The Role of NF-κB, PPAR-α, and PPAR-γ in
                    Older Adults with Metabolic Syndrome

Filiz Demirdağ; Serap Yavuzer; Mahir Cengiz; Hakan Yavuzer; Zehra Kara; Adnan Ayvacı; Suna Avcı; Mehmet Yürüyen; Hafize Uzun; Mehmet Rıza Altıparmak; Alper Döventaş; Deniz Suna Erdinçler

doi:10.1055/a-2109-1958

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2023; 55(10): 733-740
DOI: 10.1055/a-2109-1958

Original Article: Endocrine Research

The Role of NF-κB, PPAR-α, and PPAR-γ in Older Adults with Metabolic Syndrome

Filiz Demirdağ

¹Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey

²Division of Geriatrics, Department of Internal Medicine, Istanbul Medeniyet University, School of Medicine Istanbul, Turkey

,

Serap Yavuzer

³Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey

,

Mahir Cengiz

³Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey

,

Hakan Yavuzer

¹Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey

,

Zehra Kara

⁴Division of Endocrinology, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey

,

Adnan Ayvacı

⁵Department of Radiology, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey

,

Suna Avcı

¹Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey

,

Mehmet Yürüyen

¹Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey

,

Hafize Uzun

⁶Department of Biochemistry, Istanbul Atlas University, School of Medicine, Istanbul, Turkey

,

Mehmet Rıza Altıparmak

⁷Division of Nephrology, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey

,

Alper Döventaş

¹Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey

,

Deniz Suna Erdinçler

¹Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey

› Author Affiliations

Abstract

The etiopathogenesis of metabolic syndrome (MetS) has not been fully understood yet, and chronic low-grade inflammation is thought to be associated with the development of complications related to MetS. We aimed to investigate the role of Nuclear factor Kappa B ( NF-κB ), Peroxisome Proliferator-Activated Receptor- α and γ (PPAR-α, and PPAR-γ) which are the main markers of inflammation in older adults with MetS. A total of 269 patients aged≥18, 188 patients with MetS who met the diagnostic criteria of the International Diabetes Federation, and 81 controls who applied to geriatrics and general internal medicine outpatient clinics for various reasons were included in the study. Patients were separated into four groups: young with MetS (< 60, n=76), elderly with MetS (≥60, n=96), young control (< 60, n=31), elderly controls (≥60, n=38). Carotid intima-media thickness (CIMT) and NF-κB , PPAR-α, and PPAR-γ plasma levels were measured in all of the participants. Age and sex distribution were similar between MetS and control groups. C-reactive protein (CRP), NF-κB levels (p=0.001) and CIMT (p<0,001) of MetS group were significantly higher than in the control groups. On the other hand, the PPAR-γ (p=0.008) and PPAR-α (p=0.003) levels were significantly lower in MetS. ROC analysis revealed that the NF-κB, PPAR-α, and PPAR-γ could be used to indicate MetS in younger adults (AUC: 0.735, p<0.000; AUC: 0.653, p=0.003), whereas it could not be an indicator in older adults (AUC: 0.617, p=0.079; AUC:0.530, p=0.613). It seems that these markers have important roles in MetS-related inflammation. In our results, suggest that the indicator feature of NF-κB , PPAR-α and PPAR-γ in recognizing MetS in young individuals is lost in older adults with Mets.

Key words

aging - metabolic syndrome - inflammation - NF-κB

Full Text

References

References
1 Alberti KG, Zimmet P, Shaw J. et al. The metabolic syndrome – a new worldwide definition. Lancet (London, England) 2005; 366: 1059-1062
2 Grundy SM, Cleeman JI, Daniels SR. et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112: 2735-2752
3 Kraja AT, Borecki IB, North K. et al. Longitudinal and age trends of metabolic syndrome and its risk factors: the Family Heart Study. Nutr Metab 2006; 3: 41
4 Hirode G, Wong RJ. Trends in the prevalence of metabolic syndrome in the United States, 2011-2016. 2020; JAMA 323: 2526-2528
5 Baker RG, Hayden MS, Ghosh S. NF-κB, inflammation, and metabolic disease. Cell Metab 2011; 13: 11-22
6 Nunn AV, Bell J, Barter P. The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance. Nucl Recept 2007; 5: 1
7 Robinson E, Grieve DJ. Significance of peroxisome proliferator-activated receptors in the cardiovascular system in health and disease. Pharmacol Amp Therap 2009; 122: 246-263
8 Wilson PW, D’agostino RB, Parise H. et al. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005; 112: 3066-3072
9 Park GM, An H, Lee SW. et al. Impact of metabolic syndrome on subclinical atherosclerosis in asymptomatic individuals. Circ J 2015; 79: 1799
10 Yavuzer H, Yavuzer S, Cengiz M. et al. Biomarkers of lipid peroxidation related to hypertension in aging. Hyperten Res 2016; 39: 342
11 Yamashita AS, Belchior T, Lira FS. et al. Regulation of metabolic disease- associated inflammation by nutrient sensors. Mediat Inflamm 2018; 8261432
12 Sabir JS, El Omri A, Shaik NA. et al. Identification of key regulatory genes connected to NF-κB family of proteins in visceral adipose tissues using gene expression and weighted protein interaction network. PLoS One 2019; 14: e0214337
13 van Greevenbroek MM, Schalkwijk CG, Stehouwer CD. Dysfunctional adipose tissue and low-grade inflammation in the management of the metabolic syndrome: current practices and future advances. F1000Res 2016; 5: F1000 Faculty Rev-2515
14 Sonnenberg GE, Krakower GR, Kissebah AH. A novel pathway to the manifestations of metabolic syndrome. Obes Res 2004; 12: 180-186
15 Malle EK, Zammit NW, Walters SN. et al. Nuclear factor kappaB-inducing kinase activation as a mechanism of pancreatic beta cell failure in obesity. J Exp Med 2015; 212: 1239-1254
16 Tilstra JS, Clauson CL, Niedernhofer LJ. et al. NF-κB in aging and disease. Aging Dis 2011; 2: 449
17 Hasegawa Y, Saito T, Ogihara T. et al. Blockade of the NF-κB pathway in the endothelium prevents insulin resistance and prolongs lifespans. Circulation 2012; 125: 1122-1133
18 Pierce GL, Lesniewski LA, Lawson BR. et al. Nuclear factor-κB activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans. Circulation 2009; 119: 1284-1292
19 Adler AS, Kawahara TL, Segal E. et al. Reversal of aging by NFκB blockade. Cell Cycle 2008; 7: 556-559
20 Jiao P, Feng B, Ma J. et al. Constitutive activation of IKKβ in adipose tissue prevents diet-induced obesity in mice. Endocrinology 2012; 153: 154-165
21 Seki E, Brenner DA. The role of NF-κB in hepatocarcinogenesis: Promoter or suppressor?. J Hepatol 2007; 47: 307-309
22 Chung JH, Seo AY, Chung SW. et al. Molecular mechanism of PPAR in the regulation of age-related inflammation. Ageing Res Rev 2008; 7: 126-136
23 Fruchart JC. Peroxisome proliferator-activated receptor-alpha (PPARα): at the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis 2009; 205: 1-8
24 Tsuchida A, Yamauchi T, Takekawa S. et al. Peroxisome proliferator-activated receptor (PPAR) α activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARα, PPARγ, and their combination. Diabetes 2005; 54: 3358-3370
25 Stienstra R, Mandard S, Patsouris D. et al. Peroxisome proliferator-activated receptor α protects against obesity-induced hepatic inflammation. Endocrinology 2007; 148: 2753-2763
26 Chung KW, Lee EK, Lee MK. et al. Impairment of PPARα and the fatty acid oxidation pathway aggravates renal fibrosis during aging. J Am Soc Nephrol 2018; 29: 1223-1237
27 Poynter ME, Daynes RA. Peroxisome proliferator-activated receptor α activation modulates cellular redox status, represses nuclear factor-κB signaling, and reduces inflammatory cytokine production in aging. J Biol Chem 1998; 273: 32833-32841
28 Kvandova M, Majzunova M, Dovinova I. The Role of PPAR [gamma] in Cardiovascular Diseases. Physiol Res 2016; 65: S343
29 Feng X, Yu W, Li X. et al. Apigenin, a modulator of PPARγ, attenuates HFD-induced NAFLD by regulating hepatocyte lipid metabolism and oxidative stress via Nrf2 activation. Biochem Pharmacol 2017; 136: 136-149
30 Nagao K, Yanagita T. Bioactive lipids in metabolic syndrome. Prog Lipid Res 2008; 47: 127-146
31 Law RE, Meehan WP, Xi XP. et al. Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J Clin Invest 1996; 98: 1897-1905
32 Rodríguez-Calvo R, Serrano L, Coll T. et al. (2008). Activation of peroxisome proliferator-activated receptor β/δ (pparβ/δ) inhibits LPS-induced cytokine production in adipocytes by lowering NF-κB activity via ERK1/2. Diabetes 2008; 57: 2149-2157
33 Salazar G. NADPH oxidases and mitochondria in vascular senescence. Int J Mol Sci 2018; 19: 1327
34 Lim HA, Lee EK, Kim JM. et al. PPARγ activation by baicalin suppresses NF-κB-mediated inflammation in aged rat kidney. Biogerontology 2012; 13: 133-145
35 Wang Y, Zhang X, Xie X. et al. Obesity and metabolic syndrome related macrophage promotes PD-L1 expression in TNBC through IL6/JAK/STAT pathway and can be reversed by telmisartan. Cancer Biol Ther 2020; 21: 1179-1190
36 Sung B, Park S, Yu BP. et al. Amelioration of age-related inflammation and oxidative stress by PPARγ activator: suppression of NF-κB by 2, 4-thiazolidinedione. Exp Gerontol 2006; 41: 590-599
37 Recinella L, De Filippis B, Libero ML. et al. Anti-inflammatory, antioxidant, and WAT/BAT-conversion stimulation induced by novel PPAR Ligands: results from Ee vivo and in vitro studies. Pharmaceuticals (Basel, Switzerland) 2023; 16: 346
38 Zhang W, Yu H, Lin Q. et al. Anti-inflammatory effect of resveratrol attenuates the severity of diabetic neuropathy by activating the Nrf2 pathway. Aging 2021; 13: 10659-10671
39 Song Z, Zhong X, Li M. et al. 1-MNA Ameliorates high fat diet-induced heart injury by upregulating Nrf2 expression and inhibiting NF-κB in vivo and in vitro. Front Cardiovasc Med 2021; 8: 721814
40 McCoy MG, Jamaiyar A, Sausen G. et al. MicroRNA-375 repression of Kruppel-like factor 5 improves angiogenesis in diabetic critical limb ischemia. Angiogenesis 2023; 26: 107-127