Timing of Maternal Exposure to a High Fat Diet and Development of Obesity and Hyperinsulinemia in Male Rat Offspring: Same Metabolic Phenotype, Different Developmental Pathways?
Objective. Offspring born to mothers either fed an obesogenic diet throughout their life or restricted to pregnancy and lactation demonstrate obesity, hyperinsulinemia, and hyperleptinemia, irrespective of their postweaning diet. We examined whether timing of a maternal obesogenic diet results in differential regulation of pancreatic adipoinsular and inflammatory signaling pathways in offspring. Methods. Female Wistar rats were randomized into 3 groups: (1) control (CONT): fed a control diet preconceptionally and during pregnancy and lactation; (2) maternal high fat (MHF): fed an HF diet throughout their life and during pregnancy and lactation; (3) pregnancy and lactation HF (PLHF): fed a control diet throughout life until mating, then HF diet during pregnancy and lactation. Male offspring were fed the control diet postweaning. Plasma and pancreatic tissue were collected, and mRNA concentrations of key factors regulating adipoinsular axis signaling were determined. Results. MHF and PLHF offspring exhibited increased adiposity and were hyperinsulinemic and hyperleptinemic compared to CONT. Despite a similar anthropometric phenotype, MHF and PLHF offspring exhibited distinctly different expression for key pancreatic genes, dependent upon maternal preconceptional nutritional background. Conclusions. These data suggest that despite using differential signaling pathways, obesity in offspring may be an adaptive outcome of early life exposure to HF during critical developmental windows. 1. Introduction Early life events contribute substantially to the likelihood of an individual becoming obese, although underlying mechanisms are not well understood. Obesity in women of reproductive age (15 to 44 years) is increasing rapidly, and up to 50% of women in this age range in the USA are now either overweight or obese [1]. This has translated to an exponential increase in the prevalence of obesity during pregnancy with up to 20% of women entering pregnancy with a BMI which would define them as obese [2]. Obesity in pregnancy increases the risks for complications of pregnancy including miscarriage, hypertension, and gestational diabetes [3–5]. Furthermore, it is now well established that maternal obesity leads to an increased risk of obesity and metabolic and cardiovascular disorders in offspring [6–9]. In view of the rising prevalence of obesity in pregnancy and its association with adverse maternal and offspring outcomes, there is a great deal of interest in understanding the mechanistic pathways that link maternal obesity and excess maternal nutrition to increased
References
[1]
M. M. Hillemeier, C. S. Weisman, C. Chuang, D. S. Downs, J. McCall-Hosenfeld, and F. Camacho, “Transition to overweight or obesity among women of reproductive age,” Journal of Women's Health, vol. 20, no. 5, pp. 703–710, 2011.
[2]
J. E. Norman and R. M. Reynolds, “The consequences of obesity and excess weight gain in pregnancy,” Proceedings of the Nutrition Society, vol. 70, no. 4, pp. 450–456, 2011.
[3]
H. A. Abenhaim, R. A. Kinch, L. Morin, A. Benjamin, and R. Usher, “Effect of prepregnancy body mass index categories on obstetrical and neonatal outcomes,” Archives of Gynecology and Obstetrics, vol. 275, no. 1, pp. 39–43, 2007.
[4]
S. D. H. Malnick and H. Knobler, “The medical complications of obesity,” Oxford Journals: Medicine, vol. 99, no. 9, pp. 565–579, 2006.
[5]
P. M. Catalano, “Management of obesity in pregnancy,” Obstetrics and Gynecology, vol. 109, no. 2, pp. 419–433, 2007.
[6]
L. Poston, “Gestational weight gain: influences on the long-term health of the child,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 15, pp. 252–257, 2012.
[7]
H. Hochner, Y. Friedlander, R. Calderon-Margalit et al., “Associations of maternal prepregnancy body mass index and gestational weight gain with adult offspring cardiometabolic risk factors: the Jerusalem perinatal family follow-up study,” Circulation, vol. 125, no. 11, pp. 1381–1389, 2012.
[8]
S. J. Spencer, “Early life programming of obesity: the impact of the perinatal environment on the development of obesity and metabolic dysfunction in the offspring,” Current Diabetes Reviews, vol. 8, no. 1, pp. 55–68, 2012.
[9]
H. Chen, D. Simar, K. Lambert, J. Mercier, and M. J. Morris, “Maternal and postnatal overnutrition differentially impact appetite regulators and fuel metabolism,” Endocrinology, vol. 149, no. 11, pp. 5348–5356, 2008.
[10]
P. M. Catalano, “Obesity and pregnancy—the propagation of a viscous cycle?” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 8, pp. 3505–3506, 2003.
[11]
M. W. Gillman, S. L. Rifas-Shiman, K. Kleinman, E. Oken, J. W. Rich-Edwards, and E. M. Taveras, “Developmental origins of childhood overweight: potential public health impact,” Obesity, vol. 16, no. 7, pp. 1651–1656, 2008.
[12]
E. Oken, E. M. Taveras, K. P. Kleinman, J. W. Rich-Edwards, and M. W. Gillman, “Gestational weight gain and child adiposity at age 3 years,” The American Journal of Obstetrics and Gynecology, vol. 196, no. 4, pp. 322.e1–322.e8, 2007.
[13]
H. M. Ehrenberg, B. M. Mercer, and P. M. Catalano, “The influence of obesity and diabetes on the prevalence of macrosomia,” The American Journal of Obstetrics and Gynecology, vol. 191, no. 3, pp. 964–968, 2004.
[14]
G. J. Howie, D. M. Sloboda, T. Kamal, and M. H. Vickers, “Maternal nutritional history predicts obesity in adult offspring independent of postnatal diet,” Journal of Physiology, vol. 587, no. 4, pp. 905–915, 2009.
[15]
D. M. Sloboda, G. J. Howie, A. Pleasants, P. D. Gluckman, and M. H. Vickers, “Pre- and postnatal nutritional histories influence reproductive maturation and ovarian function in the rat,” PLoS ONE, vol. 4, no. 8, Article ID e6744, 2009.
[16]
M. C. Battista, M. F. Hivert, K. Duval, and J. P. Baillargeon, “Intergenerational cycle of obesity and diabetes: how can we reduce the burdens of these conditions on the health of future generations?” Experimental Diabetes Research, vol. 2011, Article ID 596060, 19 pages, 2011.
[17]
T. J. Kieffer and J. F. Habener, “The adipoinsular axis: effects of leptin on pancreatic β-cells,” The American Journal of Physiology, vol. 278, no. 1, pp. E1–E14, 2000.
[18]
S. L. Gray, C. Donald, A. Jetha, S. D. Covey, and T. J. Kieffer, “Hyperinsulinemia precedes insulin resistance in mice lacking pancreatic β-cell leptin signaling,” Endocrinology, vol. 151, no. 9, pp. 4178–4186, 2010.
[19]
S. D. Covey, R. D. Wideman, C. McDonald et al., “The pancreatic β cell is a key site for mediating the effects of leptin on glucose homeostasis,” Cell Metabolism, vol. 4, no. 4, pp. 291–302, 2006.
[20]
K. J. Dudley, D. M. Sloboda, K. L. Connor, J. Beltrand, and M. H. Vickers, “Offspring of mothers fed a high fat diet display hepatic cell cycle inhibition and associated changes in gene expression and DNA methylation,” PLoS ONE, vol. 6, no. 7, Article ID e21662, 2011.
[21]
K. L. Connor, M. H. Vickers, J. Beltrand, M. J. Meaney, and D. M. Sloboda, “Nature, nurture or nutrition? Impact of maternal nutrition on maternal care, offspring development and reproductive function,” Journal of Physiology, vol. 590, part 9, pp. 2167–2180, 2012.
[22]
J. Beltrand, D. M. Sloboda, K. L. Connor, M. Truong, and M. H. Vickers, “The effect of neonatal leptin antagonism in male rat offspring is dependent upon the interaction between prior maternal nutritional status and post-weaning diet,” Journal of Nutrition and Metabolism, vol. 2012, Article ID 296935, 10 pages, 2012.
[23]
K. L. Connor, M. H. Vickers, C. Cupido, E. Sirimanne, and D. M. Sloboda, “Maternal high fat diet during critical windows of development alters adrenal cortical and medullary enzyme expression in adult male rat offspring,” Journal of the Developmental Origins of Health and Disease, vol. 1, no. 4, pp. 245–254, 2010.
[24]
P. J. Mark, C. Sisala, K. Connor et al., “A maternal high-fat diet in rat pregnancy reduces growth of the fetus and the placental junctional zone, but not placental labyrinth zone growth,” Journal of the Developmental Origins of Health and Disease, vol. 2, no. 1, pp. 63–70, 2011.
[25]
D. R. Matthews, J. P. Hosker, A. S. Rudenski, B. A. Naylor, D. F. Treacher, and R. C. Turner, “Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man,” Diabetologia, vol. 28, no. 7, pp. 412–419, 1985.
[26]
M. P. Hermans, J. C. Levy, R. J. Morris, and R. C. Turner, “Comparison of tests of β-cell function across a range of glucose tolerance from normal to diabetes,” Diabetes, vol. 48, no. 9, pp. 1779–1786, 1999.
[27]
A. B. Bernal, M. H. Vickers, M. B. Hampton, R. A. Poynton, and D. M. Sloboda, “Maternal undernutrition significantly impacts ovarian follicle number and increases ovarian oxidative stress in adult rat offspring,” PLoS ONE, vol. 5, no. 12, Article ID e15558, 2010.
[28]
J. Vandesompele, K. de Preter, F. Pattyn et al., “Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes.,” Genome biology, vol. 3, no. 7, Article ID RESEARCH0034, 2002.
[29]
K. J. Livak and T. D. Schmittgen, “Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method,” Methods, vol. 25, no. 4, pp. 402–408, 2001.
[30]
J. Armitage, L. Poston, and P. Taylor, “Developmental origins of obesity and the metabolic syndrome: the role of maternal obesity,” Frontiers of Hormone Research, vol. 36, pp. 73–84, 2007.
[31]
S. Zhang, L. Rattanatray, J. L. Morrison, L. M. Nicholas, S. Lie, and I. C. McMillen, “Maternal obesity and the early origins of childhood obesity: weighing up the benefits and costs of maternal weight loss in the periconceptional period for the offspring,” Experimental Diabetes Research, vol. 2011, Article ID 585749, 10 pages, 2011.
[32]
N. M. Thompson, A. M. Norman, S. S. Donkin et al., “Prenatal and postnatal pathways to obesity: different underlying mechanisms, different metabolic outcomes,” Endocrinology, vol. 148, no. 5, pp. 2345–2354, 2007.
[33]
T. Fuentes, I. Ara, A. Guadalupe-Grau et al., “Leptin receptor 170？kDa (OB-R170) protein expression is reduced in obese human skeletal muscle: a potential mechanism of leptin resistance,” Experimental Physiology, vol. 95, no. 1, pp. 160–171, 2010.
[34]
Z. Wang, Y. T. Zhou, T. Kakuma et al., “Leptin resistance of adipocytes in obesity: role of suppressors of cytokine signaling,” Biochemical and Biophysical Research Communications, vol. 277, no. 1, pp. 20–26, 2000.
[35]
C. Bj？rb？k, K. El-Haschimi, J. D. Frantz, and J. S. Flier, “The role of SOCS-3 in leptin signaling and leptin resistance,” The Journal of Biological Chemistry, vol. 274, no. 42, pp. 30059–30065, 1999.
[36]
K. Laubner, T. J. Kieffer, N. T. Lam, X. Niu, F. Jakob, and J. Seufert, “Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic β-cells,” Diabetes, vol. 54, no. 12, pp. 3410–3417, 2005.
[37]
C. Peiser, G. P. McGregor, and R. E. Lang, “Leptin receptor expression and suppressor of cytokine signaling transcript levels in high-fat-fed rats,” Life Sciences, vol. 67, no. 24, pp. 2971–2981, 2000.
[38]
G. R. Steinberg, A. C. Smith, S. Wormald, P. Malenfant, C. Collier, and D. J. Dyck, “Endurance training partially reverses dietary-induced leptin resistance in rodent skeletal muscle,” The American Journal of Physiology, vol. 286, no. 1, pp. E57–E63, 2004.
[39]
G. E. White, A. Cotterill, M. R. Addley, E. J. Soilleux, and D. R. Greaves, “Suppressor of cytokine signalling protein SOCS3 expression is increased at sites of acute and chronic inflammation,” Journal of Molecular Histology, vol. 42, no. 2, pp. 137–151, 2011.
[40]
H. Yasukawa, M. Ohishi, H. Mori et al., “IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages,” Nature Immunology, vol. 4, no. 6, pp. 551–556, 2003.
[41]
J. Seufert, “Leptin effects on pancreatic β-cell gene expression and function,” Diabetes, vol. 53, no. 1, pp. S152–S158, 2004.
[42]
A. S. Metlakunta, M. Sahu, and A. Sahu, “Hypothalamic phosphatidylinositol 3-kinase pathway of leptin signaling is impaired during the development of diet-induced obesity in FVB/N mice,” Endocrinology, vol. 149, no. 3, pp. 1121–1128, 2008.
[43]
C. A. Aspinwall, W. J. Qian, M. G. Roper, R. N. Kulkarni, C. R. Kahn, and R. T. Kennedy, “Roles of insulin receptor substrate-1, phosphatidylinositol 3-kinase, and release of intracellular Ca2+ stores in insulin-stimulated insulin secretion in β-cells,” The Journal of Biological Chemistry, vol. 275, no. 29, pp. 22331–22338, 2000.
[44]
I. B. Leibiger, B. Leibiger, T. Moede, and P. O. Berggren, “Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways,” Molecular Cell, vol. 1, no. 6, pp. 933–938, 1998.
[45]
R. L. Martin, E. Perez, Y. J. He, R. Dawson Jr., and W. J. Millard, “Leptin resistance is associated with hypothalamic leptin receptor mRNA and protein downregulation,” Metabolism, vol. 49, no. 11, pp. 1479–1484, 2000.
[46]
J. Wilsey and P. J. Scarpace, “Caloric restriction reverses the deficits in leptin receptor protein and leptin signaling capacity associated with diet-induced obesity: role of leptin in the regulation of hypothalamic long-form leptin receptor expression,” Journal of Endocrinology, vol. 181, no. 2, pp. 297–306, 2004.
[47]
Y. Zhang and P. J. Scarpace, “The role of leptin in leptin resistance and obesity,” Physiology and Behavior, vol. 88, no. 3, pp. 249–256, 2006.
[48]
D. R. Grattan, S. R. Ladyman, and R. A. Augustine, “Hormonal induction of leptin resistance during pregnancy,” Physiology and Behavior, vol. 91, no. 4, pp. 366–374, 2007.
[49]
L. Rui, M. Yuan, D. Frantz, S. Shoelson, and M. F. White, “SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2,” The Journal of Biological Chemistry, vol. 277, no. 44, pp. 42394–42398, 2002.
[50]
K. Ueki, T. Kondo, and C. R. Kahn, “Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms,” Molecular and Cellular Biology, vol. 24, no. 12, pp. 5434–5446, 2004.
[51]
S. B. Jorgensen, O. 'Neill HM, L. Sylow et al., “Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity,” Diabetes, vol. 62, no. 1, pp. 56–64, 2013.
[52]
W. Becker, “Leptin signal transduction,” in Leptin and Leptin Antagonists, A. Gertler, Ed., pp. 1–9, Landes Bioscience, Austin, Tex, USA, 2009.
[53]
R. N. Kulkarni, J. N. Winnay, M. Daniels et al., “Altered function of insulin receptor substrate 1-deficient mouse islets and cultured β-cell lines,” Journal of Clinical Investigation, vol. 104, no. 12, pp. R69–R75, 1999.
[54]
W. Y. Kwong, A. E. Wild, P. Roberts, A. C. Willis, and T. P. Fleming, “Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension,” Development, vol. 127, no. 19, pp. 4195–4202, 2000.
[55]
E. S. Jungheim, E. L. Schoeller, K. L. Marquard, E. D. Louden, J. E. Schaffer, and K. H. Moley, “Diet-induced obesity model: abnormal oocytes and persistent growth abnormalities in the offspring,” Endocrinology, vol. 151, no. 8, pp. 4039–4046, 2010.
[56]
A. J. Watkins, A. Wilkins, C. Cunningham et al., “Low protein diet fed exclusively during mouse oocyte maturation leads to behavioural and cardiovascular abnormalities in offspring,” Journal of Physiology, vol. 586, no. 8, pp. 2231–2244, 2008.
[57]
E. Zambrano, P. M. Martínez-Samayoa, G. L. Rodríguez-González, and P. W. Nathanielsz, “Dietary intervention prior to pregnancy reverses metabolic programming in male offspring of obese rats,” Journal of Physiology, vol. 588, no. 10, pp. 1791–1799, 2010.
[58]
M. S. Patel and M. Srinivasan, “Metabolic programming: causes and consequences,” The Journal of Biological Chemistry, vol. 277, no. 3, pp. 1629–1632, 2002.
[59]
R. A. Simmons, “Role of metabolic programming in the pathogenesis of β-cell failure in postnatal life,” Reviews in Endocrine and Metabolic Disorders, vol. 8, no. 2, pp. 95–104, 2007.
[60]
I. B. Leibiger, B. Leibiger, and P. O. Berggren, “Insulin signaling in the pancreatic β-cell,” Annual Review of Nutrition, vol. 28, pp. 233–251, 2008.
