed more (P < 0.01), gained more weight (P < 0.01) and became heavier (P < 0.05) than F1control males. During IVGTT, Obese F1 offspring were hyperglycemic and hypoinsulinemic (P < 0.01) compared to F1 control F1. At necropsy perirenal and omental adipose depots weights were 47% and 58% greater respectively and subcutaneous fat thickness 41% greater in F1obese vs F1control males (P < 0.05). Adipocyte diameters were greater (P ≤ 0.04) in perirenal, omental and subcutaneous adipose depots in F1obese males (11, 8 and 7% increase vs. control, respectively). When adipose tissue was incubated for 2 hrs with C-14 labeled acetate, subcutaneous, perirenal, and omental adipose tissue of F1 obese males exhibited greater incorporation (290, 83, and 90% increase vs. control, respectively P < 0.05) of acetate into lipids. Expression of fatty acid transporting, binding, and syntheses mRNA and protein was increased (P < 0.05) compared to F1 control offspring. Maternal obesity increased appetite and adiposity associated with increased adipocyte diameters and increased fatty acid synthesis in over-nourished adult male offspring.</p></div

Western blot analysis measurements of fatty acid translocase (CD 36), fatty acid transporter (FATP) 1 and 4, and insulin-sensitive glucose transporter (GLUT4) protein abundance in perirenal (a), omental (b), mesenteric (c), and subcutaneous (d) adipose tissue of male offspring of control ewes (open histogram; n = 7) fed 100% of NRC recommendations and obese ewes (closed histograms; n = 6) fed 150% of NRC recommendations.

<p>Values are means ± SEM. # means tend to differ (P < 0.10), * treatment differences (P < 0.05) and ** treatment differences (P < 0.01)</p

Pattern of weight gain during feeding challenge of male offspring of control ewes (○, n = 7) fed 100% of NRC recommendations and obese ewes (●, n = 6) fed 150% of NRC recommendations during gestation.

<p>Values are means ± SEM. Trt P = 0.1669, time P < 0.0001, Trt x time P < 0.0001.* Treatment differences (P < 0.05) and ** Treatment differences (P < 0.01) compared with control.</p

Biweekly plasma concentrations of glucose (a), insulin (b) and leptin (c) during a feeding challenge of male offspring of control ewes (○, n = 7) fed 100% of NRC recommendations and obese ewes (●, n = 6) fed 150% of NRC recommendations.

<p>Values are means ± SEM. * Mean differences (P < 0.05) and ** mean differences (P < 0.01) at a specific time point between control and obese offspring.</p

Fatty Acid composition (mg/g tissue of tissue) from adult male offspring born to control and obese mothers at necropsy after an <i>ad libitum</i> feeding period

<p>Data are means ± SEM.</p><p>Fatty Acid composition (mg/g tissue of tissue) from adult male offspring born to control and obese mothers at necropsy after an <i>ad libitum</i> feeding period</p

Messenger RNA abundance of fatty acid synthase and acetyl-CoA carboxylase, nutrient transporters and associated molecules in adipose tissue depots from adult male offspring born to control and obese mothers at necropsy after an <i>ad libitum</i> feeding period

<p>Data are means ± SEM.</p><p>Messenger RNA abundance of fatty acid synthase and acetyl-CoA carboxylase, nutrient transporters and associated molecules in adipose tissue depots from adult male offspring born to control and obese mothers at necropsy after an <i>ad libitum</i> feeding period</p

Maternal obesity programs reduced leptin signaling in the pituitary and altered GH/IGF1 axis function leading to increased adiposity in adult sheep offspring

<div><p>Studies in rodents highlight a role for leptin in stimulation of pituitary growth hormone (GH) secretion, with an impact on body composition regulation. We have reported that maternal obesity (MO) during ovine pregnancy results in hyperphagia, glucose-insulin dysregulation, increased adiposity, hypercortisolemia and hyperleptinemia in mature offspring subjected to a bout of <i>ad libitum</i> feeding. We hypothesized that MO reduces leptin signaling in the pituitary and down regulates the GH/IGF1 axis and increases circulating cortisol leading to increased adiposity in their adult offspring. Male lambs born to MO (n = 6) or control (CON, n = 6) ewes were fed only to requirements until placed on a 12 week <i>ad libitum</i> feeding trial at maturity. The pituitary, hypothalamic arcuate nucleus, and liver were collected at necropsy and mRNA and protein expression determined. Plasma cortisol concentrations were increased (P<0.05) in MO vs. CON offspring at the end of the feeding trial. Further, serum concentrations of IGF1 decreased (P<0.01) and GH tended to decrease (P<0.08) in MO vs. CON offspring. Pituitary mRNA and leptin receptor protein expression were decreased in MO vs. CON offspring in association with decreased GH mRNA expression, and decreased IGF1 mRNA and protein expression in liver. Liver 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) expression was increased (P<0.01) and its cofactor hexose-6-phosphate dehydrogenase tended to increase (P<0.06) in MO vs. CON offspring. 11βHSD2 expression remained unchanged. These data indicate that MO induced an increase in liver conversion of cortisone to cortisol in adult offspring and support a role for leptin signaling in the pituitary in mediating offspring adiposity.</p></div

Body and organ weights, adipocyte diameters, acetate incorporation of adipose tissue explants of adult male offspring born to control and Obese mothers at necropsy after an <i>ad libitum</i> feeding challenge.

<p>Data are means ± SEM.</p><p>Body and organ weights, adipocyte diameters, acetate incorporation of adipose tissue explants of adult male offspring born to control and Obese mothers at necropsy after an <i>ad libitum</i> feeding challenge.</p