J Clin Neurol.  2015 Jan;11(1):48-56. 10.3988/jcn.2015.11.1.48.

Improved Serum Leptin and Ghrelin Following Bariatric Surgery Predict Better Postoperative Cognitive Function

• Alosco ML
• Spitznagel MB
• Strain G
• Devlin M
• Cohen R
• Crosby RD
• Mitchell J
• Gunstad J

• KMID: 2179572
• DOI: http://doi.org/10.3988/jcn.2015.11.1.48

Abstract

BACKGROUND AND PURPOSE
Bariatric surgery is associated with improved cognitive function, but the mechanisms underlying these gains remain poorly understood. Disturbed leptin and ghrelin systems are common in obese individuals and are associated with impaired cognitive function in other samples. Bariatric surgery has been shown to improve serum leptin and ghrelin levels, and these changes may underlie postoperative cognitive improvements.
METHODS
Eighty-four patients completed a computerized cognitive test battery prior to bariatric surgery and at 12 months postoperatively. Participants also submitted to an 8-hour fasting blood draw to quantify serum leptin and ghrelin concentrations at these same time points.
RESULTS
Baseline cognitive impairments and disturbed leptin and ghrelin levels improved at the 12-month follow-up compared to presurgery. Higher leptin levels were associated with worse attention/executive function at baseline; no such findings emerged for ghrelin. Regression analyses controlling for baseline factors and demographic characteristics showed that both decreased leptin and increased ghrelin following surgery was associated with better attention/executive function at the 12-month follow-up. These effects diminished after controlling for the postoperative change in body mass index (BMI); however, BMI change did not predict 12-month cognitive function.
CONCLUSIONS
Improvements in leptin and ghrelin levels following bariatric surgery appear to contribute to postoperative cognitive benefits. These gains may involve multiple mechanisms, such as reduced inflammation and improved glycemic control. Future studies that employ neuroimaging are needed to clarify the underlying mechanisms and determine whether the effects of bariatric surgery on leptin and ghrelin levels can attenuate adverse brain changes and/or risk of dementia in severely obese individuals.

Keyword

obesity; bariatric surgery; cognitive function; leptin; ghrelin

MeSH Terms

Bariatric Surgery*
Body Mass Index
Brain
Dementia
Fasting
Follow-Up Studies
Ghrelin*
Humans
Inflammation
Leptin*
Neuroimaging
Obesity
Ghrelin
Leptin

Reference

1. Fitzpatrick AL, Kuller LH, Lopez OL, Diehr P, O'Meara ES, Longstreth WT Jr, et al. Midlife and late-life obesity and the risk of dementia: cardiovascular health study. Arch Neurol. 2009; 66:336–342.

2. Bolzenius JD, Laidlaw DH, Cabeen RP, Conturo TE, McMichael AR, Lane EM, et al. Impact of body mass index on neuronal fiber bundle lengths among healthy older adults. Brain Imaging Behav. 2013; 7:300–306.

3. Stanek KM, Strain G, Devlin M, Cohen R, Paul R, Crosby RD, et al. Body mass index and neurocognitive functioning across the adult lifespan. Neuropsychology. 2013; 27:141–151.

4. Lokken KL, Boeka AG, Austin HM, Gunstad J, Harmon CM. Evidence of executive dysfunction in extremely obese adolescents: a pilot study. Surg Obes Relat Dis. 2009; 5:547–552.

5. Gunstad J, Strain G, Devlin MJ, Wing R, Cohen RA, Paul RH, et al. Improved memory function 12 weeks after bariatric surgery. Surg Obes Relat Dis. 2011; 7:465–472.

6. Alosco ML, Spitznagel MB, Strain G, Devlin M, Cohen R, Paul R, et al. Improved memory function two years after bariatric surgery. Obesity (Silver Spring). 2014; 22:32–38.

7. Miller LA, Crosby RD, Galioto R, Strain G, Devlin MJ, Wing R, et al. Bariatric surgery patients exhibit improved memory function 12 months postoperatively. Obes Surg. 2013; 23:1527–1535.

8. Alosco ML, Galioto R, Spitznagel MB, Strain G, Devlin M, Cohen R, et al. Cognitive function after bariatric surgery: evidence for improvement 3 years after surgery. Am J Surg. 2014; 207:870–876.

9. Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007; 8:21–34.

10. Sahu A. Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. Front Neuroendocrinol. 2003; 24:225–253.

11. Dos Santos VV, Rodrigues AL, De Lima TC, de Barioglio SR, Raisman-Vozari R, Prediger RD. Ghrelin as a neuroprotective and palliative agent in Alzheimer's and Parkinson's disease. Curr Pharm Des. 2013; 19:6773–6790.

12. McNay EC. Insulin and ghrelin: peripheral hormones modulating memory and hippocampal function. Curr Opin Pharmacol. 2007; 7:628–632.

13. Spitznagel MB, Benitez A, Updegraff J, Potter V, Alexander T, Glickman E, et al. Serum ghrelin is inversely associated with cognitive function in a sample of non-demented elderly. Psychiatry Clin Neurosci. 2010; 64:608–611.

14. Zeki Al, Haan MN, Whitmer RA, Yaffe K, Neuhaus J. Central obesity, leptin and cognitive decline: the Sacramento Area Latino Study on Aging. Dement Geriatr Cogn Disord. 2012; 33:400–409.

15. Labad J, Price JF, Strachan MW, Deary IJ, Seckl JR, Sattar N, et al. Serum leptin and cognitive function in people with type 2 diabetes. Neurobiol Aging. 2012; 33:2938–2941.e2.

16. Bonda DJ, Stone JG, Torres SL, Siedlak SL, Perry G, Kryscio R, et al. Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance. J Neurochem. 2014; 128:162–172.

17. Terra X, Auguet T, Guiu-Jurado E, Berlanga A, Orellana-Gavaldà JM, Hernàndez M, et al. Long-term changes in leptin, chemerin and ghrelin levels following different bariatric surgery procedures: Roux-en-Y gastric bypass and sleeve gastrectomy. Obes Surg. 2013; 23:1790–1798.

18. Dimitriadis E, Daskalakis M, Kampa M, Peppe A, Papadakis JA, Melissas J. Alterations in gut hormones after laparoscopic sleeve gastrectomy: a prospective clinical and laboratory investigational study. Ann Surg. 2013; 257:647–654.

19. Belle SH, Berk PD, Courcoulas AP, Flum DR, Miles CW, Mitchell JE, et al. Safety and efficacy of bariatric surgery: Longitudinal Assessment of Bariatric Surgery. Surg Obes Relat Dis. 2007; 3:116–126.

20. Paul RH, Lawrence J, Williams LM, Richard CC, Cooper N, Gordon E. Preliminary validity of "integneuro": a new computerized battery of neurocognitive tests. Int J Neurosci. 2005; 115:1549–1567.

21. Williams LM, Simms E, Clark CR, Paul RH, Rowe D, Gordon E. The test-retest reliability of a standardized neurocognitive and neurophysiological test battery: "neuromarker". Int J Neurosci. 2005; 115:1605–1630.

22. Reitan RM. Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills. 1958; 8:271–276.

23. Golden CJ. Stroop color and word test : cat. no. 30150M; a manual for clinical and experimental uses. Wood Dale, IL: Stoelting;1978.

24. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D Jr. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med. 1996; 2:589–593.

25. Holden KF, Lindquist K, Tylavsky FA, Rosano C, Harris TB, Yaffe K, et al. Serum leptin level and cognition in the elderly: Findings from the Health ABC Study. Neurobiol Aging. 2009; 30:1483–1489.

26. Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, et al. Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA. 2009; 302:2565–2572.

27. Lee JH, Reed DR, Price RA. Leptin resistance is associated with extreme obesity and aggregates in families. Int J Obes Relat Metab Disord. 2001; 25:1471–1473.

28. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet. 1996; 348:159–161.

29. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996; 334:292–295.

30. Arch JR. Central regulation of energy balance: inputs, outputs and leptin resistance. Proc Nutr Soc. 2005; 64:39–46.

31. Banks WA, Coon AB, Robinson SM, Moinuddin A, Shultz JM, Nakaoke R, et al. Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes. 2004; 53:1253–1260.

32. Steinberg GR, McAinch AJ, Chen MB, O'Brien PE, Dixon JB, Cameron-Smith D, et al. The suppressor of cytokine signaling 3 inhibits leptin activation of AMP-kinase in cultured skeletal muscle of obese humans. J Clin Endocrinol Metab. 2006; 91:3592–3597.

33. Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T. Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience. 2002; 113:607–615.

34. Liu Y, Wang PS, Xie D, Liu K, Chen L. Ghrelin reduces injury of hippocampal neurons in a rat model of cerebral ischemia/reperfusion. Chin J Physiol. 2006; 49:244–250.

35. Chung H, Kim E, Lee DH, Seo S, Ju S, Lee D, et al. Ghrelin inhibits apoptosis in hypothalamic neuronal cells during oxygen-glucose deprivation. Endocrinology. 2007; 148:148–159.

36. Miao Y, Xia Q, Hou Z, Zheng Y, Pan H, Zhu S. Ghrelin protects cortical neuron against focal ischemia/reperfusion in rats. Biochem Biophys Res Commun. 2007; 359:795–800.

37. Selim M, Jones R, Novak P, Zhao P, Novak V. The effects of body mass index on cerebral blood flow velocity. Clin Auton Res. 2008; 18:331–338.

38. Song YM, Sung J, Davey Smith G, Ebrahim S. Body mass index and ischemic and hemorrhagic stroke: a prospective study in Korean men. Stroke. 2004; 35:831–836.

39. Pulkkinen L, Ukkola O, Kolehmainen M, Uusitupa M. Ghrelin in diabetes and metabolic syndrome. Int J Pept. 2010; 2010:pii: 248948.

40. Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci. 2006; 9:381–388.

41. Rigamonti AE, Pincelli AI, Corrà B, Viarengo R, Bonomo SM, Galimberti D, et al. Plasma ghrelin concentrations in elderly subjects: comparison with anorexic and obese patients. J Endocrinol. 2002; 175:R1–R5.

42. Gahete MD, Rubio A, Córdoba-Chacón J, Gracia-Navarro F, Kineman RD, Avila J, et al. Expression of the ghrelin and neurotensin systems is altered in the temporal lobe of Alzheimer's disease patients. J Alzheimers Dis. 2010; 22:819–828.

43. Harvey J, Solovyova N, Irving A. Leptin and its role in hippocampal synaptic plasticity. Prog Lipid Res. 2006; 45:369–378.

44. Martins I, Gomes S, Costa RO, Otvos L, Oliveira CR, Resende R, et al. Leptin and ghrelin prevent hippocampal dysfunction induced by Aβ oligomers. Neuroscience. 2013; 241:41–51.

45. Ghanim H, Monte SV, Sia CL, Abuaysheh S, Green K, Caruana JA, et al. Reduction in inflammation and the expression of amyloid precursor protein and other proteins related to Alzheimer's disease following gastric bypass surgery. J Clin Endocrinol Metab. 2012; 97:E1197–E1201.

46. Tuulari JJ, Karlsson HK, Hirvonen J, Hannukainen JC, Bucci M, Helmiö M, et al. Weight loss after bariatric surgery reverses insulin-induced increases in brain glucose metabolism of the morbidly obese. Diabetes. 2013; 62:2747–2751.

47. Huang JS, Letendre S, Marquie-Beck J, Cherner M, McCutchan JA, Grant I, et al. Low CSF leptin levels are associated with worse learning and memory performance in HIV-infected men. J Neuroimmune Pharmacol. 2007; 2:352–358.