The Metabolic Response to Postnatal Leptin in Rats Varies with Age and may be Litter Dependent

Abstract

Hyperleptinemia during postnatal life induces long-term effects on metabolism. However, these effects are controversial as both increased and decreased propensity towards obesity has been reported. To further analyze the effects of chronic neonatal hyperleptinemia on the subsequent metabolic profile, male Wistar rats proceeding from 18 different litters (8 pups/litter) received a daily subcutaneous injection of either saline (10 ml/kg, n=36) or leptin (3 μg/g, n=36) from postnatal day (PND) 2 to PND9. Rats were sacrificed at 10, 40, or 150 days of age. At 10 days of age, leptin treated rats had decreased body weight (p<0.001) and body fat (p<0.05). Leptin levels and glycemia were increased (p<0.01), whereas insulin, total lipids, triglycerides and glycerol levels were decreased (p<0.05). At PND40 rats receiving leptin had increased glycemia (p<0.01) and plasma HDL and LDL levels, but decreased total lipids (p<0.05). At PND150 neonatal leptin treatment induced different effects in rats raised in different litters. Rats from litter 1 had increased body weight (p<0.05), body fat (p<0.01), and plasma leptin (p<0.001), cholesterol (p<0.001), triglyceride (p<0.001), total lipid (p<0.001), LDL (p<0.05), and glycerol (p<0.001) levels. In rats from litter 2 these parameters did not differ from controls. Rats from litter 3 had decreased body weight (p<0.05), visceral fat (p<0.01) and plasma leptin (p<0.001), cholesterol (p<0.001), triglyceride (p<0.001), glycerol (p<0.001), and HDL (p<0.001) levels. In conclusion, the metabolic response to postnatal leptin varies with age, with the response in adulthood being variable and most likely influenced by other factors, including the genetic make-up.

Key words

postnatal leptin - metabolic programming - hypothalamus

• References

• 1 McMillen IC, Robinson JS. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 2005; 85: 571-633
• 2 Sallout B, Walker M. The fetal origin of adult diseases. J Obstet Gynaecol 2003; 23: 555-560
• 3 Samuelsson AM, Clark J, Rudyk O, Shattock MJ, Bae SE, South T, Pombo J, Redington K, Uppal E, Coen CW, Poston L, Taylor PD. Experimental Hyperleptinemia in Neonatal Rats Leads to Selective Leptin Responsiveness, Hypertension, and Altered Myocardial Function. Hypertension 2013; 62: 627-633
• 4 Dyer JS, Rosenfeld CR. Metabolic imprinting by prenatal, perinatal, and postnatal overnutrition: a review. Semin Reprod Med 2011; 29: 266-276
• 5 Spencer SJ. Early life programming of obesity: the impact of the perinatal environment on the development of obesity and metabolic dysfunction in the offspring. Curr Diabetes Rev 2012; 8: 55-68
• 6 Levin BE. Metabolic imprinting: critical impact of the perinatal environment on the regulation of energy homeostasis. Philos Trans R Soc Lond B Biol Sci 2006; 361: 1107-1121
• 7 Plagemann A. Perinatal nutrition and hormone-dependent programming of food intake. Horm Res 2006; 65 (Suppl. 03) 83-89
• 8 Sullivan EL, Grove KL. Metabolic imprinting in obesity. Forum Nutr 2010; 63: 186-194
• 9 Bouret SG. Neurodevelopmental actions of leptin. Brain Res 2010; 1350: 2-9
• 10 Symonds ME, Sebert SP, Budge H. The impact of diet during early life and its contribution to later disease: critical checkpoints in development and their long-term consequences for metabolic health. Proc Nutr Soc 2009; 68: 416-421
• 11 Symonds ME, Sebert SP, Hyatt MA, Budge H. Nutritional programming of the metabolic syndrome. Nat Rev Endocrinol 2009; 5: 604-610
• 12 Gautron L, Elmquist JK. Sixteen years and counting: an update on leptin in energy balance. J Clin Invest 2011; 121: 2087-2093
• 13 Bouret SG. Leptin, nutrition, and the programming of hypothalamic feeding circuits. Nestle Nutr Workshop Ser Pediatr Program 2010; 65: 2535 discussion 35–39
• 14 Steppan CM, Swick AG. A role for leptin in brain development. Biochem Biophys Res Commun 1999; 256: 600-602
• 15 Bouret SG, Draper SJ, Simerly RB. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004; 304: 108-110
• 16 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
• 17 Ahima RS, Prabakaran D, Flier JS. Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest 1998; 101: 1020-1027
• 18 Delahaye F, Breton C, Risold P-Y, Enache M, Dutriez-Casteloot I, Laborie C, Lesage J, Vieau D. 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
• 19 Attig L, Solomon G, Ferezou J, Abdennebi-Najar L, Taouis M, Gertler A, Djiane J. Early postnatal leptin blockage leads to a long-term leptin resistance and susceptibility to diet-induced obesity in rats. Int J Obes (Lond) 2008; 32: 1153-1160
• 20 Viveros M-P, Díaz F, Mateos B, Rodríguez N, Chowen JA. Maternal deprivation induces a rapid decline in circulating leptin levels and sexually dimorphic modifications in hypothalamic trophic factors and cell turnover. Horm Behav 2010; 57: 405-414
• 21 Granado M, García-Cáceres C, Fuente-Martín E, Díaz F, Mela V, Viveros M-P, Argente J, Chowen JA. Effects of acute changes in neonatal leptin levels on food intake and long-term metabolic profiles in rats. Endocrinology 2011; 152: 4116-4126
• 22 Mela V, Díaz F, Gertler A, Solomon G, Argente J, Viveros M-P, Chowen JA. Neonatal treatment with a pegylated leptin antagonist has a sexually dimorphic effect on hypothalamic trophic factors and neuropeptide levels. J Neuroendocrinol 2012; 24: 756-765
• 23 Picó C, Oliver P, Sánchez J, Miralles O, Caimari A, Priego T, Palou A. The intake of physiological doses of leptin during lactation in rats prevents obesity in later life. Int J Obes (Lond) 2007; 31: 1199-1209
• 24 de Oliveira Cravo C, Teixeira CV, Passos MCF, Dutra SCP, de Moura EG, Ramos C. Leptin treatment during the neonatal period is associated with higher food intake and adult body weight in rats. Horm Metab Res 2002; 34: 400-405
• 25 Toste FP, de Moura EG, Lisboa PC, Fagundes AT, de Oliveira E, Passos MCF. Neonatal leptin treatment programmes leptin hypothalamic resistance and intermediary metabolic parameters in adult rats. Br J Nutr 2006; 95: 830-837
• 26 Haffner SM, Stern MP, Hazuda HP, Pugh JA, Patterson JK. Hyperinsulinemia in a population at high risk for non-insulin-dependent diabetes mellitus. N Engl J Med 1986; 315: 220-224
• 27 Psyrogiannis A, Kyriazopoulou V, Symeonidis A, Leotsinidis M, Vagenakis AG. Relative iron “overload” in offspring of patients with type 2 diabetes mellitus: a new component in the conundrum of insulin resistance syndrome?. Hormones (Athens) 2003; 2: 161-168
• 28 Chomczynski P. A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. Biotechniques 1993; 15: 532-534 536–537
• 29 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408
• 30 Vickers MH, Gluckman PD, Coveny AH, Hofman PL, Cutfield WS, Gertler A, Breier BH, Harris M. Neonatal leptin treatment reverses developmental programming. Endocrinology 2005; 146: 4211-4216
• 31 Varma A, He J, Shin B-C, Weissfeld LA, Devaskar SU. Postnatal intracerebroventricular exposure to leptin causes an altered adult female phenotype. Am J Physiol Endocrinol Metab 2004; 287: E1132-E1141
• 32 Vickers MH, Gluckman PD, Coveny AH, Hofman PL, Cutfield WS, Gertler A, Breier BH, Harris M. The effect of neonatal leptin treatment on postnatal weight gain in male rats is dependent on maternal nutritional status during pregnancy. Endocrinology 2008; 149: 1906-1913
• 33 Yuan CS, Attele AS, Zhang L, Lynch JP, Xie JT, Shi ZQ. Leptin reduces body weight gain in neonatal rats. Pediatr Res 2000; 48: 380-383
• 34 Ahima RS, Hileman SM. Postnatal regulation of hypothalamic neuropeptide expression by leptin: implications for energy balance and body weight regulation. Regul Pept 2000; 92: 1-7
• 35 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
• 36 Vickers MH. Developmental programming and adult obesity: the role of leptin. Curr Opin Endocrinol Diabetes Obes 2007; 14: 17-22
• 37 Proulx K, Richard D, Walker C-D. Leptin regulates appetite-related neuropeptides in the hypothalamus of developing rats without affecting food intake. Endocrinology 2002; 143: 4683-4692
• 38 Wagoner B, Hausman DB, Harris RBS. Direct and indirect effects of leptin on preadipocyte proliferation and differentiation. Am J Physiol Regul Integr Comp Physiol 2006; 290: R1557-R1564
• 39 Almog B, Gold R, Tajima K, Dantes A, Salim K, Rubinstein M, Barkan D, Homburg R, Lessing JB, Nevo N, Gertler A, Amsterdam A. Leptin attenuates follicular apoptosis and accelerates the onset of puberty in immature rats. Mol Cell Endocrinol 2001; 183: 179-191
• 40 Cannady WE, Brann DW, Mahesh VB. The potential role of periovarian fat and leptin in initiation of puberty in the immature rat. Int J Obes Relat Metab Disord 2000; 24 (Suppl. 02) S146-S147
• 41 Parent AS, Lebrethon MC, Gérard A, Vandersmissen E, Bourguignon JP. Leptin effects on pulsatile gonadotropin releasing hormone secretion from the adult rat hypothalamus and interaction with cocaine and amphetamine regulated transcript peptide and neuropeptide Y. Regul Pept 2000; 92: 17-24
• 42 Lebrethon MC, Vandersmissen E, Gérard A, Parent AS, Junien JL, Bourguignon JP. In vitro stimulation of the prepubertal rat gonadotropin-releasing hormone pulse generator by leptin and neuropeptide Y through distinct mechanisms. Endocrinology 2000; 141: 1464-1469
• 43 Ogura K, Irahara M, Kiyokawa M, Tezuka M, Matsuzaki T, Yasui T, Kamada M, Aono T. Effects of leptin on secretion of LH and FSH from primary cultured female rat pituitary cells. Eur J Endocrinol 2001; 144: 653-658
• 44 Beltrand J, Sloboda DM, Connor KL, Truong M, Vickers MH. The Effect of Neonatal Leptin Antagonism in Male Rat Offspring Is Dependent upon the Interaction between Prior Maternal Nutritional Status and Post-Weaning Diet. J Nutr Metab 2012; 2012: 296935
• 45 Levin BE. Factors promoting and ameliorating the development of obesity. Physiol Behav 2005; 86: 633-639
• 46 Pereira-Toste F, Toste FP, Oliveira E, Trotta PA, Lisboa PC, de Moura EG, Passos MCF. Early maternal hyperleptinemia programs adipogenic phenotype in rats. Horm Metab Res 2009; 41: 874-879
• 47 Fraga-Marques MC, Moura EG, Silva JO, Claudio-Neto S, Pereira-Toste F, Passos MCF, Lisboa PC, Manhães AC. Effects of maternal hyperleptinaemia during lactation on short-term memory/learning, anxiety-like and novelty-seeking behavioral traits of adult male rats. Behav Brain Res 2010; 206: 147-150