Original Article | Published:

Integrative Biology

Sex differences in serotonin–hypothalamic connections underpin a diminished sense of emotional well-being with increasing body weight

International Journal of Obesity volume 40, pages 12681277 (2016) | Download Citation

Abstract

Background/Objectives:

The neurobiological mechanisms linking obesity to emotional distress related to weight remain largely unknown.

Participants/Methods:

Here we combined positron emission tomography, using the serotonin transporter (5-HTT) radiotracer [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, with functional connectivity magnetic resonance imaging, the Beck Depression Inventory (BDI-II) and the Impact of Weight on Quality of Life–Lite questionnaire (IWQOL-Lite) to investigate the role of central serotonin in the severity of depression (BDI-II), as well as in the loss of emotional well-being with body weight (IWQOL-Lite).

Results:

In a group of lean to morbidly obese individuals (n=28), we found sex differences in the 5-HTT availability-related connectivity of the hypothalamus. Males (n=11) presented a strengthened connectivity to the lateral orbitofrontal cortex, whereas in females (n=17) we found strengethened projections to the ventral striatum. Both regions are known as reward regions involved in mediating the emotional response to food. Their resting-state activity correlated positively to the body mass index (BMI) and IWQOL-Lite scores, suggesting that each region in both sexes also underpins a diminished sense of emotional well-being with body weight. Contrarily to males, we found that in females also the BDI-II positively correlated with the BMI and by trend with the activity in ventral striatum, suggesting that in females an increased body weight may convey to other mood dimensions than those weight-related ones included in the IWQOL-Lite.

Conclusions:

This study suggests sex differences in serotonin–hypothalamic connections to brain regions of the reward circuitry underpinning a diminished sense of emotional well-being with an increasing body weight.

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References

  1. 1.

    , , , , , et al. Attention-deficit/hyperactivity disorder (ADHD) and obesity: a systematic review of the literature. Crit Rev Food Sci Nutr 2008; 48: 524–537.

  2. 2.

    , , , , , . Elevated body mass index is associated with executive dysfunction in otherwise healthy adults. Compr Psychiatry 2007; 48: 57–61.

  3. 3.

    , , . Changing perspectives regarding late-life dementia. Nat Rev Neurol 2009; 5: 649–658.

  4. 4.

    , , , , , . Are mood disorders and obesity related? A review for the mental health professional. J Clin Psych 2004; 65: 634–651; (quiz 730).

  5. 5.

    , , . Relationship of obesity to depression: a family-based study. Int J Obes Relat Metab Disord 2004; 28: 790–795.

  6. 6.

    . Brain monoamines and peptides: role in the control of eating behavior. Fed Proc 1986; 45: 1396–1403.

  7. 7.

    , , . Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn Sci 2011; 15: 37–46.

  8. 8.

    . Multiple neural systems controlling food intake and body weight. Neurosci Biobehav Rev 2002; 26: 393–428.

  9. 9.

    , , , , , et al. The central nervous norepinephrine network links a diminished sense of emotional well-being to an increased body weight. Int J Obes (Lond) 2015; 40: 779–787.

  10. 10.

    , , , , . Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB. Eur J Nucl Med 2000; 27: 1719–1722.

  11. 11.

    , , , , . In vitro and in vivo characterisation of [11C]-DASB: a probe for in vivo measurements of the serotonin transporter by positron emission tomography. Nucl Med Biol 2002; 29: 509–515.

  12. 12.

    , , , , , et al. Central serotonin transporter availability in highly obese individuals compared with non-obese controls - a [11C] DASB positron emission tomography study. Eur J Nucl Med Mol Imaging 2015; 43: 1096–1104.

  13. 13.

    , . Structure and function of the brain serotonin system. Physiol Rev 1992; 72: 165–229.

  14. 14.

    Vertes RL, Linley SB. Efferent and afferent connections of the dorsal and median raphe nuclei in the rat. In: Monti JM, Pandi-Perumal SR, Jacobs BL, Nutt DJ (eds). Serotonin and Sleep: Molecular, Functional and Clinical Aspects. Birkhäuser Verlag: Basel, Switzerland, 2008, pp 69–102.

  15. 15.

    , , , , , et al. Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry. Neuroimage 2012; 61: 884–888.

  16. 16.

    , , , , , et al. A whole-brain atlas of inputs to serotonergic neurons of the dorsal and median raphe nuclei. Neuron 2014; 83: 663–678.

  17. 17.

    , , . Serotonin, eating behavior, and fat intake. Obes Res 1995; 3 (Suppl 4): 471S–476S.

  18. 18.

    , . Serotonin and its place in the pathogenesis of depression. J Clin Psych 1988; 49: 4–11.

  19. 19.

    , . Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 1994; 40: 288–295.

  20. 20.

    , , , , , et al. Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry 2004; 61: 1271–1279.

  21. 21.

    , , , . The serotonin transporter in psychiatric disorders: insights from PET imaging. Lancet Psychiatry 2015; 2: 743–755.

  22. 22.

    . Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatr Neurosci 2007; 32: 86–102.

  23. 23.

    . The role of dexfenfluramine in the regulation of energy balance. Neuroendocrine abnormalities in human obesity. Metabolism 1995; 44 (Suppl 2): 38–41.

  24. 24.

    , , , , , . The concentrations of monoamine metabolites and neuropeptides in the cerebrospinal fluid of obese women with different body fat distribution. Int J Obes Relat Metab Disord 1996; 20: 361–368.

  25. 25.

    Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory-II. Psychological Corporation: San Antonio, TX, USA, 1996.

  26. 26.

    , , , . Development of a brief measure to assess quality of life in obesity. Obes Res 2001; 9: 102–111.

  27. 27.

    , , , , . The relationship between health-related quality of life and weight loss. Obes Res 2001; 9: 564–571.

  28. 28.

    , , , , . Self-reported stigmatization among candidates for bariatric surgery. Obesity 2008; 16 (Suppl 2): S75–S79.

  29. 29.

    , , . Depression in obese men. Int J Obes 1989; 13: 479–485.

  30. 30.

    , . Cynical hostility, depression, and obesity: the moderating role of education and gender. Int J Eat Disord 2000; 27: 106–109.

  31. 31.

    , , , , , et al. Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci USA 1997; 94: 5308–5313.

  32. 32.

    , , , , , et al. Sex differences in the serotonin 1 A receptor and serotonin transporter binding in the human brain measured by PET. Neuroimage 2008; 39: 1408–1419.

  33. 33.

    , , , . Gender differences in routine treatment of depressed outpatients with the selective serotonin reuptake inhibitor sertraline. Int Clin Psychopharmacol 2005; 20: 1–7.

  34. 34.

    , , , , , et al. Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab 2003; 23: 1096–1112.

  35. 35.

    , , , , , et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007; 27: 1533–1539.

  36. 36.

    , , , . An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 2003; 19: 1233–1239.

  37. 37.

    , , , , . Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol 2005; 493: 63–71.

  38. 38.

    , , , , . Representation of pleasant and aversive taste in the human brain. J Neurophysiol 2001; 85: 1315–1321.

  39. 39.

    , , , , , et al. Human cortical gustatory areas: a review of functional neuroimaging data. Neuroreport 1999; 10: 7–14.

  40. 40.

    , , , , , . Widespread reward-system activation in obese women in response to pictures of high-calorie foods. Neuroimage 2008; 41: 636–647.

  41. 41.

    , . Psychometric evaluation of the impact of weight on quality of life-lite questionnaire (IWQOL-lite) in a community sample. Qual Life Res 2002; 11: 157–171.

  42. 42.

    , , , , , et al. Obesity is a marker of reduction in QoL and disability. ScientificWorldJournal 2012; 2012: 167520.

  43. 43.

    , , , . The tempted brain eats: pleasure and desire circuits in obesity and eating disorders. Brain Res 2010; 1350: 43–64.

  44. 44.

    , , , , , et al. Cerebral serotonin transporter binding is inversely related to body mass index. Neuroimage 2010; 52: 284–289.

  45. 45.

    , , , , , et al. Association of central serotonin transporter availability and body mass index in healthy Europeans. Eur Neuropsychopharmacol 2014; 24: 1240–1247.

  46. 46.

    , , , , , et al. Central 5-HT neurotransmission modulates weight loss following gastric bypass surgery in obese individuals. J Neurosci 2015; 35: 5884–5889.

  47. 47.

    , , , , , et al. Common genetic variation near MC4R has a sex-specific impact on human brain structure and eating behavior. PLoS One 2013; 8: e74362.

  48. 48.

    , , , , , et al. Fasting biases brain reward systems towards high-calorie foods. Eur J Neurosci 2009; 30: 1625–1635.

  49. 49.

    , , , . Aversive gustatory stimulation activates limbic circuits in humans. Brain 1998; 121(Pt 6): 1143–1154.

  50. 50.

    , , , , . Flavor processing: more than the sum of its parts. Neuroreport 1997; 8: 3913–3917.

  51. 51.

    . Brain mechanisms underlying flavour and appetite. Philos Trans R Soc Lond B Biol Sci 2006; 361: 1123–1136.

  52. 52.

    , , . Where is the comfort in comfort foods? Mechanisms linking fat signaling, reward, and emotion. Neurogastroenterol Motil 2014; 26: 303–315.

  53. 53.

    , , , . Inducing negative affect increases the reward value of appetizing foods in dieters. J Cogn Neurosci 2012; 24: 1625–1633.

  54. 54.

    , . Stress-induced eating. Psychol Bull 1994; 115: 444–464.

  55. 55.

    , . Emotions and eating in everyday life. Appetite 2000; 35: 65–71.

  56. 56.

    , , . The perceived function of eating is changed during examination stress: a field study. Eat Behav 2005; 6: 109–112.

  57. 57.

    , , , , , . Pharmacologic treatment of binge eating disorder. Int J Eat Disord 2003; 34: S74–S88.

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Acknowledgements

This study is supported by the IFB AdiposityDiseases, Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01E01001 (http://www.bmbf.de) and the German Research Foundation (DFG) (http://www.dfg.de), within the framework of the CRC 1052 Obesity Mechanisms to Project A6 (to BP and MR), to Project A1 (to AV and MS) and to Project B1 (to MB).

Author information

Affiliations

  1. IFB Adiposity Diseases, University Medical Centre, Leipzig, Germany

    • J Melasch
    • , M Rullmann
    • , A Hilbert
    • , M Stumvoll
    • , M Blüher
    • , A Villringer
    • , K Arelin
    • , O Sabri
    • , S Hesse
    •  & B Pleger
  2. Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany

    • J Melasch
    • , M Rullmann
    • , J Luthardt
    • , G A Becker
    • , M Patt
    • , P M Meyer
    • , A Bresch
    • , O Sabri
    •  & S Hesse
  3. Medical Department III, University Hospital Leipzig, Leipzig, Germany

    • M Stumvoll
    •  & M Blüher
  4. Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany

    • A Villringer
    • , K Arelin
    •  & B Pleger
  5. Clinic for Cognitive Neurology, University Hospital Leipzig, Leipzig, Germany

    • A Villringer
    • , K Arelin
    •  & B Pleger
  6. BG University Clinic Bergmannsheil, Department of Neurology, Ruhr University Bochum, Bochum, Germany

    • B Pleger

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to B Pleger.

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DOI

https://doi.org/10.1038/ijo.2016.63

Supplementary Information accompanies this paper on International Journal of Obesity website (http://www.nature.com/ijo)

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