Horm Metab Res 2013; 45(13): 935-944
DOI: 10.1055/s-0033-1351281
Review
© Georg Thieme Verlag KG Stuttgart · New York

Effects of Neonatal Programming on Hypothalamic Mechanisms Controlling Energy Balance

C. Contreras*
1   Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
2   CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
,
M. G. Novelle*
1   Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
2   CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
,
R. Leis
3   Department of Pediatrics, University of Santiago de Compostela, Santiago de Compostela, Spain
,
C. Diéguez
1   Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
2   CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
,
S. Skrede
4   Dr. Einar Martens’ Research Group for Biological Psychiatry, Department of Clinical Science, University of Bergen, Bergen, Norway
5   Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
,
M. López
1   Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
2   CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
› Author Affiliations
Further Information

Publication History

received 03 May 2013

accepted 25 June 2013

Publication Date:
02 August 2013 (online)

Abstract

The prevalence of overweight and obesity in most developed countries has markedly increased during the last decades. In addition to genetic, hormonal, and metabolic influences, environmental factors like fetal and neonatal nutrition play key roles in the development of obesity. Interestingly, overweight during critical developmental periods of fetal and/or neonatal life has been demonstrated to increase the risk of obesity throughout juvenile life into adulthood. In spite of this evidence, the specific mechanisms underlying this fetal/neonatal programming are not perfectly understood. However, it is clear that circulating hormones such as insulin and leptin play a critical role in the development and programming of hypothalamic circuits regulating energy balance. Here, we review what is currently known about the impact of perinatal malnutrition on the mechanisms regulating body weight homeostasis. Understanding these molecular mechanisms may provide new targets for the treatment of obesity.

* These authors have contributed equally to this work.


 
  • References

  • 1 Friedman JM. A war on obesity, not the obese. Science 2003; 299: 856-858
  • 2 Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004; 116: 337-350
  • 3 Farooqi IS, O’rahilly S. Genetic factors in human obesity. Obes Rev 2007; 8: 37-40
  • 4 Martínez de Morentin PB, Varela L, Ferno J, Nogueiras R, Diéguez C, López M. Hypothalamic lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 2010; 1801: 350-361
  • 5 Virtue S, Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome – an allostatic perspective. Biochim Biophys Acta 2010; 1801: 338-349
  • 6 de Morentin PB, López M. “Mens sana in corpore sano”: exercise and hypothalamic ER stress. PLoS Biol 2010; 8: e1000464
  • 7 Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992; 35: 595-601
  • 8 Plagemann A, Heidrich I, Gotz F, Rohde W, Dorner G. Obesity and enhanced diabetes and cardiovascular risk in adult rats due to early postnatal overfeeding. Exp Clin Endocrinol 1992; 99: 154-158
  • 9 Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull 2001; 60: 5-20
  • 10 Ozanne SE, Hales CN. Lifespan: catch-up growth and obesity in male mice. Nature 2004; 427: 411-412
  • 11 McMillen IC, Robinson JS. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 2005; 85: 571-633
  • 12 Plagemann A. Perinatal nutrition and hormone-dependent programming of food intake. Horm Res 2006; 65: 83-89
  • 13 Roth CL, Sathyanarayana S. Mechanisms affecting neuroendocrine and epigenetic regulation of body weight and onset of puberty: potential implications in the child born small for gestational age (SGA). Rev Endocr Metab Disord 2012; 13: 129-140
  • 14 Galjaard S, Pexsters A, Devlieger R, Guelinckx I, Abdallah Y, Lewis C, van CB, Bourne T, Timmerman D, Luts J. The influence of weight gain patterns in pregnancy on fetal growth using cluster analysis in an obese and nonobese population. Obesity (Silver Spring) 2013; DOI: 10.1002/oby.20348. [Epub ahead of print]
  • 15 Galjaard S, Devlieger R, Van Assche FA. Fetal growth and developmental programming. J Perinat Med 2013; 41: 101-105
  • 16 López M, Seoane LM, Tovar S, García MC, Nogueiras R, Diéguez C, Señaris RM. A possible role of neuropeptide Y, agouti-related protein and leptin receptor isoforms in hypothalamic programming by perinatal feeding in the rat. Diabetologia 2005; 48: 140-148
  • 17 López M, Tovar S, Vázquez MJ, Nogueiras R, Seoane LM, García M, Señarís R, Diéguez C. Perinatal overfeeding in rats results in increased levels of plasma leptin but unchanged cerebrospinal leptin in adulthood. Int J Obes (Lond) 2007; 31: 371-377
  • 18 Harder T, Plagemann A. Low birth weight and blood pressure: The role of neonatal factors in the “small-baby-syndrome”. J Pediatr 2005; 146: 148-149
  • 19 Lucas A. Programming by early nutrition in man. Ciba Found Symp 1991; 156: 38-50
  • 20 McCance RB. Food growth and time. Lancet 1962; 2: 271-272
  • 21 Lucas A. Programming by early nutrition: an experimental approach. J Nutr 1998; 128: 401S-406S
  • 22 Plagemann A, Harder T, Rake A, Voits M, Fink H, Rohde W, Dorner G. Perinatal elevation of hypothalamic insulin, acquired malformation of hypothalamic galaninergic neurons, and syndrome x-like alterations in adulthood of neonatally overfed rats. Brain Res 1999; 836: 146-155
  • 23 Plagemann A, Harder T, Rake A, Waas T, Melchior K, Ziska T, Rohde W, Dorner G. Observations on the orexigenic hypothalamic neuropeptide Y-system in neonatally overfed weanling rats. J Neuroendocrinol 1999; 11: 541-546
  • 24 Davidowa H, Li Y, Plagemann A. Hypothalamic ventromedial and arcuate neurons of normal and postnatally overnourished rats differ in their responses to melanin-concentrating hormone. Regul Pept 2002; 108: 103-111
  • 25 Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 1999; 20: 68-100
  • 26 Coll AP, Farooqi IS, O’Rahilly S. The hormonal control of food intake. Cell 2007; 129: 251-262
  • 27 López M, Tovar S, Vázquez MJ, Williams LM, Diéguez C. Peripheral tissue-brain interactions in the regulation of food intake. Proc Nutr Soc 2007; 66: 131-155
  • 28 Gao Q, Horvath TL. Neurobiology of feeding and energy expenditure. Annu Rev Neurosci 2007; 30: 367-398
  • 29 Williams KW, Elmquist JK. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat Neurosci 2012; 15: 1350-1355
  • 30 López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, Morgan DA, Schoenmakers E, Agassandian K, Lage R, de Morentin PB, Tovar S, Nogueiras R, Carling D, Lelliott C, Gallego R, Oresic M, Chatterjee K, Saha AK, Rahmouni K, Diéguez C, Vidal-Puig A. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 2010; 16: 1001-1008
  • 31 Martínez de Morentin PB, Whittle AJ, Ferno J, Nogueiras R, Diéguez C, Vidal-Puig A, López M. Nicotine induces negative energy balance through hypothalamic AMP-activated protein kinase. Diabetes 2012; 61: 807-817
  • 32 Varela L, Horvath TL. Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep 2012; 13: 1079-1086
  • 33 Whittle AJ, Carobbio S, Martíns L, Slawik M, Hondares E, Vázquez MJ, Morgan D, Csikasz RI, Gallego R, Rodriguez-Cuenca S, Dale M, Virtue S, Villarroya F, Cannon B, Rahmouni K, López M, Vidal-Puig A. Bmp8b increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 2012; 149: 871-885
  • 34 Bazinet RP, Rao JS, Chang L, Rapoport SI, Lee HJ. Chronic carbamazepine decreases the incorporation rate and turnover of arachidonic acid but not docosahexaenoic acid in brain phospholipids of the unanesthetized rat: relevance to bipolar disorder. Biol Psychiatry 2006; 59: 401-407
  • 35 Asensio C, Muzzin P, Rohner-Jeanrenaud F. Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance. Int J Obes Relat Metab Disord 2004; 28: S45-S52
  • 36 Xiao XQ, Williams SM, Grayson BE, Glavas MM, Cowley MA, Smith MS, Grove KL. Excess weight gain during the early postnatal period is associated with permanent reprogramming of brown adipose tissue adaptive thermogenesis. Endocrinology 2007; 148: 4150-4159
  • 37 Glavas MM, Kirigiti MA, Xiao XQ, Enriori PJ, Fisher SK, Evans AE, Grayson BE, Cowley MA, Smith MS, Grove KL. Early overnutrition results in early-onset arcuate leptin resistance and increased sensitivity to high-fat diet. Endocrinology 2010; 151: 1598-1610
  • 38 Biddinger JE, Fox EA. Meal parameters and vagal gastrointestinal afferents in mice that experienced early postnatal overnutrition. Physiol Behav 2010; 101: 184-191
  • 39 Ross CN, Power ML, Artavia JM, Tardif SD. Relation of food intake behaviors and obesity development in young common marmoset monkeys. Obesity (Silver Spring) 2013; DOI: 10.1002/oby.20432. [Epub ahead of print]
  • 40 Farooqi IS, ORahilly S. Monogenic obesity in humans. Annu Rev Med 2005; 56: 443-458
  • 41 Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature 2006; 443: 289-295
  • 42 López M, Lelliott CJ, Vidal-Puig A. Hypothalamic fatty acid metabolism: a housekeeping pathway that regulates food intake. Bioessays 2007; 29: 248-261
  • 43 Yeo GS, Heisler LK. Unraveling the brain regulation of appetite: lessons from genetics. Nat Neurosci 2012; 15: 1343-1349
  • 44 Obici S, Feng Z, Tan J, Liu L, Karkanias G, Rossetti L. Central melanocortin receptors regulate insulin action. J Clin Invest 2001; 108: 1079-1085
  • 45 Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 2002; 5: 566-572
  • 46 Obici S, Feng Z, Arduini A, Conti R, Rossetti L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 2003; 9: 756-761
  • 47 Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, Schwartz GJ, Rossetti L. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med 2005; 11: 320-327
  • 48 Lam TK, Schwartz GJ, Rossetti L. Hypothalamic sensing of fatty acids. Nat Neurosci 2005; 8: 579-584
  • 49 Buettner C, Patel R, Muse ED, Bhanot S, Monia BP, McKay R, Obici S, Rossetti L. Severe impairment in liver insulin signaling fails to alter hepatic insulin action in conscious mice. J Clin Invest 2005; 115: 1306-1313
  • 50 Pocai A, Lam TK, Obici S, Gutierrez-Juarez R, Muse ED, Arduini A, Rossetti L. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J Clin Invest 2006; 116: 1081-1091
  • 51 Ono H, Pocai A, Wang Y, Sakoda H, Asano T, Backer JM, Schwartz GJ, Rossetti L. Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats. J Clin Invest 2008; 118: 2959-2968
  • 52 Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, Castaneda TR, Muzzin P, Schurmann A, Szanto I, Tschop MH, Rohner-Jeanrenaud F. Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest 2006; 116: 1983-1993
  • 53 Perez-Tilve D, Nogueiras R, Mallo F, Benoit SC, Tschoep M. Gut Hormones Ghrelin, PYY, and GLP-1 in the Regulation of Energy, Balance, and Metabolism. Endocrine 2006; 29: 61-72
  • 54 Lam TK, Gutierrez-Juarez R, Pocai A, Bhanot S, Tso P, Schwartz GJ, Rossetti L. Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins. Nat Med 2007; 13: 171-180
  • 55 Nogueiras R, Wiedmer P, Perez-Tilve D, Veyrat-Durebex C, Keogh JM, Sutton GM, Pfluger PT, Castaneda TR, Neschen S, Hofmann SM, Howles PN, Morgan DA, Benoit SC, Szanto I, Schrott B, Schurmann A, Joost HG, Hammond C, Hui DY, Woods SC, Rahmouni K, Butler AA, Farooqi IS, O’rahilly S, Rohner-Jeanrenaud F, Tschop MH. The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest 2007; 117: 3475-3488
  • 56 Vázquez MJ, González CR, Varela L, Lage R, Tovar S, Sangiao-Alvarellos S, Williams LM, Vidal-Puig A, Nogueiras R, López M, Diéguez C. Central resistin regulates hypothalamic and peripheral lipid metabolism in a nutritional-dependent fashion. Endocrinology 2008; 149: 4534-4543
  • 57 Buettner C, Muse ED, Cheng A, Chen L, Scherer T, Pocai A, Su K, Cheng B, Li X, Harvey-White J, Schwartz GJ, Kunos G, Rossetti L, Buettner C. Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nat Med 2008; 14: 667-675
  • 58 Sangiao-Alvarellos S, Vázquez MJ, Varela L, Nogueiras R, Saha AK, Cordido F, López M, Diéguez C. Central ghrelin regulates peripheral lipid metabolism in a growth hormone-independent fashion. Endocrinology 2009; 150: 4562-4574
  • 59 Nogueiras R, López M, Diéguez C. Regulation of lipid metabolism by energy availability: a role for the central nervous system. Obes Rev 2010; 11: 185-201
  • 60 Imbernon M, Beiroa D, Vazquez MJ, Morgan DA, Veyrat-Durebex C, Porteiro B, Diaz-Arteaga A, Senra A, Busquets S, Velasquez DA, Al-Massadi O, Varela L, Gandara M, Lopez-Soriano FJ, Gallego R, Seoane LM, Argiles JM, López M, Davis RJ, Sabio G, Rohner-Jeanrenaud F, Rahmouni K, Diéguez C, Nogueiras R. Central Melanin-Concentrating Hormone Influences Liver and Adipose Metabolism Via Specific Hypothalamic Nuclei and Efferent Autonomic/JNK1 Pathways. Gastroenterology 2013; 144: 636-649
  • 61 Minokoshi Y, Kahn BB. Role of AMP-activated protein kinase in leptin-induced fatty acid oxidation in muscle. Biochem Soc Trans 2003; 31: 196-201
  • 62 Cha SH, Hu Z, Chohnan S, Lane MD. Inhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle. Proc Natl Acad Sci USA 2005; 102: 14557-14562
  • 63 Cha SH, Rodgers JT, Puigserver P, Chohnan S, Lane MD. Hypothalamic malonyl-CoA triggers mitochondrial biogenesis and oxidative gene expression in skeletal muscle: Role of PGC-1{alpha}. Proc Natl Acad Sci USA 2006; 103: 15410-15415
  • 64 Cannon B, Nedergaard J. Thyroid hormones: igniting brown fat via the brain. Nat Med 2010; 16: 965-967
  • 65 Horvath TL, Diano S. Opinion: The floating blueprint of hypothalamic feeding circuits. Nat Rev Neurosci 2004; 5: 662-667
  • 66 Plagemann A, Harder T, Rake A, Melchior K, Rohde W, Dorner G. Hypothalamic nuclei are malformed in weanling offspring of low protein malnourished rat dams. J Nutr 2000; 130: 2582-2589
  • 67 Plagemann A, Rake A, Harder T, Melchior K, Rohde W, Dorner G. Reduction of cholecystokinin-8S-neurons in the paraventricular hypothalamic nucleus of neonatally overfed weanling rats. Neurosci Lett 1998; 258: 13-16
  • 68 Plagemann A, Harder T, Rake A, Melchior K, Rohde W, Dorner G. Increased number of galanin-neurons in the paraventricular hypothalamic nucleus of neonatally overfed weanling rats. Brain Res 1999; 818: 160-163
  • 69 Plagemann A, Rittel F, Waas T, Harder T, Rohde W. Cholecystokinin-8S levels in discrete hypothalamic nuclei of weanling rats exposed to maternal protein malnutrition. Regul Pept 1999; 85: 109-113
  • 70 Plagemann A, Waas T, Harder T, Rittel F, Ziska T, Rohde W. Hypothalamic neuropeptide Y levels in weaning offspring of low-protein malnourished mother rats. Neuropeptides 2000; 34: 1-6
  • 71 Plagemann A, Harder T, Melchior K, Rake A, Rohde W, Dorner G. Elevation of hypothalamic neuropeptide Y-neurons in adult offspring of diabetic mother rats. Neuroreport 1999; 10: 3211-3216
  • 72 Heidel E, Plagemann A, Davidowa H. Increased response to NPY of hypothalamic VMN neurons in postnatally overfed juvenile rats. Neuroreport 1999; 10: 1827-1831
  • 73 Davidowa H, Li Y, Plagemann A. Differential response to NPY of PVH and dopamine-responsive VMH neurons in overweight rats. Neuroreport 2002; 13: 1523-1527
  • 74 Li Y, Plagemann A, Davidowa H. Increased inhibition by agouti-related peptide of ventromedial hypothalamic neurons in rats overweight due to early postnatal overfeeding. Neurosci Lett 2002; 330: 33-36
  • 75 Davidowa H, Li Y, Plagemann A. Altered responses to orexigenic (AGRP, MCH) and anorexigenic (alpha-MSH, CART) neuropeptides of paraventricular hypothalamic neurons in early postnatally overfed rats. Eur J Neurosci 2003; 18: 613-621
  • 76 Kozak R, Richy S, Beck B. Persistent alterations in neuropeptide Y release in the paraventricular nucleus of rats subjected to dietary manipulation during early life. Eur J Neurosci 2005; 21: 2887-2892
  • 77 Davidowa H, Heidel E, Plagemann A. Differential involvement of dopamine D1 and D2 receptors and inhibition by dopamine of hypothalamic VMN neurons in early postnatally overfed juvenile rats. Nutr Neurosci 2002; 5: 27-36
  • 78 Davidowa H, Li Y, Plagemann A. Altered neuronal responses to feeding-relevant peptides as sign of developmental plasticity in the hypothalamic regulatory system of body weight. Zh Vyssh Nerv Deiat Im I P Pavlova 2003; 53: 663-670
  • 79 Orozco-Solis R, Lopes de SS, Barbosa Matos RJ, Grit I, Le BJ, Nguyen P, Manhaes de CR, Bolanos-Jimenez F. Perinatal undernutrition-induced obesity is independent of the developmental programming of feeding. Physiol Behav 2009; 96: 481-492
  • 80 Ikenasio-Thorpe BA, Breier BH, Vickers MH, Fraser M. Prenatal influences on susceptibility to diet-induced obesity are mediated by altered neuroendocrine gene expression. J Endocrinol 2007; 193: 31-37
  • 81 Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD, Low MJ. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 2001; 411: 480-484
  • 82 Davidowa H, Ziska T, Plagemann A. GABA receptor antagonists prevent abnormalities in leptin, insulin and amylin actions on paraventricular hypothalamic neurons of overweight rats. Eur J Neurosci 2006; 23: 1248-1254
  • 83 Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, Kuhajda FP. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 2000; 288: 2379-2381
  • 84 Kim EK, Miller I, Landree LE, Borisy-Rudin FF, Brown P, Tihan T, Townsend CA, Witters LA, Moran TH, Kuhajda FP, Ronnett GV. Expression of FAS within hypothalamic neurons: a model for decreased food intake after C75 treatment. Am J Physiol Endocrinol Metab 2002; 283: E867-E879
  • 85 Hu Z, Cha SH, Chohnan S, Lane MD. Hypothalamic malonyl-CoA as a mediator of feeding behavior. Proc Natl Acad Sci USA 2003; 100: 12624-12629
  • 86 Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 2004; 428: 569-574
  • 87 Lelliott CJ, López M, Curtis RK, Parker N, Laudes M, Yeo G, Jimenez-Liñan M, Grosse J, Saha AK, Wiggins D, Hauton D, Brand MD, O’Rahilly S, Griffin JL, Gibbons GF, Vidal-Puig A. Transcript and metabolite analysis of the effects of tamoxifen in rat liver reveals inhibition of fatty acid synthesis in the presence of hepatic steatosis. FASEB J 2005; 19: 1108-1119
  • 88 Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ. Hypothalamic mTOR signaling regulates food intake. Science 2006; 312: 927-930
  • 89 Wolfgang MJ, Kurama T, Dai Y, Suwa A, Asaumi M, Matsumoto S, Cha SH, Shimokawa T, Lane MD. The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis. Proc Natl Acad Sci USA 2006; 103: 7282-7287
  • 90 He W, Lam TK, Obici S, Rossetti L. Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat Neurosci 2006; 9: 227-233
  • 91 López M, Lelliott CJ, Tovar S, Kimber W, Gallego R, Virtue S, Blount M, Vázquez MJ, Finer N, Powles T, O’Rahilly S, Saha AK, Diéguez C, Vidal-Puig AJ. Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA. Diabetes 2006; 55: 1327-1336
  • 92 Chakravarthy MV, Zhu Y, López M, Yin L, Wozniak DW, Coleman T, Hu Z, Wolfgang M, Vidal-Puig A, Lane MD, Semenkovich CF. Brain fatty acid synthase activates PPAR-alpha to maintain energy homeostasis. J Clin Invest 2007; 117: 2539-2552
  • 93 Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LG, Clements M, Al Qassab H, Heffron H, Xu AW, Speakman JR, Barsh GS, Viollet B, Vaulont S, Ashford ML, Carling D, Withers DJ. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest 2007; 117: 2325-2336
  • 94 Woods SC, Seeley RJ, Cota D. Regulation of food intake through hypothalamic signaling networks involving mTOR. Annu Rev Nutr 2008; 28: 295-311
  • 95 López M, Lage R, Saha AK, Pérez-Tilve D, Vázquez MJ, Varela L, Sangiao-Alvarellos S, Tovar S, Raghay K, Rodríguez-Cuenca S, Deoliveira RM, Castañeda T, Datta R, Dong JZ, Culler M, Sleeman MW, Álvarez CV, Gallego R, Lelliott CJ, Carling D, Tschop MH, Diéguez C, Vidal-Puig A. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab 2008; 7: 389-399
  • 96 Andrews ZB, Liu ZW, Walllingford N, Erion DM, Borok E, Friedman JM, Tschop MH, Shanabrough M, Cline G, Shulman GI, Coppola A, Gao XB, Horvath TL, Diano S. UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals. Nature 2008; 454: 846-851
  • 97 Lage R, Vázquez MJ, Varela L, Saha AK, Vidal-Puig A, Nogueiras R, Diéguez C, López M. 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
  • 98 Velasquez DA, Martinez G, Romero A, Vazquez MJ, Boit KD, Dopeso-Reyes IG, Lopez M, Vidal A, Nogueiras R, Dieguez C. The central Sirtuin 1/p53 pathway is essential for the orexigenic action of ghrelin. Diabetes 2011; 60: 1177-1185
  • 99 Varela L, Martínez-Sánchez N, Gallego R, Vázquez MJ, Roa J, Gándara M, Schoenmakers E, Nogueiras R, Chatterjee K, Tena-Sempere M, Diéguez C, López M. Hypothalamic mTOR pathway mediates thyroid hormone-induced hyperphagia in hyperthyroidism. J Pathol 2012; 227: 209-222
  • 100 Martins L, Fernette B, Novelle MG, Vázquez MJ, Tena-Sempere M, Nogueiras R, López M, Diéguez C. Hypothalamic mTOR signaling mediates the orexigenic action of ghrelin. PLoS ONE 2012; 7: e46923
  • 101 Ramadori G, Fujikawa T, Fukuda M, Anderson J, Morgan DA, Mostoslavsky R, Stuart RC, Perello M, Vianna CR, Nillni EA, Rahmouni K, Coppari R. SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab 2010; 12: 78-87
  • 102 Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, Horvath TL, Sinclair DA, Pfluger PT, Tschop MH. Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiol Rev 2012; 92: 1479-1514
  • 103 Ramírez S, Martíns L, Jacas J, Carrasco P, Pozo M, Clotet J, Serra D, Hegardt FG, Diéguez C, López M, Casals N. Hypothalamic ceramide levels regulated by CPT1C mediate the orexigenic effect of ghrelin. Diabetes 2013; 62: 2329-2337
  • 104 Boullu-Ciocca S, Dutour A, Guillaume V, Achard V, Oliver C, Grino M. Postnatal diet-induced obesity in rats upregulates systemic and adipose tissue glucocorticoid metabolism during development and in adulthood: its relationship with the metabolic syndrome. Diabetes 2005; 54: 197-203
  • 105 Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, Friedman JM, Horvath TL. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 2004; 304: 110-115
  • 106 Bouret SG, Draper SJ, Simerly RB. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004; 304: 108-110
  • 107 Schwartz MW, Figlewicz DP, Baskin DG, Woods SC, Porte Jr D. Insulin in the brain: a hormonal regulator of energy balance. Endocr Rev 1992; 13: 387-414
  • 108 Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000; 404: 661-671
  • 109 Nataf V, Monier S. Effect of insulin and insulin-like growth factor I on the expression of the catecholaminergic phenotype by neural crest cells. Brain Res Dev Brain Res 1992; 69: 59-66
  • 110 Woods SC, Seeley RJ, Baskin DG, Schwartz MW. Insulin and the blood-brain barrier. Curr Pharm Des 2003; 9: 795-800
  • 111 Plagemann A, Harder T, Rake A, Janert U, Melchior K, Rohde W, Dorner G. Morphological alterations of hypothalamic nuclei due to intrahypothalamic hyperinsulinism in newborn rats. Int J Dev Neurosci 1999; 17: 37-44
  • 112 Wang J, Leibowitz KL. Central insulin inhibits hypothalamic galanin and neuropeptide Y gene expression and peptide release in intact rats. Brain Res 1997; 777: 231-236
  • 113 Schwartz MW, Sipols AJ, Marks JL, Sanacora G, White JD, Scheurink A, Kahn SE, Baskin DG, Woods SC, Figlewicz DP. Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology 1992; 130: 3608-3616
  • 114 Dorner G, Plagemann A. Perinatal hyperinsulinism as possible predisposing factor for diabetes mellitus, obesity and enhanced cardiovascular risk in later life. Horm Metab Res 1994; 26: 213-221
  • 115 Davidowa H, Plagemann A. Inhibition by insulin of hypothalamic VMH neurons in rats overweight due to postnatal overfeeding. Neuroreport 2001; 12: 3201-3204
  • 116 Schmidt I, Fritz A, Scholch C, Schneider D, Simon E, Plagemann A. The effect of leptin treatment on the development of obesity in overfed suckling Wistar rats. Int J Obes Relat Metab Disord 2001; 8: 1168-1174
  • 117 Schmidt I, Schoelch C, Ziska T, Schneider D, Simon E, Plagemann A. Interaction of genetic and environmental programming of the leptin system and of obesity disposition. Physiol Genomics 2000; 3: 113-120
  • 118 Davidowa H, Plagemann A. Decreased inhibition by leptin of hypothalamic arcuate neurons in neonatally overfed young rats. Neuroreport 2000; 11: 2795-2798
  • 119 Davidowa H, Plagemann A. Different responses of ventromedial hypothalamic neurons to leptin in normal and early postnatal overfed rats. Neurosci Lett 2000; 293: 21-24
  • 120 García MC, López M, Gualillo O, Seoane L, Diéguez C, Señarís R. Hypothalamic levels of NPY, MCH, and prepro-orexin mRNA during pregnancy and lactation in the rat: role of prolactin. FASEB J 2003; 17: 1392-1400
  • 121 Seeber RM, Smith JT, Waddell BJ. Plasma leptin-binding activity and hypothalamic leptin receptor expression during pregnancy and lactation in the rat. Biol Reprod 2002; 66: 1762-1767
  • 122 Van Heek M, Compton DS, France CF, Tedesco RP, Fawzi AB, Graziano MP, Sybertz EJ, Strader CD, Davis Jr HR. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest 1997; 99: 385-390
  • 123 Burguera B, Couce ME, Curran GL, Jensen MD, Lloyd RV, Cleary MP, Poduslo JF. Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats. Diabetes 2000; 49: 1219-1223
  • 124 Furuhata Y, Kagaya R, Hirabayashi K, Ikeda A, Chang KT, Nishihara M, Takahashi M. Development of obesity in transgenic rats with low circulating growth hormone levels: involvement of leptin resistance. Eur J Endocrinol 2000; 143: 535-541
  • 125 Banks WA, Farrell CL. Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. Am J Physiol Endocrinol Metab 2003; 285: E10-E15
  • 126 Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656-660
  • 127 Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000; 407: 908-913
  • 128 Seoane LM, López M, Tovar S, Casanueva F, Señarís R, Diéguez C. Agouti-related peptide, neuropeptide Y, and somatostatin-producing neurons are targets for ghrelin actions in the rat hypothalamus. Endocrinology 2003; 144: 544-551
  • 129 Nogueiras R, Tovar S, Mitchell SE, Rayner DV, Archer ZA, Dieguez C, Williams LM. Regulation of growth hormone secretagogue receptor gene expression in the arcuate nuclei of the rat by leptin and ghrelin. Diabetes 2004; 53: 2552-2558
  • 130 Sangiao-Alvarellos S, Varela L, Vázquez MJ, Boit KD, Saha AK, Cordido F, Diéguez C, López M. Influence of ghrelin and GH deficiency on AMPK and hypothalamic lipid metabolism. J Neuroendocrinol 2010; 22: 543-556
  • 131 Varela L, Vazquez MJ, Cordido F, Nogueiras R, Vidal-Puig A, Dieguez C, Lopez M. Ghrelin and lipid metabolism: key partners in energy balance. J Mol Endocrinol 2011; 46: R43-R63
  • 132 Piao H, Hosoda H, Kangawa K, Murata T, Narita K, Higuchi T. Ghrelin stimulates milk intake by affecting adult type feeding behaviour in postnatal rats. J Neuroendocrinol 2008; 20: 330-334
  • 133 Steculorum SM, Bouret SG. Developmental effects of ghrelin. Peptides 2011; 32: 2362-2366
  • 134 Bouret SG. Organizational actions of metabolic hormones. Front Neuroendocrinol 2013; 34: 18-26
  • 135 Dembinski A, Warzecha Z, Ceranowicz P, Bielanski W, Cieszkowski J, Dembinski M, Pawlik WW, Kuwahara A, Kato I, Konturek PC. Variable effect of ghrelin administration on pancreatic development in young rats. Role of insulin-like growth factor-1. J Physiol Pharmacol 2005; 56: 555-570
  • 136 Warzecha Z, Dembinski A, Ceranowicz P, Dembinski M, Cieszkowski J, Bielanski W, Pawlik WW, Kuwahara A, Kato I. Dual age-dependent effect of ghrelin administration on serum level of insulin-like growth factor-1 and gastric growth in young rats. Eur J Pharmacol 2006; 529: 145-150
  • 137 Tronche F, Kellendonk C, Reichardt HM, Schutz G. Genetic dissection of glucocorticoid receptor function in mice. Curr Opin Genet Dev 1998; 8: 532-538
  • 138 Freedman MR, Horwitz BA, Stern JS. Effect of adrenalectomy and glucocorticoid replacement on development of obesity. Am J Physiol 1986; 250: R595-R607
  • 139 Zakrzewska KE, Cusin I, Sainsbury A, Rohner-Jeanrenaud F, Jeanrenaud B. Glucocorticoids as counterregulatory hormones of leptin: toward an understanding of leptin resistance. Diabetes 1997; 46: 717-719
  • 140 Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS. A transgenic model of visceral obesity and the metabolic syndrome. Science 2001; 294: 2166-2170
  • 141 Meaney MJ, Diorio J, Francis D, Widdowson J, LaPlante P, Caldji C, Sharma S, Seckl JR, Plotsky PM. Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress. Dev Neurosci 1996; 18: 49-72
  • 142 Seckl JR, Meaney MJ. Glucocorticoid programming. Ann N Y Acad Sci 2004; 1032: 63-84
  • 143 Velkoska E, Cole TJ, Morris MJ. Early dietary intervention: long-term effects on blood pressure, brain neuropeptide Y, and adiposity markers. Am J Physiol Endocrinol Metab 2005; 288: E1236-E1243
  • 144 Drake AJ, Raubenheimer PJ, Kerrigan D, McInnes KJ, Seckl JR, Walker BR. Prenatal dexamethasone programs expression of genes in liver and adipose tissue and increased hepatic lipid accumulation but not obesity on a high-fat diet. Endocrinology 2010; 151: 1581-1587
  • 145 Park JH, Stoffers DA, Nicholls RD, Simmons RA. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 2008; 118: 2316-2324
  • 146 Raychaudhuri N, Raychaudhuri S, Thamotharan M, Devaskar SU. Histone code modifications repress glucose transporter 4 expression in the intrauterine growth-restricted offspring. J Biol Chem 2008; 283: 13611-13626
  • 147 Plagemann A, Harder T, Brunn M, Harder A, Roepke K, Wittrock-Staar M, Ziska T, Schellong K, Rodekamp E, Melchior K, Dudenhausen JW. Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. J Physiol 2009; 587: 4963-4976
  • 148 Plagemann A, Roepke K, Harder T, Brunn M, Harder A, Wittrock-Staar M, Ziska T, Schellong K, Rodekamp E, Melchior K, Dudenhausen JW. Epigenetic malprogramming of the insulin receptor promoter due to developmental overfeeding. J Perinat Med 2010; 38: 393-400
  • 149 Begum G, Stevens A, Smith EB, Connor K, Challis JR, Bloomfield F, White A. Epigenetic changes in fetal hypothalamic energy regulating pathways are associated with maternal undernutrition and twinning. FASEB J 2012; 26: 1694-1703
  • 150 Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991; 303: 1019-1022
  • 151 Ozanne SE, Hales CN. Early programming of glucose-insulin metabolism. Trends Endocrinol Metab 2002; 13: 368-373
  • 152 Susser M, Stein Z. Timing in prenatal nutrition: a reprise of the Dutch Famine Study. Nutr Rev 1994; 52: 84-94
  • 153 Roseboom TJ, van der Meulen JH, Ravelli AC, Osmond C, Barker DJ, Bleker OP. Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Mol Cell Endocrinol 2001; 185: 93-98
  • 154 Lussana F, Painter RC, Ocke MC, Buller HR, Bossuyt PM, Roseboom TJ. Prenatal exposure to the Dutch famine is associated with a preference for fatty foods and a more atherogenic lipid profile. Am J Clin Nutr 2008; 88: 1648-1652
  • 155 Li Y, He Y, Qi L, Jaddoe VW, Feskens EJ, Yang X, Ma G, Hu FB. Exposure to the Chinese famine in early life and the risk of hyperglycemia and type 2 diabetes in adulthood. Diabetes 2010; 59: 2400-2406
  • 156 Li Y, Jaddoe VW, Qi L, He Y, Wang D, Lai J, Zhang J, Fu P, Yang X, Hu FB. Exposure to the chinese famine in early life and the risk of metabolic syndrome in adulthood. Diabetes Care 2011; 34: 1014-1018
  • 157 Perala MM, Mannisto S, Kaartinen NE, Kajantie E, Osmond C, Barker DJ, Valsta LM, Eriksson JG. Body size at birth is associated with food and nutrient intake in adulthood. PLoS One 2012; 7: e46139
  • 158 Gillman MW, Rifas-Shiman S, Berkey CS, Field AE, Colditz GA. Maternal gestational diabetes, birth weight, and adolescent obesity. Pediatrics 2003; 111: e221-e226
  • 159 Stettler N, Kumanyika SK, Katz SH, Zemel BS, Stallings VA. Rapid weight gain during infancy and obesity in young adulthood in a cohort of African Americans. Am J Clin Nutr 2003; 77: 1374-1378
  • 160 Mandic Z, Piricki AP, Kenjeric D, Hanicar B, Tanasic I. Breast vs. bottle: differences in the growth of Croatian infants. Matern Child Nutr 2011; 7: 389-396
  • 161 Phillips DI, Fall CH, Cooper C, Norman RJ, Robinson JS, Owens PC. Size at birth and plasma leptin concentrations in adult life. Int J Obes Relat Metab Disord 1999; 23: 1025-1029
  • 162 Singhal A, Farooqi IS, O’Rahilly S, Cole TJ, Fewtrell M, Lucas A. Early nutrition and leptin concentrations in later life. Am J Clin Nutr 2002; 75: 993-999
  • 163 Davidowa H, Ziska T, Plagemann A. Arcuate neurons of overweight rats differ in their responses to amylin from controls. Neuroreport 2004; 15: 2801-2805
  • 164 Bouret SG, Simerly RB. Leptin and development of hypothalamic feeding circuits. Endocrinology 2004; 145: 2621-2626
  • 165 Bouret SG, Draper SJ, Simerly RB. Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci 2004; 24: 2797-2805
  • 166 Bouret SG, Simerly RB. Developmental programming of hypothalamic feeding circuits. Clin Genet 2006; 70: 295-301
  • 167 Diano S, Farr SA, Benoit SC, McNay EC, da SI, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschop MH, Horvath TL. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 2006; 9: 381-388
  • 168 Bouret SG, Gorski JN, Patterson CM, Chen S, Levin BE, Simerly RB. Hypothalamic neural projections are permanently disrupted in diet-induced obese rats. Cell Metab 2008; 7: 179-185
  • 169 Patterson CM, Bouret SG, Dunn-Meynell AA, Levin BE. Three weeks of postweaning exercise in DIO rats produces prolonged increases in central leptin sensitivity and signaling. Am J Physiol Regul Integr Comp Physiol 2009; 296: R537-R548