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Mechanism of programmed obesity: altered central insulin sensitivity in growth-restricted juvenile female rats

Published online by Cambridge University Press:  21 February 2013

T. Fukami ,
X. Sun ,
T. Li ,
M. Yamada ,
M. Desai  and
M. G. Ross
T. Fukami
Affiliation:
Department of Obstetrics and Gynecology, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
X. Sun
Affiliation:
Department of Obstetrics and Gynecology, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA
T. Li
Affiliation:
Department of Obstetrics and Gynecology, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA
M. Yamada
Affiliation:
Department of Obstetrics and Gynecology, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA
M. Desai
Affiliation:
Department of Obstetrics and Gynecology, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA
M. G. Ross*
Affiliation:
Department of Obstetrics and Gynecology, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA
*
*Address for ccorrespondence: Dr M. G. Ross, Department of Obstetrics and Gynecology, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA90502, USA. (Email [email protected])
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Abstract

Intrauterine growth-restricted (IUGR) offspring are at increased risk of adult obesity, as a result of changes in energy balance mechanisms. We hypothesized that impairment of hypothalamic insulin signaling contributes to hyperphagia in IUGR offspring. Study pregnant dams were 50% food restricted from days 10 to 21 to create IUGR newborns. At 5 weeks of age, food intake was measured following intracerebroventricular (icv) injection of vehicle or insulin (10 mU) in control and IUGR pups. At 6 weeks of age, with pups in fed or fasted (48 h) states, pups received icv vehicle or insulin after which they were decapitated, and hypothalamic arcuate (ARC) nucleus dissected for RNA and protein expression. IUGR rats consumed more food than controls under basal conditions, consistent with upregulated ARC phospho AMP-activated protein kinase (pAMPK) and neuropeptide Y (NPY). Insulin acutely reduced food intake in both control and IUGR rats. Consistent with anorexigenic stimulation, central insulin decreased AMP-activated protein kinase and NPY mRNA expression and increased proopiomelanocortin mRNA expression and pAkt, with significantly reduced responses in IUGR as compared with controls. Despite feeding, IUGR offspring exhibit a persistent state of orexigenic stimulation in the ARC nucleus and relative resistance to the anorexigenic effects of icv insulin. These results suggest that impaired insulin signaling contributes to hyperphagia and obesity in IUGR offspring.

Keywords

appetitefetal programminghyperphagiaintrauterine growth restrictioninsulin resistance
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 4 , Issue 3 , June 2013 , pp. 239 - 248
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2013 

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References

1.Whitlock, EP, O'Connor, EA, Williams, SB, Beil, TL, Lutz, KW. Effectiveness of weight management interventions in children: a targeted systematic review for the USPSTF. Pediatrics. 2010; 125, e396–e418.CrossRefGoogle ScholarPubMed
2.Ramachandrappa, S, Farooqi, IS. Genetic approaches to understanding human obesity. J Clin Invest. 2011; 121, 2080–2086.CrossRefGoogle ScholarPubMed
3.Harder, T, Schellong, K, Stupin, J, Dudenhausen, JW, Plagemann, A. Where is the evidence that low birthweight leads to obesity? Lancet. 2007; 369, 1859.CrossRefGoogle ScholarPubMed
4.Vickers, MH, Breier, BH, Cutfield, WS, Hofman, PL, Gluckman, PD. Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab. 2000; 279, E83–E87.CrossRefGoogle ScholarPubMed
5.Godfrey, KM, Lillycrop, KA, Burdge, GC, Gluckman, PD, Hanson, MA. Epigenetic mechanisms and the mismatch concept of the developmental origins of health and disease. Pediatr Res. 2007; 61, 5R–10R.CrossRefGoogle ScholarPubMed
6.Gluckman, PD, Hanson, MA. Living with the past: evolution, development, and patterns of disease. Science. 2004; 305, 1733–1736.CrossRefGoogle ScholarPubMed
7.Yura, S, Itoh, H, Sagawa, N, et al. Role of premature leptin surge in obesity resulting from intrauterine undernutrition. Cell Metab. 2005; 1, 371–378.CrossRefGoogle ScholarPubMed
8.Delahaye, F, Breton, C, Risold, PY, et al. Maternal perinatal undernutrition drastically reduces postnatal leptin surge and affects the development of arcuate nucleus proopiomelanocortin neurons in neonatal male rat pups. Endocrinology. 2008; 149, 470–475.CrossRefGoogle ScholarPubMed
9.García, AP, Palou, M, Priego, T, et al. Moderate caloric restriction during gestation results in lower arcuate nucleus NPY- and alphaMSH-neurons and impairs hypothalamic response to fed/fasting conditions in weaned rats. Diabetes Obes Metab. 2010; 12, 403–413.CrossRefGoogle ScholarPubMed
10.Desai, M, Byrne, CD, Zhang, J, et al. Programming of hepatic insulin-sensitive enzymes in offspring of rat dams fed a protein-restricted diet. Am J Physiol. 1997; 272, G1083–G1090.Google ScholarPubMed
11.Zinkhan, EK, Fu, Q, Wang, Y, et al. Maternal hyperglycemia disrupts histone 3 lysine 36 trimethylation of the IGF-1 gene. J Nutr Metab. 2012; doi:10.1155/2012/930364.CrossRefGoogle ScholarPubMed
12.Fukami, T, Sun, X, Li, T, Desai, M, Ross, MG. Mechanism of programmed obesity in intrauterine fetal growth restricted offspring: paradoxically enhanced appetite stimulation in fed and fasting states. Reprod Sci. 2012; 19, 423–430.CrossRefGoogle ScholarPubMed
13.Desai, M, Gayle, D, Babu, J, Ross, MG. The timing of nutrient restriction during rat pregnancy/lactation alters metabolic syndrome phenotype. Am J Obstet Gynecol. 2007; 196, e551–e557.CrossRefGoogle ScholarPubMed
14.Desai, M, Gayle, D, Han, G, Ross, MG. Programmed hyperphagia due to reduced anorexigenic mechanisms in intrauterine growth-restricted offspring. Reprod Sci. 2007; 14, 329–337.CrossRefGoogle ScholarPubMed
15.Woods, SC, Chavez, M, Park, CR, et al. The evaluation of insulin as a metabolic signal influencing behavior via the brain. Neurosci Biobehav Rev. 1996; 20, 139–144.CrossRefGoogle ScholarPubMed
16.Havrankova, J, Schmechel, D, Roth, J, Brownstein, M. Identification of insulin in rat brain. Proc Natl Acad Sci USA. 1978; 75, 5737–5741.CrossRefGoogle ScholarPubMed
17.Muroya, S, Funahashi, H, Yamanaka, A, et al. Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. Eur J Neurosci. 2004; 19, 1524–1534.CrossRefGoogle Scholar
18.Brown, LM, Clegg, DJ, Benoit, SC, Woods, SC. Intraventricular insulin and leptin reduce food intake and body weight in C57BL/6J mice. Physiol Behav. 2006; 89, 687–691.CrossRefGoogle ScholarPubMed
19.Schwartz, MW, Sipols, AJ, Marks, JL, et al. Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology. 1992; 130, 3608–3616.CrossRefGoogle ScholarPubMed
20.Koide, Y, Kimura, S, Inoue, S, et al. Responsiveness of hypophyseal-adrenocortical axis to repetitive administration of synthetic ovine corticotropin-releasing hormone in patients with isolated adrenocorticotropin deficiency. J Clin Endocrinol Metab. 1986; 63, 329–335.CrossRefGoogle ScholarPubMed
21.Wood, TL, Berelowitz, M, Gelato, MC, et al. Hormonal regulation of rat hypothalamic neuropeptide mRNAs: effect of hypophysectomy and hormone replacement on growth-hormone-releasing factor, somatostatin and the insulin-like growth factors. Neuroendocrinology. 1991; 53, 298–305.CrossRefGoogle ScholarPubMed
22.McGowan, MK, Andrews, KM, Fenner, D, Grossman, SP. Chronic intrahypothalamic insulin infusion in the rat: behavioral specificity. Physiol Behav. 1993; 54, 1031–1034.CrossRefGoogle ScholarPubMed
23.Hallschmid, M, Benedict, C, Born, J, Fehm, HL, Kern, W. Manipulating central nervous mechanisms of food intake and body weight regulation by intranasal administration of neuropeptides in man. Physiol Behav. 2004; 83, 55–64.CrossRefGoogle ScholarPubMed
24.Sipols, AJ, Baskin, DG, Schwartz, MW. Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes. 1995; 44, 147–151.CrossRefGoogle ScholarPubMed
25.Desai, M, Gayle, D, Babu, J, Ross, MG. Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. Am J Physiol Regul Integr Comp Physiol. 2005; 288, R91–R96.CrossRefGoogle ScholarPubMed
26.Desai, M, Gayle, D, Babu, J, Ross, MG. Permanent reduction in heart and kidney organ growth in offspring of undernourished rat dams. Am J Obstet Gynecol. 2005; 193, 1224–1232.CrossRefGoogle ScholarPubMed
27.Desai, M, Guang, H, Ferelli, M, Kallichanda, N, Lane, RH. Programmed upregulation of adipogenic transcription factors in intrauterine growth-restricted offspring. Reprod Sci. 2008; 15, 785–796.CrossRefGoogle ScholarPubMed
28Desai, M, Babu, J, Ross, MG. Programmed metabolic syndrome: prenatal undernutrition and postweaning overnutrition. Am J Physiol Regul Integr Comp Physiol. 2007; 293, R2306–R2314.CrossRefGoogle ScholarPubMed
29.Matthews, PA, Samuelsson, AM, Seed, P, et al. Fostering in mice induces cardiovascular and metabolic dysfunction in adulthood. J Physiol. 2011; 589, 3969–3981.CrossRefGoogle ScholarPubMed
30Clark, JT, Kalra, PS, Kalra, SP. Neuropeptide Y stimulates feeding but inhibits sexual behavior in rats. Endocrinology. 1985; 117, 2435–2442.CrossRefGoogle ScholarPubMed
31.Keen-Rhinehart, E, Desai, M, Ross, MG. Central insulin sensitivity in male and female juvenile rats. Horm Behav. 2009; 56, 275–280.CrossRefGoogle ScholarPubMed
32.Synowski, SJ, Smart, AB, Warwick, ZS. Meal size of high-fat food is reliably greater than high-carbohydrate food across externally-evoked single-meal tests and long-term spontaneous feeding in rat. Appetite. 2005; 45, 191–194.CrossRefGoogle ScholarPubMed
33.Bassil, MS, Hwalla, N, Obeid, OA. Meal pattern of male rats maintained on histidine-, leucine-, or tyrosine-supplemented diet. Obesity. 2007; 15, 616–623.CrossRefGoogle ScholarPubMed
34.Yamada, M, Wolfe, D, Han, G, et al. Early onset of fatty liver in growth-restricted rat fetuses and newborns. Congenit Anom (Kyoto). 2011; 51, 167–173.CrossRefGoogle ScholarPubMed
35.Schwartz, MW, Woods, SC, Porte, D Jr, Seeley, RJ, Baskin, DG. Central nervous system control of food intake. Nature. 2000; 404, 661–671.CrossRefGoogle ScholarPubMed
36.Murphy, KG, Bloom, SR. Gut hormones and the regulation of energy homeostasis. Nature. 2006; 444, 854–859.CrossRefGoogle ScholarPubMed
37.Belgardt, BF, Brüning, JC. CNS leptin and insulin action in the control of energy homeostasis. Ann NY Acad Sci. 2010; 1212, 97–113.CrossRefGoogle ScholarPubMed
38.Duffey, KJ, Popkin, BM. Energy density, portion size, and eating occasions: contributions to increased energy intake in the United States, 1977–2006. PLoS Med. 2011; 8, e1001050.CrossRefGoogle ScholarPubMed
39.Davidowa, H, Plagemann, A. Insulin resistance of hypothalamic arcuate neurons in neonatally overfed rats. Neuroreport. 2007; 18, 521–524.CrossRefGoogle ScholarPubMed
40.Jia, Y, Nguyen, T, Desai, M, Ross, MG. Programmed alterations in hypothalamic neuronal orexigenic responses to ghrelin following gestational nutrient restriction. Reprod Sci. 2008; 15, 702–709.CrossRefGoogle Scholar
41.Martin, TL, Alquier, T, Asakura, K, et al. Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle. J Biol Chem. 2006; 281, 18933–18941.CrossRefGoogle ScholarPubMed
42.Minokoshi, Y, Alquier, T, Furukawa, N, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004; 428, 569–574.CrossRefGoogle ScholarPubMed
43.Kahn, BB, Alquier, T, Carling, D, Hardie, DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005; 1, 15–25.CrossRefGoogle ScholarPubMed
44.Ramamurthy, S, Ronnett, GV. Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain. J Physiol. 2006; 574, 85–93.CrossRefGoogle ScholarPubMed
45.Minokoshi, Y, Shiuchi, T, Lee, S, Suzuki, A, Okamoto, S. Role of hypothalamic AMP-kinase in food intake regulation. Nutrition. 2008; 24, 786–790.CrossRefGoogle ScholarPubMed
46.Andersson, U, Filipsson, K, Abbott, CR, et al. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem. 2004; 279, 12005–12008.CrossRefGoogle Scholar
47.Kim, MS, Park, JY, Namkoong, C, et al. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med. 2004; 10, 727–733.CrossRefGoogle ScholarPubMed
48.Lage, R, Vázquez, MJ, Varela, L, et al. Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. FASEB J. 2010; 24, 2670–2679.CrossRefGoogle Scholar
49.Kola, B, Hubina, E, Tucci, SA, et al. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem. 2005; 280, 25196–25201.CrossRefGoogle ScholarPubMed
50.Roman, EA, Cesquini, M, Stoppa, GR, et al. Activation of AMPK in rat hypothalamus participates in cold-induced resistance to nutrient-dependent anorexigenic signals. J Physiol. 2005; 568, 993–1001.CrossRefGoogle ScholarPubMed
51.Schultz-Klarr, S, Wright-Richey, J, Dunbar, JC. Plasma glucose, insulin and cardiovascular responses after intravenous intracerebroventricular injections of insulin, 2-deoxyglucose and glucose in rats. Diabetes Res Clin Pract. 1994; 26, 81–89.CrossRefGoogle ScholarPubMed
52.Stoppa, GR, Cesquini, M, Roman, EA, et al. Intracerebroventricular injection of citrate inhibits hypothalamic AMPK and modulates feeding behavior and peripheral insulin signaling. J Endocrinol. 2008; 198, 157–168.CrossRefGoogle ScholarPubMed
53.Duckworth, WC, Bennett, RG, Hamel, FG. Insulin degradation: progress and potential. Endocr Rev. 1998; 19, 608–624.Google ScholarPubMed
54.Lehrer, S. Rats on 22.5-hr light:dark cycles have vaginal opening earlier than rats on 26-hr light:dark cycles. J Pineal Res. 1986; 3, 375–378.CrossRefGoogle ScholarPubMed
55.Eckel, LA, Houpt, TA, Geary, N. Spontaneous meal patterns in female rats with and without access to running wheels. Physiol Behav. 2000; 70, 397–405.CrossRefGoogle ScholarPubMed
56.Spary, EJ, Maqbool, A, Batten, TF. Changes in oestrogen receptor alpha expression in the nucleus of the solitary tract of the rat over the oestrous cycle and following ovariectomy. J Neuroendocrinol. 2010; 22, 492–502.CrossRefGoogle ScholarPubMed
57.Jeffery, GS, Peng, KC, Wagner, EJ. The role of phosphatidylinositol-3-kinase and AMP-activated kinase in the rapid estrogenic attenuation of cannabinoid-induced changes in energy homeostasis. Pharmaceuticals. 2011; 4, 630–651.CrossRefGoogle Scholar
58.Gao, Q, Mezei, G, Nie, Y, et al. Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nat Med. 2007; 13, 89–94.CrossRefGoogle ScholarPubMed
59.Musatov, S, Chen, W, Pfaff, DW, et al. Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc Natl Acad Sci USA. 2007; 104, 2501–2506.Google ScholarPubMed
60.Pelletier, G, Rhéaume, E, Simard, J. Variations of pre-proNPY mRNA in the arcuate nucleus during the rat estrous cycle. Neuroreport. 1992; 3, 253–255.CrossRefGoogle ScholarPubMed