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Psychopharmacology

, Volume 234, Issue 12, pp 1923–1932 | Cite as

Body and liver fat content and adipokines in schizophrenia: a magnetic resonance imaging and spectroscopy study

  • Jong-Hoon KimEmail author
  • Jung-Hyun Kim
  • Pil-Whan Park
  • Jürgen Machann
  • Michael Roden
  • Sheen-Woo Lee
  • Jong-Hee HwangEmail author
Original Investigation

Abstract

Rationale

Although antipsychotic treatment often causes weight gain and lipid abnormalities, quantitative analyses of tissue-specific body fat content and its distribution along with adipokines have not been reported for antipsychotic-treated patients.

Objectives

The purposes of the present study were to quantitatively assess abdominal and liver fat in patients with schizophrenia on antipsychotic treatment and age- and body mass index (BMI)-matched healthy controls and to evaluate their associations with plasma leptin and adiponectin levels.

Methods

In 13 schizophrenia patients on antipsychotic treatment and 11 age- and BMI-matched controls, we simultaneously quantified visceral and subcutaneous fat content using T1-weighted magnetic resonance imaging and liver fat content by 1H magnetic resonance spectroscopy. Associations of tissue-specific fat content with plasma levels of leptin and adiponectin were evaluated.

Results

Plasma adiponectin level (μg/mL) was not statistically different between groups (7.02 ± 2.67 vs. 7.59 ± 2.92), whereas plasma leptin level (ng/mL) trended to be higher in patients than in controls (11.82 ± 7.89 vs. 7.93 ± 5.25). The values of liver fat (%), visceral fat (L), and subcutaneous fat (L) were 9.64 ± 8.03 vs. 7.07 ± 7.35, 4.41 ± 1.64 vs. 3.31 ± 1.97, and 8.37 ± 3.34 vs. 7.16 ± 2.99 in patients vs. controls, respectively. Liver fat content was inversely correlated with adiponectin in controls (r =  − 0.87, p < 0.001) but not in patients (r =  − 0.26, p = 0.39). In both groups, visceral fat was inversely associated with adiponectin (controls : r =  − 0.66, p = 0.03; patients : r =  − 0.65, p = 0.02), while subcutaneous fat was positively correlated with leptin (controls : r = 0.90, p < 0.001; patients : r = 0.67, p = 0.01).

Conclusions

These findings suggest that antipsychotic treatment may disrupt the physiological relationship between liver fat content and adiponectin but does not essentially affect the associations of adiponectin and leptin with visceral and subcutaneous compartments.

Keywords

Antipsychotics Schizophrenia Adiponectin Leptin Abdominal and liver fat MRI and magnetic resonance spectroscopy 

Notes

Acknowledgments

This study was supported by the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2015R1C1A2A01051461), and Gachon University Gil Medical Center (Grant #2013-33). For Jong-Hoon Kim, this work was partly supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (number: HI14C2750). The authors thank Prof. Jun-Young Chung for technical support with the Siemens scanner and Prof. Daniel T Stein at Albert Einstein College of Medicine (New York, USA) for fruitful discussion on the procedure of blood sampling and analyses. The authors also thank the radiographers for scanning participants.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Press, Washington DCGoogle Scholar
  2. Aye IL, Rosario FJ, Powell TL, Jansson T (2015) Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth. Proc Natl Acad Sci U S A 112:12858–12863CrossRefPubMedPubMedCentralGoogle Scholar
  3. Baptista T, Beaulieu S (2002) Are leptin and cytokines involved in body weight gain during treatment with antipsychotic drugs? Can J Psychiatr 47:742–749Google Scholar
  4. Bartoli F, Crocamo C, Clerici M, Carrà G (2015) Second-generation antipsychotics and adiponectin levels in schizophrenia: a comparative meta-analysis. Eur Neuropsychopharmacol 25:1767–1774CrossRefPubMedGoogle Scholar
  5. Baum T, Cordes C, Dieckmeyer M, Ruschke S, Franz D, Hauner H, Kirschke JS, Karampinos DC (2016) MR-based assessment of body fat distribution and characteristics. Eur J Radiol 85:1512–1518CrossRefPubMedGoogle Scholar
  6. Birkenaes AB, Birkeland KI, Engh JA, Faerden A, Jonsdottir H, Ringen PA, Friis S, Opjordsmoen S, Andreassen OA (2008) Dyslipidemia independent of body mass in antipsychotic-treated patients under real-life conditions. J Clin Psychopharmacol 28:132–137CrossRefPubMedGoogle Scholar
  7. Bohte AE, van Werven JR, Bipat S, Stoker J (2011) The diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta-analysis. Eur Radiol 21:87–97CrossRefPubMedGoogle Scholar
  8. Bredella MA, Torriani M, Ghomi RH, Thomas BJ, Brick DJ, Gerweck AV, Harrington LM, Miller KK (2011) Adiponectin is inversely associated with intramyocellular and intrahepatic lipids in obese premenopausal women. Obesity (Silver Spring) 19:911–916CrossRefGoogle Scholar
  9. Chan DC, Watts GF, Ng TW, Hua J, Song S, Barrett PH (2006) Measurement of liver fat by magnetic resonance imaging: relationships with body fat distribution, insulin sensitivity and plasma lipids in healthy men. Diabetes Obes Metab 8:698–702CrossRefPubMedGoogle Scholar
  10. de Leon J, Correa JC, Ruano G, Windemuth A, Arranz MJ, Diaz FJ (2008) Exploring genetic variations that may be associated with the direct effects of some antipsychotics on lipid levels. Schizophr Res 98:40–46CrossRefPubMedGoogle Scholar
  11. Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, Okunade A, Klein S (2009) Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A 106:15430–15435CrossRefPubMedPubMedCentralGoogle Scholar
  12. Fernandez-Egea E, Bernardo M, Donner T, Conget I, Parellada E, Justicia A, Esmatjes E, Garcia-Rizo C, Kirkpatrick B (2009) Metabolic profile of antipsychotic-naive individuals with non-affective psychosis. Br J Psychiatry 194:434–438CrossRefPubMedPubMedCentralGoogle Scholar
  13. Fernández-Real JM, Castro A, Vázquez G, Casamitjana R, López-Bermejo A, Peñarroja G, Ricart W (2004) Adiponectin is associated with vascular function independent of insulin sensitivity. Diabetes Care 27:739–745CrossRefPubMedGoogle Scholar
  14. First MB, Spitzer RL, Gibbon M, Williams JBW (1996) Structured clinical interview for DSM-IV axis I disorders research version (SCID-I). New York State Psychiatric Institute Biometrics Research, New YorkGoogle Scholar
  15. Fox CS, Massaro JM, Hoffmann U, Pou KM, Maurovich-Horvat P, Liu CY, Vasan RS, Murabito JM, Meigs JB, Cupples LA, D’Agostino RB Sr, O’Donnell CJ (2007) Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 116:39–48CrossRefPubMedGoogle Scholar
  16. Fu Y (2014) Adiponectin signaling and metabolic syndrome. Prog Mol Biol Transl Sci 121:293–319CrossRefPubMedGoogle Scholar
  17. Gil-Campos M, Cañete RR, Gil A (2004) Adiponectin, the missing link in insulin resistance and obesity. Clin Nutr 23:963–974CrossRefPubMedGoogle Scholar
  18. Goncalves P, Araujo JR, Martel F (2015) Antipsychotics-induced metabolic alterations: focus on adipose tissue and molecular mechanisms. Eur Neuropsychopharmacol 25:1–16CrossRefPubMedGoogle Scholar
  19. Hanssens L, van Winkel R, Wampers M, Van Eyck D, Scheen A, Reginster JY, Collette J, Peuskens J, De Hert M (2008) A cross-sectional evaluation of adiponectin plasma levels in patients with schizophrenia and schizoaffective disorder. Schizophr Res 106:308–314CrossRefPubMedGoogle Scholar
  20. Henderson DC, Vincenzi B, Andrea NV, Ulloa M, Copeland PM (2015) Pathophysiological mechanisms of increased cardiometabolic risk in people with schizophrenia and other severe mental illnesses. Lancet Psychiatry 2:452–464CrossRefPubMedGoogle Scholar
  21. Hosojima H, Togo T, Odawara T, Hasegawa K, Miura S, Kato Y, Kanai A, Kase A, Uchikado H, Hirayasu Y (2006) Early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in patients with schizophrenia. J Psychopharmacol 20:75–79CrossRefPubMedGoogle Scholar
  22. Hwang JH, Stein DT, Barzilai N, Cui MH, Tonelli J, Kishore P, Hawkins M (2007) Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies. Am J Physiol Endocrinol Metab 293:E1663–E1669CrossRefPubMedGoogle Scholar
  23. Jin H, Meyer JM, Mudaliar S, Jeste DV (2008) Impact of atypical antipsychotic therapy on leptin, ghrelin, and adiponectin. Schizophr Res 100:70–85CrossRefPubMedPubMedCentralGoogle Scholar
  24. Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276CrossRefPubMedGoogle Scholar
  25. Kirk SL, Glazebrook J, Grayson B, Neill JC, Reynolds GP (2009) Olanzapine-induced weight gain in the rat: role of 5-HT2C and histamine H1 receptors. Psychopharmacology 207:119–125CrossRefPubMedGoogle Scholar
  26. Kishida K, Kim KK, Funahashi T, Matsuzawa Y, Kang HC, Shimomura I (2011) Relationships between circulating adiponectin levels and fat distribution in obese subjects. J Atheroscler Thromb 18:592–595CrossRefPubMedGoogle Scholar
  27. Koch C, Augustine RA, Steger J, Ganjam GK, Benzler J, Pracht C, Lowe C, Schwartz MW, Shepherd PR, Anderson GM, Grattan DR, Tups A (2010) Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity. J Neurosci 30:16180–16187CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kotronen A, Seppanen-Laakso T, Westerbacka J, Kiviluoto T, Arola J, Ruskeepaa AL, Yki-Jarvinen H, Oresic M (2010) Comparison of lipid and fatty acid composition of the liver, subcutaneous and intra-abdominal adipose tissue, and serum. Obesity(Silver Spring) 18:937–944Google Scholar
  29. Kumada M, Kihara S, Ouchi N, Kobayashi H, Okamoto Y, Ohashi K, Maeda K, Nagaretani H, Kishida K, Maeda N, Nagasawa A, Funahashi T, Matsuzawa Y (2004) Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation 109:2046–2049CrossRefPubMedGoogle Scholar
  30. Lilja M, Rolandsson O, Norberg M, Söderberg S (2012) The impact of leptin and adiponectin on incident type 2 diabetes is modified by sex and insulin resistance. Metab Syndr Relat Disord 10:143–151CrossRefPubMedGoogle Scholar
  31. Livingstone RS, Begovatz P, Kahl S, Nowotny B, Strassburger K, Giani G, Bunke J, Roden M, Hwang JH (2014) Initial clinical application of modified Dixon with flexible echo times: hepatic and pancreatic fat assessments in comparison with (1)H MRS. MAGMA 27:397–405CrossRefPubMedGoogle Scholar
  32. Lu ML, Wang TN, Lin TY, Shao WC, Chang SH, Chou JY, Ho YF, Liao YT, Chen VC (2015 ) Differential effects of olanzapine and clozapine on plasma levels of adipocytokines and total ghrelin. Prog Neuropsychopharmacol Biol Psychiatry: 47–50Google Scholar
  33. Machann J, Thamer C, Stefan N, Schwenzer NF, Kantartzis K, Haring HU, Claussen CD, Fritsche A, Schick F (2010) Follow-up whole-body assessment of adipose tissue compartments during a lifestyle intervention in a large cohort at increased risk for type 2 diabetes. Radiology 257:353–363CrossRefPubMedGoogle Scholar
  34. Mattioli B, Straface E, Matarrese P, Quaranta MG, Giordani L, Malorni W, Viora M (2008) Leptin as an immunological adjuvant: enhanced migratory and CD8+ T cell stimulatory capacity of human dendritic cells exposed to leptin. FASEB J 22:2012–2022CrossRefPubMedGoogle Scholar
  35. Meyer JM (2002) A retrospective comparison of weight, lipid, and glucose changes between risperidone- and olanzapine-treated inpatients: metabolic outcomes after 1 year. J Clin Psychiatry 63:425–433CrossRefPubMedGoogle Scholar
  36. Meyer JM, Koro CE (2004) The effects of antipsychotic therapy on serum lipids: a comprehensive review. Schizophr Res 70:1–17CrossRefPubMedGoogle Scholar
  37. Morris DL, Rui L (2009) Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab 297:E1247–E1259CrossRefPubMedPubMedCentralGoogle Scholar
  38. Murashita M, Inoue T, Kusumi I, Nakagawa S, Itoh K, Tanaka T, Izumi T, Hosoda H, Kangawa K, Koyama T (2007) Glucose and lipid metabolism of long-term risperidone monotherapy in patients with schizophrenia. Psychiatry Clin Neurosci 61:54–58CrossRefPubMedGoogle Scholar
  39. Murashita M, Kusumi I, Inoue T, Takahashi Y, Hosoda H, Kangawa K, Koyama T (2005) Olanzapine increases plasma ghrelin level in patients with schizophrenia. Psychoneuroendocrinology 30:106–110CrossRefPubMedGoogle Scholar
  40. Myers MG, Cowley MA, Münzberg H (2008) Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 70:537–556CrossRefPubMedGoogle Scholar
  41. Neamat-Allah J, Johnson T, Nabers D, Hüsing A, Teucher B, Katzke V, Delorme S, Kaaks R, Kühn T (2015) Can the use of blood-based biomarkers in addition to anthropometric indices substantially improve the prediction of visceral fat volume as measured by magnetic resonance imaging? Eur J Nutr 54:701–708CrossRefPubMedGoogle Scholar
  42. Neeland IJ, Turer AT, Ayers CR, Powell-Wiley TM, Vega GL, Farzaneh-Far R, Grundy SM, Khera A, McGuire DK, de Lemos JA (2012) Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults. JAMA 308:1150–1159CrossRefPubMedPubMedCentralGoogle Scholar
  43. Ohashi K, Ouchi N, Kihara S, Funahashi T, Nakamura T, Sumitsuji S, Kawamoto T, Matsumoto S, Nagaretani H, Kumada M, Okamoto Y, Nishizawa H, Kishida K, Maeda N, Hiraoka H, Iwashima Y, Ishikawa K, Ohishi M, Katsuya T, Rakugi H, Ogihara T, Matsuzawa Y (2004) Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease. J Am Coll Cardiol 43:1195–1200CrossRefPubMedGoogle Scholar
  44. Paredes RM, Quinones M, Marballi K, Gao X, Valdez C, Ahuja SS, Velligan D, Walss-Bass C (2014) Metabolomic profiling of schizophrenia patients at risk for metabolic syndrome. Int J Neuropsychopharmacol 17:1139–1148CrossRefPubMedGoogle Scholar
  45. Richards AA, Hickman IJ, Wang AY, Jones AL, Newell F, Mowry BJ, Whitehead JP, Prins JB, Macdonald GA (2006) Olanzapine treatment is associated with reduced high molecular weight adiponectin in serum: a potential mechanism for olanzapine-induced insulin resistance in patients with schizophrenia. J Clin Psychopharmacol 26:232–237CrossRefPubMedGoogle Scholar
  46. Skrede S, Ferno J, Vazquez MJ, Fjaer S, Pavlin T, Lunder N, Vidal-Puig A, Dieguez C, Berge RK, Lopez M, Steen VM (2012) Olanzapine, but not aripiprazole, weight-independently elevates serum triglycerides and activates lipogenic gene expression in female rats. Int J Neuropsychopharmacol 15:163–179CrossRefPubMedGoogle Scholar
  47. Sporn AL, Bobb AJ, Gogtay N, Stevens H, Greenstein DK, Clasen LS, Tossell JW, Nugent T, Gochman PA, Sharp WS, Mattai A, Lenane MC, Yanovski JA, Rapoport JL (2005) Hormonal correlates of clozapine-induced weight gain in psychotic children: an exploratory study. J Am Acad Child Adolesc Psychiatry 44:925–933CrossRefPubMedGoogle Scholar
  48. Staiger H, Tschritter O, Machann J, Thamer C, Fritsche A, Maerker E, Schick F, Häring HU, Stumvoll M (2003) Relationship of serum adiponectin and leptin concentrations with body fat distribution in humans. Obes Res 11:368–372CrossRefPubMedGoogle Scholar
  49. Starrenburg FC, Bogers JP (2009) How can antipsychotics cause diabetes mellitus? Insights based on receptor-binding profiles, humoral factors and transporter proteins. Eur Psychiatry 24:164–170CrossRefPubMedGoogle Scholar
  50. Steiger JH (1980) Tests for comparing elements of a correlation matrix. Psychol Bull 87:245–251CrossRefGoogle Scholar
  51. Stubbs B, Wang AK, Vancampfort D, Miller BJ (2016) Are leptin levels increased among people with schizophrenia versus controls? A systematic review and comparative meta-analysis. Psychoneuroendocrinology 63:144–154CrossRefPubMedGoogle Scholar
  52. Sugai T, Suzuki Y, Fukui N, Ono S, Watanabe J, Tsuneyama N, Someya T (2012) Dysregulation of adipocytokines related to second-generation antipsychotics in normal fasting glucose patients with schizophrenia. J Clin Psychopharmacol 32:390–393CrossRefPubMedGoogle Scholar
  53. Tai E, Lau TN, Ho SC, Fok AC, Tan CE (2000) Body fat distribution and cardiovascular risk in normal weight women. Associations with insulin resistance, lipids and plasma leptin. Int J Obes Relat Metab Disord 24:751–757CrossRefPubMedGoogle Scholar
  54. Tanyanskiy DA, Martynikhin IA, Rotar OP, Konradi AO, Sokolian NA, Neznanov NG, Denisenko AD (2015) Association of adipokines with metabolic disorders in patients with schizophrenia: results of comparative study with mental healthy cohort. Diabetes Metab Syndr 9:163–167CrossRefPubMedGoogle Scholar
  55. Thomas EL, Frost G, Taylor-Robinson SD, Bell JD (2012a) Excess body fat in obese and normal-weight subjects. Nutr Res Rev 25:150–161CrossRefPubMedGoogle Scholar
  56. Thomas EL, Parkinson JR, Frost GS, Goldstone AP, Doré CJ, McCarthy JP, Collins AL, Fitzpatrick JA, Durighel G, Taylor-Robinson SD, Bell JD (2012b) The missing risk: MRI and MRS phenotyping of abdominal adiposity and ectopic fat. Obesity (Silver Spring) 20:76–87CrossRefGoogle Scholar
  57. Togo T, Kojima K, Shoji M, Kase A, Uchikado H, Katsuse O, Iseki E, Kosaka K (2004) Serum adiponectin concentrations during treatment with olanzapine or risperidone: a pilot study. Int Clin Psychopharmacol 19:37–40CrossRefPubMedGoogle Scholar
  58. Wampers M, Hanssens L, van Winkel R, Heald A, Collette J, Peuskens J, Reginster JY, Scheen A, De Hert M (2012) Differential effects of olanzapine and risperidone on plasma adiponectin levels over time: results from a 3-month prospective open-label study. Eur Neuropsychopharmacol 22:17–26CrossRefPubMedGoogle Scholar
  59. Whitney Z, Procyshyn RM, Fredrikson DH, Barr AM (2015) Treatment of clozapine-associated weight gain: a systematic review. Eur J Clin Pharmacol 71:389–401CrossRefPubMedGoogle Scholar
  60. Woods SC, D’Alessio DA (2008) Central control of body weight and appetite. J Clin Endocrinol Metab 93(11 Suppl 1):S37–S50CrossRefPubMedPubMedCentralGoogle Scholar
  61. Yan H, Chen JD, Zheng XY (2013) Potential mechanisms of atypical antipsychotic-induced hypertriglyceridemia. Psychopharmacology 229:1–7CrossRefPubMedGoogle Scholar
  62. Yang R, Barouch LA (2007) Leptin signaling and obesity: cardiovascular consequences. Circ Res 101:545–559CrossRefPubMedGoogle Scholar
  63. Zhang ZJ, Yao ZJ, Liu W, Fang Q, Reynolds GP (2004) Effects of antipsychotics on fat deposition and changes in leptin and insulin levels. Magnetic resonance imaging study of previously untreated people with schizophrenia. Br J Psychiatry 184:58–62CrossRefPubMedGoogle Scholar
  64. Zimmermann U, Kraus T, Himmerich H, Schuld A, Pollmacher T (2003) Epidemiology, implications and mechanisms underlying drug-induced weight gain in psychiatric patients. J Psychiatr Res 37:193–220CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Jong-Hoon Kim
    • 1
    • 2
    • 3
    Email author
  • Jung-Hyun Kim
    • 4
  • Pil-Whan Park
    • 5
  • Jürgen Machann
    • 6
    • 7
  • Michael Roden
    • 8
    • 9
    • 10
  • Sheen-Woo Lee
    • 11
  • Jong-Hee Hwang
    • 12
    Email author
  1. 1.Department of Psychiatry, Gil Medical Center, Gachon University School of MedicineGachon UniversityIncheonRepublic of Korea
  2. 2.Neuroscience Research InstituteGachon UniversityIncheonRepublic of Korea
  3. 3.Department of Psychiatry, Gil Medical Center, Gachon University School of Medicine, Neuroscience Research InstituteGachon UniversityIncheonRepublic of Korea
  4. 4.Division of Molecular Medicine, Gachon University School of MedicineGachon UniversityIncheonRepublic of Korea
  5. 5.Department of Laboratory Medicine, Gil Medical Center, Gachon University School of MedicineGachon UniversityIncheonRepublic of Korea
  6. 6.Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen; German Center for Diabetes Research (DZD)München-NeuherbergGermany
  7. 7.Section on Experimental Radiology, Department of Diagnostic and Interventional RadiologyUniversity Hospital TübingenTübingenGermany
  8. 8.Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University DüsseldorfDüsseldorfGermany
  9. 9.Department of Endocrinology and Diabetology, Medical FacultyHeinrich-Heine UniversityDüsseldorfGermany
  10. 10.German Center for Diabetes ResearchMünchen-NeuherbergGermany
  11. 11.Department of Diagnostic Radiology, Gil Medical CenterGachon University School of Medicine, Gachon UniversityIncheonRepublic of Korea
  12. 12.Metabolic Imaging, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich-Heine University DüsseldorfDüsseldorfGermany

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