Altered Brain Response to Drinking Glucose and Fructose in Obese Adolescents

Ania M Jastreboff, Rajita Sinha, Jagriti Arora, Cosimo Giannini, Jessica Kubat, Saima Malik, Michelle A Van Name, Nicola Santoro, Mary Savoye, Elvira J Duran, Bridget Pierpont, Gary Cline, R Todd Constable, Robert S Sherwin, Sonia Caprio, Ania M Jastreboff, Rajita Sinha, Jagriti Arora, Cosimo Giannini, Jessica Kubat, Saima Malik, Michelle A Van Name, Nicola Santoro, Mary Savoye, Elvira J Duran, Bridget Pierpont, Gary Cline, R Todd Constable, Robert S Sherwin, Sonia Caprio

Abstract

Increased sugar-sweetened beverage consumption has been linked to higher rates of obesity. Using functional MRI, we assessed brain perfusion responses to drinking two commonly consumed monosaccharides, glucose and fructose, in obese and lean adolescents. Marked differences were observed. In response to drinking glucose, obese adolescents exhibited decreased brain perfusion in brain regions involved in executive function (prefrontal cortex [PFC]) and increased perfusion in homeostatic appetite regions of the brain (hypothalamus). Conversely, in response to drinking glucose, lean adolescents demonstrated increased PFC brain perfusion and no change in perfusion in the hypothalamus. In addition, obese adolescents demonstrated attenuated suppression of serum acyl-ghrelin and increased circulating insulin level after glucose ingestion; furthermore, the change in acyl-ghrelin and insulin levels after both glucose and fructose ingestion was associated with increased hypothalamic, thalamic, and hippocampal blood flow in obese relative to lean adolescents. Additionally, in all subjects there was greater perfusion in the ventral striatum with fructose relative to glucose ingestion. Finally, reduced connectivity between executive, homeostatic, and hedonic brain regions was observed in obese adolescents. These data demonstrate that obese adolescents have impaired prefrontal executive control responses to drinking glucose and fructose, while their homeostatic and hedonic responses appear to be heightened. Thus, obesity-related brain adaptations to glucose and fructose consumption in obese adolescents may contribute to excessive consumption of glucose and fructose, thereby promoting further weight gain.

Trial registration: ClinicalTrials.gov NCT01808846.

© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Figures

Figure 1
Figure 1
CBF main effect of group and main effect of drink. The main effect of group (ANOVA) (A) and the main effect of group covaried (ANCOVA) for change in acyl-ghrelin (B) and insulin (C) levels after drink consumption. D: The main effect of drink and the main effect of drink covaried (ANCOVA) for change in acyl-ghrelin (E) and insulin (F) levels after drink consumption. There was no significant group-by-drink interaction.
Figure 2
Figure 2
CBF in obese vs. lean adolescents and glucose vs. fructose drink. A: A significant group main effect in obese vs. lean (drink vs. baseline) was observed with reduced blood flow (in blue) in obese relative to lean adolescents in the medial PFC and ACC. Additionally, drink-related changes in acyl-ghrelin (B) and insulin (C) levels promote increased CBF in the hypothalamus and thalamus in obese vs. lean adolescents (in yellow-red). D: Comparing response to glucose vs. fructose drink in all adolescents demonstrated a significant CBF main effect of drink with increased ventral striatum (putamen) activity in response to fructose (in blue) relative to glucose. E: Accounting for the drink-related acyl-ghrelin changes led to significantly greater hypothalamus and thalamus CBF with glucose relative to fructose drink (in yellow-red), while greater changes with fructose relative to glucose drink were demonstrated in the left insula and striatum (in blue). F: This effect was not observed in relation to change in insulin levels.
Figure 3
Figure 3
Within-group functional connectivity with the hypothalamus as the seed region in response to drinking glucose. A: At baseline (before drink ingestion), lean adolescents demonstrated no increased connectivity, whereas obese adolescents demonstrated increased corticolimbic-striatal connectivity with the hypothalamic seed. B: After drink ingestion, obese adolescents continued to demonstrate a pattern of connectivity similar to what they demonstrated at baseline, whereas now lean adolescents also exhibited increased connectivity with striatal and limbic regions. C: Interestingly, in examination of the difference between before drink consumption and after drink consumption, lean adolescents exhibited relatively strengthened connectivity in response to drinking glucose, whereas obese adolescents did not have a relative change in connectivity relative to their state before drinking glucose. SN/VTA, substantia nigra/ventral tegmental area.
Figure 4
Figure 4
Schematic diagram to illustrate altered regional CBF response to glucose in lean and obese adolescents. When lean adolescents drink glucose they demonstrate increase CBF in the PFC, which may exert inhibitory signals to the hypothalamus and striatum, decreasing CBF in these regions. On the other hand, when obese adolescents drink glucose they exhibit decreased CBF in the PFC, which then may exert less inhibitory control on the striatum and hypothalamus, perhaps increasing striatal perfusion.

References

    1. Ogden CL, Carroll MD, Curtin LR, Lamb MM, Flegal KM. Prevalence of high body mass index in US children and adolescents, 2007-2008. JAMA 2010;303:242–249
    1. Popkin BM, Nielsen SJ. The sweetening of the world’s diet. Obes Res 2003;11:1325–1332
    1. Ludwig DS, Peterson KE, Gortmaker SL. Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet 2001;357:505–508
    1. Weiss R, Dziura J, Burgert TS, et al. . Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004;350:2362–2374
    1. Williams DE, Cadwell BL, Cheng YJ, et al. . Prevalence of impaired fasting glucose and its relationship with cardiovascular disease risk factors in US adolescents, 1999-2000. Pediatrics 2005;116:1122–1126
    1. Guthrie JF, Morton JF. Food sources of added sweeteners in the diets of Americans. J Am Diet Assoc 2000;100:43–51; quiz 49–50
    1. Page KA, Chan O, Arora J, et al. . Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways. JAMA 2013;309:63–70
    1. Spear LP. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 2000;24:417–463
    1. Avena NM, Bocarsly ME, Hoebel BG. Animal models of sugar and fat bingeing: relationship to food addiction and increased body weight. Methods Mol Biol 2012;829:351–365
    1. Avena NM, Rada P, Hoebel BG. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neuroscience Biobehav Rev 2008;32:20–39
    1. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000;404:661–671
    1. Avena NM, Gold JA, Kroll C, Gold MS. Further developments in the neurobiology of food and addiction: update on the state of the science. Nutrition 2012;28:341–343
    1. Curry DL. Effects of mannose and fructose on the synthesis and secretion of insulin. Pancreas 1989;4:2–9
    1. Lindqvist A, Baelemans A, Erlanson-Albertsson C. Effects of sucrose, glucose and fructose on peripheral and central appetite signals. Regul Pept 2008;150:26–32
    1. Prodam F, Me E, Riganti F, et al. . The nutritional control of ghrelin secretion in humans: the effects of enteral vs. parenteral nutrition. Eur J Nutr 2006;45:399–405
    1. Teff KL, Elliott SS, Tschöp M, et al. . Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 2004;89:2963–2972
    1. Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E. The role of the central ghrelin system in reward from food and chemical drugs. Mol Cell Endocrinol 2011;340:80–87
    1. Woods SC. The control of food intake: behavioral versus molecular perspectives. Cell Metab 2009;9:489–498
    1. Van Name M, Giannini C, Santoro N, et al. . Blunted suppression of acyl-ghrelin in response to fructose ingestion in obese adolescents: the role of insulin resistance. Obesity (Silver Spring) 2015;23:653–661
    1. Welsh JA, Sharma AJ, Grellinger L, Vos MB. Consumption of added sugars is decreasing in the United States. Am J Clin Nutr 2011;94:726–734
    1. Weiss R, Dufour S, Taksali SE, et al. . Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning. Lancet 2003;362:951–957
    1. Page KA, Seo D, Belfort-DeAguiar R, et al. . Circulating glucose levels modulate neural control of desire for high-calorie foods in humans. J Clin Invest 2011;121:4161–4169
    1. Page KA, Arora J, Qiu M, Relwani R, Constable RT, Sherwin RS. Small decrements in systemic glucose provoke increases in hypothalamic blood flow prior to the release of counterregulatory hormones. Diabetes 2009;58:448–452
    1. Aguirre GK, Detre JA, Zarahn E, Alsop DC. Experimental design and the relative sensitivity of BOLD and perfusion fMRI. Neuroimage 2002;15:488–500
    1. Nolf E. XMedCon - an open-source medical image conversion toolkit. Eur J Nucl Med 2003;30:S246
    1. Friston KJ, Williams S, Howard R, Frackowiak RS, Turner R. Movement-related effects in fMRI time-series. 1996;35:346–355
    1. Wong EC, Buxton RB, Frank LR. Implementation of quantitative perfusion imaging techniques for functional brain mapping using pulsed arterial spin labeling. NMR Biomed 1997;10:237–249
    1. Duncan JS, Papademetris X, Yang J, Jackowski M, Zeng X, Staib LH. Geometric strategies for neuroanatomic analysis from MRI. Neuroimage 2004;23(Suppl. 1):S34–S45
    1. Papademetris X, Jackowski M, Rajeevan N, Constable R, Staib L. BioImage Suite. New Haven, CT, Yale School of Medicine. Available from . Accessed 28 July 2011
    1. Holmes CJ, Hoge R, Collins L, Woods R, Toga AW, Evans AC. Enhancement of MR images using registration for signal averaging. J Comput Assist Tomogr 1998;22:324–333
    1. Evans AC, Collins DL, Mills SR, Brown ED, Kelly RL, Peters TM. 3D statistical neuroanatomical models from 305 MRI volumes. Late-breaking abstract presented at the Nuclear Science Symposium and Medical Imaging Conference, San Francisco, CA, 31 October–6 November 1993
    1. Hommer RE, Seo D, Lacadie CM, et al. . Neural correlates of stress and favorite-food cue exposure in adolescents: a functional magnetic resonance imaging study. Hum Brain Mapp 2013;34:2561–2573
    1. Lubsen J, Vohr B, Myers E, et al. . Microstructural and functional connectivity in the developing preterm brain. Semin Perinatol 2011;35:34–43
    1. Myers EH, Hampson M, Vohr B, et al. . Functional connectivity to a right hemisphere language center in prematurely born adolescents. Neuroimage 2010;51:1445–1452
    1. Cox RW. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res 1996;29:162–173
    1. Van Dijk KR, Sabuncu MR, Buckner RL. The influence of head motion on intrinsic functional connectivity MRI. Neuroimage 2012;59:431–438
    1. Finn ES, Shen X, Holahan JM, et al. Disruption of functional networks in dyslexia: a whole-brain, data-driven analysis of connectivity. Biol Psychiatry 2014;76:397–404
    1. Greicius MD, Supekar K, Menon V, Dougherty RF. Resting-state functional connectivity reflects structural connectivity in the default mode network. Cereb Cortex 2009;19:72–78
    1. Pruessner JC, Champagne F, Meaney MJ, Dagher A. Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride. J Neurosci 2004;24:2825–2831
    1. Kelley AE, Baldo BA, Pratt WE, Will MJ. Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward. Physiol Behav 2005;86:773–795
    1. Ongür D, An X, Price JL. Prefrontal cortical projections to the hypothalamus in macaque monkeys. J Comp Neurol 1998;401:480–505
    1. Ongür D, Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex 2000;10:206–219
    1. Volkow ND, Wang GJ, Telang F, et al. . Inverse association between BMI and prefrontal metabolic activity in healthy adults. Obesity (Silver Spring) 2009;17:60–65
    1. Ross N, Yau PL, Convit A. Obesity, fitness, and brain integrity in adolescence. Appetite 2015;93:44–50
    1. Maayan L, Hoogendoorn C, Sweat V, Convit A. Disinhibited eating in obese adolescents is associated with orbitofrontal volume reductions and executive dysfunction. Obesity (Silver Spring) 2011;19:1382–1387
    1. Avena NM, Rada P, Hoebel BG. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev 2008;32:20–39
    1. Banks WA, Tschöp M, Robinson SM, Heiman ML. Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther 2002;302:822–827
    1. Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther 2012;136:82–93
    1. Schwartz MW, Figlewicz DP, Baskin DG, Woods SC, Porte D Jr. Insulin in the brain: a hormonal regulator of energy balance. Endocr Rev 1992;13:387–414
    1. Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature 1978;272:827–829
    1. Figlewicz DP, Evans SB, Murphy J, Hoen M, Baskin DG. Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat. Brain Res 2003;964:107–115
    1. Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev 2005;85:495–522
    1. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 2008;132:387–396
    1. Kern A, Grande C, Smith RG. Apo-Ghrelin Receptor (apo-GHSR1a) Regulates Dopamine Signaling in the Brain. Front Endocrinol (Lausanne) 2014;5:129.
    1. Cowley MA, Smith RG, Diano S, et al. . The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003;37:649–661
    1. Baicy K, London ED, Monterosso J, et al. . Leptin replacement alters brain response to food cues in genetically leptin-deficient adults. Proc Natl Acad Sci U S A 2007;104:18276–18279

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