Midlife obesity is related to late-onset dementia. Studying adipose tissue-secreted adipokines in the context of brain aging may help us understand this association.
Objective
To investigate associations between adipokines and brain MRI markers in middle-aged adults from the Third-Generation cohort of the Framingham Heart Study.
Methods
Serum adiponectin, retinol-binding protein 4 (RBP4), fetuin-A, and Fatty Acid-Binding Protein 4 (FABP4) concentrations were measured by enzymatic immunoassays. MRI measures included total brain, cortical gray matter, hippocampal (total and anterior), lateral ventricular, and white matter hyperintensity volumes. We used linear regression models to separately relate adipokine concentrations to MRI measures, adjusting for potential confounders.
Results
We included 1882 participants (mean age of 48 ± 8 years, 54% women). Higher RBP4 concentrations were related to markers of brain atrophy, including smaller total (Beta ± standard error, −0.05 ± 0.02; p = 0.014) and cortical gray brain volumes (−0.06 ± 0.02; p = 0.004), and larger lateral ventricular volumes (0.06 ± 0.02; p = 0.006). Additionally, higher RBP4 (−0.06 ± 0.03; p = 0.042), Fetuin-A (−0.06 ± 0.03; p = 0.039), and FABP4 (−0.09 ± 0.03; p = 0.008) concentrations were associated with smaller anterior hippocampal volumes. Most associations remained after additional adjustment for vascular risk factors. In exploratory analyses, higher FABP4 was related to larger total brain in non-obese participants, and to smaller anterior hippocampal volumes in obese participants. Finally, higher adiponectin concentrations were related to smaller cortical gray, only in non-obese participants.
Conclusions
Our results suggest that adipokines are associated with markers of brain atrophy during midlife. Further studies are needed to replicate these findings and elucidate any potential mechanisms contributing to abnormal brain aging.
WhitmerRAGundersonEPQuesenberryCPJr., et al.Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Curr Alzheimer Res2007; 4: 103–109.
2.
FitzpatrickALKullerLHLopezOL, et al.Midlife and late-life obesity and the risk of dementia: cardiovascular health study. Arch Neurol2009; 66: 336–342.
3.
KivipeltoMNganduTFratiglioniL, et al.Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol2005; 62: 1556–1560.
4.
GustafsonDRBackmanKWaernM, et al.Adiposity indicators and dementia over 32 years in Sweden. Neurology2009; 73: 1559–1566.
5.
KiliaanAJArnoldussenIAGustafsonDR. Adipokines: a link between obesity and dementia?Lancet Neurol2014; 13: 913–923.
6.
HartwigSDe FilippoEGoddekeS, et al.Exosomal proteins constitute an essential part of the human adipose tissue secretome. Biochim Biophys Acta Proteins Proteom2019; 1867: 140172.
7.
RodriguezAEzquerroSMendez-GimenezL, et al.Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism. Am J Physiol Endocrinol Metab2015; 309: E691–E714.
8.
ChatterjeeTKStollLLDenningGM, et al.Proinflammatory phenotype of perivascular adipocytes: influence of high-fat feeding. Circ Res2009; 104: 541–549.
9.
FriedSKBunkinDAGreenbergAS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab1998; 83: 847–850.
10.
MooldijkSSIkramMKIkramMA. Adiponectin, leptin, and resistin and the risk of dementia. J Gerontol A Biol Sci Med Sci2022; 77: 1245–1249.
11.
VarhelyiZPKalmanJOlahZ, et al.Adiponectin receptors are less sensitive to stress in a transgenic mouse model of Alzheimer's disease. Front Neurosci2017; 11: 199.
12.
PedrosIPetrovDArtiachG, et al.Adipokine pathways are altered in hippocampus of an experimental mouse model of Alzheimer's disease. J Nutr Health Aging2015; 19: 403–412.
13.
SanbornVPreisSRAngA, et al.Association between leptin, cognition, and structural brain measures among “early” middle-aged adults: results from the Framingham heart study third generation cohort. J Alzheimers Dis2020; 77: 1279–1289.
14.
CharisisSShortMIBernalR, et al.Leptin bioavailability and markers of brain atrophy and vascular injury in the middle age. Alzheimers Dement2024. doi: https://doi.org/10.1002/alz.13879
15.
ZachariahJPQuirozRNelsonKP, et al.Prospective relation of circulating adipokines to incident metabolic syndrome: the Framingham heart study. J Am Heart Assoc2017; 6: e004974.
16.
RyoMNakamuraTKiharaS, et al.Adiponectin as a biomarker of the metabolic syndrome. Circ J2004; 68: 975–981.
17.
ThundyilJPavlovskiDSobeyCG, et al.Adiponectin receptor signalling in the brain. Br J Pharmacol2012; 165: 313–327.
18.
WennbergAMGustafsonDHagenCE, et al.Serum adiponectin levels, neuroimaging, and cognition in the Mayo clinic study of aging. J Alzheimers Dis2016; 53: 573–581.
19.
van HimbergenTMBeiserASAiM, et al.Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and Alzheimer disease: results from the Framingham heart study. Arch Neurol2012; 69: 594–600.
20.
OstADanielssonALidenM, et al.Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. FASEB J2007; 21: 3696–3704.
21.
KaessBMEnserroDMMcManusDD, et al.Cardiometabolic correlates and heritability of fetuin-A, retinol-binding protein 4, and fatty-acid binding protein 4 in the Framingham heart study. J Clin Endocrinol Metab2012; 97: E1943–E1947.
22.
ZhuYYZhangJLLiuL, et al.Evaluation of serum retinol-binding protein-4 levels as a biomarker of poor short-term prognosis in ischemic stroke. Biosci Rep2018; 38: BSR20180786.
23.
MauryCPTeppoAM. Immunodetection of protein composition in cerebral amyloid extracts in Alzheimer's disease: enrichment of retinol-binding protein. J Neurol Sci1987; 80: 221–228.
24.
IxJHChertowGMShlipakMG, et al.Association of fetuin-A with mitral annular calcification and aortic stenosis among persons with coronary heart disease: data from the heart and soul study. Circulation2007; 115: 2533–2539.
25.
LaughlinGAMcEvoyLKBarrett-ConnorE, et al.Fetuin-A, a new vascular biomarker of cognitive decline in older adults. Clin Endocrinol (Oxf)2014; 81: 134–140.
26.
SmithERNilforooshanRWeavingG, et al.Plasma fetuin-A is associated with the severity of cognitive impairment in mild-to-moderate Alzheimer's disease. J Alzheimers Dis2011; 24: 327–333.
27.
HotamisligilGSBernlohrDA. Metabolic functions of FABPs-mechanisms and therapeutic implications. Nat Rev Endocrinol2015; 10: 592–605.
28.
FuruhashiMHotamisligilGS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov2008; 7: 489–503.
29.
IshimuraSFuruhashiMWatanabeY, et al.Circulating levels of fatty acid-binding protein family and metabolic phenotype in the general population. PloS One2013; 8: e81318.
30.
TsoAWLamTKXuA, et al.Serum adipocyte fatty acid-binding protein associated with ischemic stroke and early death. Neurology2011; 76: 1968–1975.
31.
O'BryantSEXiaoGEdwardsM, et al.Biomarkers of Alzheimer's disease among Mexican Americans. J Alzheimers Dis2013; 34: 841–849.
32.
PaseMPBeiserAEnserroD, et al.Association of ideal cardiovascular health with vascular brain injury and incident dementia. Stroke2016; 47: 1201–1206.
33.
SplanskyGLCoreyDYangQ, et al.The third generation cohort of the national heart, lung, and blood institute's Framingham heart study: design, recruitment, and initial examination. Am J Epidemiol2007; 165: 1328–1335.
34.
KannelWBFeinleibMMcNamaraPM, et al.An investigation of coronary heart disease in families. The Framingham offspring study. Am J Epidemiol1979; 110: 281–290.
35.
DawberTRMeadorsGFMooreFEJr. Epidemiological approaches to heart disease: the Framingham study. Am J Public Health Nations Health1951; 41: 279–281.
36.
DeCarliCMillerBLSwanGE, et al.Predictors of brain morphology for the men of the NHLBI twin study. Stroke1999; 30: 529–536.
37.
RajapakseJCGieddJNDeCarliC, et al.A technique for single-channel MR brain tissue segmentation: application to a pediatric sample. Magn Reson Imaging1996; 14: 1053–1065.
38.
FletcherESinghBHarveyD, et al.Adaptive image segmentation for robust measurement of longitudinal brain tissue change. Conf Proc IEEE Eng Med Biol Soc2012; 2012: 5319–5322.
39.
VercauterenTPennecXPerchantA, et al.Non-parametric diffeomorphic image registration with the demons algorithm. Med Image Comput Comput Assist Interv2007; 10: 319–326.
40.
McGrathERHimaliJJLevyD, et al.Circulating IGFBP-2: a novel biomarker for incident dementia. Ann Clin Transl Neurol2019; 6: 1659–1670.
41.
AljabarPHeckemannRAHammersA, et al.Multi-atlas based segmentation of brain images: atlas selection and its effect on accuracy. Neuroimage2009; 46: 726–738.
42.
MangroliaPMurphyRM. Retinol-binding protein interferes with transthyretin-mediated beta-amyloid aggregation inhibition. Biochemistry2018; 57: 5029–5040.
43.
IshiiMKamelHIadecolaC. Retinol binding protein 4 levels are not altered in preclinical Alzheimer's disease and not associated with cognitive decline or incident dementia. J Alzheimers Dis2019; 67: 257–263.
44.
ShuLHooRLWuX, et al.A-FABP mediates adaptive thermogenesis by promoting intracellular activation of thyroid hormones in brown adipocytes. Nat Commun2017; 8: 14147.
45.
XuAWangYXuJY, et al.Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin Chem2006; 52: 405–413.
46.
RheeEJSeoMHJeonWS, et al.The association of baseline adipocytokine levels with glycemic progression in nondiabetic Korean adults in 4 years of follow-up. Diabetes Res Clin Pract2012; 98: 501–507.
47.
CaoHSekiyaMErtuncME, et al.Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab2013; 17: 768–778.
48.
KralischSKlotingNEbertT, et al.Circulating adipocyte fatty acid-binding protein induces insulin resistance in mice in vivo. Obesity2015; 23: 1007–1013.
49.
AparicioHJPetreaREMassaroJM, et al.Association of descending thoracic aortic plaque with brain atrophy and white matter hyperintensities: the Framingham heart study. Atherosclerosis2017; 265: 305–311.
50.
SatizabalCLZhuYCMazoyerB, et al.Circulating IL-6 and CRP are associated with MRI findings in the elderly: the 3C-Dijon study. Neurology2012; 78: 720–727.
51.
MakowskiLBrittinghamKCReynoldsJM, et al.The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities. J Biol Chem2005; 280: 12888–12895.
52.
FuruhashiMFuseyaTMurataM, et al.Local production of fatty acid-binding protein 4 in epicardial/perivascular fat and macrophages is linked to coronary atherosclerosis. Arterioscler Thromb Vasc Biol2016; 36: 825–834.
53.
DuffyCMXuHNixonJP, et al.Identification of a fatty acid binding protein4-UCP2 axis regulating microglial mediated neuroinflammation. Mol Cell Neurosci2017; 80: 52–57.
54.
GrimsrudPAPickloMJGriffinTJ, et al.Carbonylation of adipose proteins in obesity and insulin resistance: identification of adipocyte fatty acid-binding protein as a cellular target of 4-hydroxynonenal. Mol Cell Proteomics2007; 6: 624–637.
55.
Garin-ShkolnikTRudichAHotamisligilGS, et al.FABP4 Attenuates PPARgamma and adipogenesis and is inversely correlated with PPARgamma in adipose tissues. Diabetes2014; 63: 900–911.
56.
HenekaMTFinkADoblhammerG. Effect of pioglitazone medication on the incidence of dementia. Ann Neurol2015; 78: 284–294.
57.
ZhangZYuanHZhaoH, et al.PPARgamma activation ameliorates postoperative cognitive decline probably through suppressing hippocampal neuroinflammation in aged mice. Int Immunopharmacol2017; 43: 53–61.
58.
BraakHBraakEBohlJ. Staging of Alzheimer-related cortical destruction. Eur Neurol1993; 33: 403–408.
59.
WestMJColemanPDFloodDG, et al.Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet1994; 344: 769–772.
60.
YuSLeviLCasadesusG, et al.Fatty acid-binding protein 5 (FABP5) regulates cognitive function both by decreasing anandamide levels and by activating the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) in the brain. J Biol Chem2014; 289: 12748–12758.
61.
AdamsHHHibarDPChourakiV, et al.Novel genetic loci underlying human intracranial volume identified through genome-wide association. Nat Neurosci2016; 19: 1569–1582.
62.
TeunissenCEVeerhuisRDe VenteJ, et al.Brain-specific fatty acid-binding protein is elevated in serum of patients with dementia-related diseases. Eur J Neurol2011; 18: 865–871.
63.
SteinackerPMollenhauerBBiblM, et al.Heart fatty acid binding protein as a potential diagnostic marker for neurodegenerative diseases. Neurosci Lett2004; 370: 36–39.
64.
MollenhauerBSteinackerPBahnE, et al.Serum heart-type fatty acid-binding protein and cerebrospinal fluid tau: marker candidates for dementia with Lewy bodies. Neurodegener Dis2007; 4: 366–375.
65.
Forny-GermanoLDe FeliceFGVieiraM. The role of leptin and adiponectin in obesity-associated cognitive decline and Alzheimer's disease. Front Neurosci2018; 12: 1027.
66.
BloemerJPinkyPDGovindarajuluM, et al.Role of adiponectin in central nervous system disorders. Neural Plast2018; 2018: 4593530.
67.
CauncaMRSimonettoMAlperinN, et al.Measures of adiposity and Alzheimer's disease-related MRI markers: the northern Manhattan study. J Alzheimers Dis2019; 70: 995–1004.
68.
CauncaMRGardenerHSimonettoM, et al.Measures of obesity are associated with MRI markers of brain aging: the northern Manhattan study. Neurology2019; 93: e791–e803.
69.
ArnoldussenIACGustafsonDRLeijsenEMC, et al.Adiposity is related to cerebrovascular and brain volumetry outcomes in the RUN DMC study. Neurology2019; 93: e864–e878.
70.
QuanHYuTLinY, et al.Adiponectin levels are associated with white matter lesions (WMLs) and cognitive impairment. Biomed Res Int2022; 2022: 9943250.
71.
ArnlovJPencinaMJNamBH, et al.Relations of insulin sensitivity to longitudinal blood pressure tracking: variations with baseline age, body mass index, and blood pressure. Circulation2005; 112: 1719–1727.
72.
YeRSchererPE. Adiponectin, driver or passenger on the road to insulin sensitivity?Mol Metab2013; 2: 133–141.
73.
JackCRJr.KnopmanDSJagustWJ, et al.Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol2013; 12: 207–216.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
