The prevalence of adolescent obesity has increased dramatically, becoming a serious public health concern. While previous evidence suggests that in utero- and early postnatal overnutrition increases adult-onset obesity risk, the neurobiological mechanisms underlying this outcome are not well understood. Non-neuronal cells play an underestimated role in the physiological responses to metabolic/nutrient signals. Hypothalamic glial-mediated inflammation is now considered a contributing factor in the development and perpetuation of obesity; however, attention on the role of gliosis and microglia activation in other nuclei is still needed.
Here, we demonstrate that early life consumption of high-fat/sucrose diet (HFSD) is sufficient to increase offspring body weight, hyperleptinemia and potentially maladaptive cytoarchitectural changes in the brainstem dorsal-vagal-complex (DVC), an essential energy balance processing hub, across postnatal development. Our data demonstrate that pre- and postnatal consumption of HFSD result in increased body weight, hyperleptinemia and dramatically affects the non-neuronal landscape, and therefore the plasticity of the DVC in the developing offspring.
Current findings are very provocative, considering the importance of the DVC in appetite regulation, suggesting that HFSD-consumption during early life may contribute to subsequent obesity risk via DVC cytoarchitectural changes.
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Reynolds CM, Segovia SA, Vickers MH. Experimental models of maternal obesity and neuroendocrine programming of metabolic disorders in offspring. Front Endocrinol (Lausanne). 2017;8:245.
Salam RA, Das JK, Bhutta ZA. Impact of intrauterine growth restriction on long-term health. Curr Opin Clin Nutr Metab Care. 2014;17:249–54.
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:E83–7.
Noble EE, Kanoski SE. Early life exposure to obesogenic diets and learning and memory dysfunction. Curr Opin Behav Sci. 2016;9:7–14.
Kanoski SE, Davidson TL. Different patterns of memory impairments accompany short- and longer-term maintenance on a high-energy diet. J Exp Psychol Anim Behav Process. 2010;36:313–9.
Kanoski SE, Davidson TL. Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity. Physiol Behav. 2011;103:59–68.
Fuente-Martin E, Garcia-Caceres C, Diaz F, Argente-Arizon P, Granado M, Barrios V, et al. Hypothalamic inflammation without astrogliosis in response to high sucrose intake is modulated by neonatal nutrition in male rats. Endocrinology. 2013;154:2318–30.
Grill HJ, Hayes MR. Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab. 2012;16:296–309.
Bayol SA, Farrington SJ, Stickland NC. A maternal ‘junk food’ diet in pregnancy and lactation promotes an exacerbated taste for ‘junk food’ and a greater propensity for obesity in rat offspring. Br J Nutr. 2007;98:843–51.
Howie GJ, Sloboda DM, Kamal T, Vickers MH. Maternal nutritional history predicts obesity in adult offspring independent of postnatal diet. J Physiol. 2009;587:905–15.
Gorski JN, Dunn-Meynell AA, Hartman TG, Levin BE. Postnatal environment overrides genetic and prenatal factors influencing offspring obesity and insulin resistance. Am J Physiol Regul Integr Comp Physiol. 2006;291:R768–78.
Steculorum SM, Bouret SG. Maternal diabetes compromises the organization of hypothalamic feeding circuits and impairs leptin sensitivity in offspring. Endocrinology. 2011;152:4171–9.
Bouret SG. Role of early hormonal and nutritional experiences in shaping feeding behavior and hypothalamic development. J Nutr. 2010;140:653–7.
Morris MJ, Chen H. Established maternal obesity in the rat reprograms hypothalamic appetite regulators and leptin signaling at birth. Int J Obes (Lond). 2009;33:115–22.
Grill HJ. Distributed neural control of energy balance: contributions from hindbrain and hypothalamus. Obesity (Silver Spring). 2006;14(Suppl 5):216S–21S.
Grill HJ, Kaplan JM. The neuroanatomical axis for control of energy balance. Front Neuroendocrinol. 2002;23:2–40.
Reemst K, Noctor SC, Lucassen PJ, Hol EM. The Indispensable Roles of Microglia and Astrocytes during Brain Development. Front Hum Neurosci. 2016;10:566.
Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91:461–553.
Edlow AG, Glass RM, Smith CJ, Tran PK, James K, Bilbo S. Placental macrophages: a window into fetal microglial function in maternal obesity. Int J Dev Neurosci. 2018;77:60–8.
Havel PJ. Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis. Exp Biol Med (Maywood). 2001;226:963–77.
Pan W, Hsuchou H, Jayaram B, Khan RS, Huang EY, Wu X, et al. Leptin action on nonneuronal cells in the CNS: potential clinical applications. Ann NY Acad Sci. 2012;1264:64–71.
Reiner DJ, Mietlicki-Baase EG, McGrath LE, Zimmer DJ, Bence KK, Sousa GL, et al. Astrocytes regulate GLP-1 receptor-mediated effects on energy balance. J Neurosci. 2016;36:3531–40.
Marina N, Turovsky E, Christie IN, Hosford PS, Hadjihambi A, Korsak A, et al. Brain metabolic sensing and metabolic signaling at the level of an astrocyte. Glia. 2018;66:1185–99.
Burda JE, Sofroniew MV. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron. 2014;81:229–48.
Dorfman MD, Thaler JP. Hypothalamic inflammation and gliosis in obesity. Curr Opin Endocrinol Diabetes Obes. 2015;22:325–30.
Thaler JP, Guyenet SJ, Dorfman MD, Wisse BE, Schwartz MW. Hypothalamic inflammation: marker or mechanism of obesity pathogenesis? Diabetes. 2013;62:2629–34.
Horvath TL, Sarman B, Garcia-Caceres C, Enriori PJ, Sotonyi P, Shanabrough M, et al. Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci USA. 2010;107:14875–80.
Buckman LB, Thompson MM, Moreno HN, Ellacott KL. Regional astrogliosis in the mouse hypothalamus in response to obesity. J Comp Neurol. 2013;521:1322–33.
Dong Y, Benveniste EN. Immune function of astrocytes. Glia. 2001;36:180–90.
Streit WJ, Mrak RE, Griffin WS. Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation. 2004;1:14.
Bandeira F, Lent R, Herculano-Houzel S. Changing numbers of neuronal and non-neuronal cells underlie postnatal brain growth in the rat. Proc Natl Acad Sci USA. 2009;106:14108–13.
Hartfuss E, Galli R, Heins N, Gotz M. Characterization of CNS precursor subtypes and radial glia. Dev Biol. 2001;229:15–30.
Alves JA, Barone P, Engelender S, Froes MM, Menezes JR. Initial stages of radial glia astrocytic transformation in the early postnatal anterior subventricular zone. J Neurobiol. 2002;52:251–65.
Schmechel DE, Rakic P. A Golgi study of radial glial cells in developing monkey telencephalon: morphogenesis and transformation into astrocytes. Anat Embryol (Berl). 1979;156:115–52.
Voigt T. Development of glial cells in the cerebral wall of ferrets: direct tracing of their transformation from radial glia into astrocytes. J Comp Neurol. 1989;289:74–88.
Group TS, Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012;366:2247–56.
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;361:1107–21.
Armitage JA, Khan IY, Taylor PD, Nathanielsz PW, Poston L. Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals? J Physiol. 2004;561:355–77.
Khan IY, Dekou V, Douglas G, Jensen R, Hanson MA, Poston L, et al. A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring. Am J Physiol Regul Integr Comp Physiol. 2005;288:R127–33.
Ventura AK, Worobey J. Early influences on the development of food preferences. Curr Biol. 2013;23:R401–8.
Ainge H, Thompson C, Ozanne SE, Rooney KB. A systematic review on animal models of maternal high fat feeding and offspring glycaemic control. Int J Obes (Lond). 2011;35:325–35.
Liberini CG, Lhamo R, Ghidewon M, Ling T, Juntereal N, Chen J, et al. Liraglutide pharmacotherapy reduces body weight and improves glycaemic control in juvenile obese/hyperglycaemic male and female rats. Diabetes Obes Metab. 2019;21:866–75.
Sun B, Purcell RH, Terrillion CE, Yan J, Moran TH, Tamashiro KL. Maternal high-fat diet during gestation or suckling differentially affects offspring leptin sensitivity and obesity. Diabetes. 2012;61:2833–41.
Parlee SD, MacDougald OA. Maternal nutrition and risk of obesity in offspring: the Trojan horse of developmental plasticity. Biochim Biophys Acta. 2014;1842:495–506.
Cordero P, Gomez-Uriz AM, Milagro FI, Campion J, Martinez JA. Maternal weight gain induced by an obesogenic diet affects adipose accumulation, liver weight, and insulin homeostasis in the rat offspring depending on the sex. J Endocrinol Invest. 2012;35:981–6.
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;101:1020–7.
Cottrell EC, Cripps RL, Duncan JS, Barrett P, Mercer JG, Herwig A, et al. Developmental changes in hypothalamic leptin receptor: relationship with the postnatal leptin surge and energy balance neuropeptides in the postnatal rat. Am J Physiol Regul Integr Comp Physiol. 2009;296:R631–9.
Yura S, Itoh H, Sagawa N, Yamamoto H, Masuzaki H, Nakao K, et al. Role of premature leptin surge in obesity resulting from intrauterine undernutrition. Cell Metab. 2005;1:371–8.
Bouret SG, Simerly RB. Developmental programming of hypothalamic feeding circuits. Clin Genet. 2006;70:295–301.
Tamashiro KL, Moran TH. Perinatal environment and its influences on metabolic programming of offspring. Physiol Behav. 2010;100:560–6.
Stocker CJ, Cawthorne MA. The influence of leptin on early life programming of obesity. Trends Biotechnol. 2008;26:545–51.
Kirk SL, Samuelsson AM, Argenton M, Dhonye H, Kalamatianos T, Poston L, et al. Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring. PLoS ONE. 2009;4:e5870.
Nusken E, Wohlfarth M, Lippach G, Rauh M, Schneider H, Dotsch J, et al. Reduced perinatal leptin availability may contribute to adverse metabolic programming in a rat model of uteroplacental insufficiency. Endocrinology. 2016;157:1813–25.
Fields RD, Stevens-Graham B. New insights into neuron-glia communication. Science. 2002;298:556–62.
Perea G, Navarrete M, Araque A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 2009;32:421–31.
Tasker JG, Oliet SH, Bains JS, Brown CH, Stern JE. Glial regulation of neuronal function: from synapse to systems physiology. J Neuroendocrinol. 2012;24:566–76.
Moran TH. Gut peptide signaling in the controls of food intake. Obesity (Silver Spring). 2006;14:250S–3S.
Heindel JJ, vom Saal FS. Role of nutrition and environmental endocrine disrupting chemicals during the perinatal period on the aetiology of obesity. Mol Cell Endocrinol. 2009;304:90–6.
Anzman SL, Rollins BY, Birch LL. Parental influence on children’s early eating environments and obesity risk: implications for prevention. Int J Obes (Lond). 2010;34:1116–24.
Rosales FJ, Reznick JS, Zeisel SH. Understanding the role of nutrition in the brain and behavioral development of toddlers and preschool children: identifying and addressing methodological barriers. Nutr Neurosci. 2009;12:190–202.
This research was supported by NIH-DK115762 (M.R.H.) and the Swiss National Foundation FNSNF-P22HP3_172289 (CGL). M.R.H. receives research support from Eli Lilly & Co., and Boehringer Ingelheim, none of which was used in the collection of these data.
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Liberini, C.G., Ghidewon, M., Ling, T. et al. Early life overnutrition impairs plasticity of non-neuronal brainstem cells and drives obesity in offspring across development in rats. Int J Obes 44, 2405–2418 (2020). https://doi.org/10.1038/s41366-020-00658-5