*Agnieszka Baranowska-Bik1, 2, Małgorzata Waszkiewicz-Hanke2
Adiponectin as a neuropeptide
Adiponektyna jako neuropeptyd
1Department of Endocrinology, Centre Bielański Hospital of Postgraduate Medical Education, Warsaw
Head of Department: Professor Wojciech Zgliczyński, MD, PhD
2Department of Endocrinology, Bielanski Hospital, Warsaw
Head of Department: Professor Wojciech Zgliczyński, MD, PhD
Streszczenie
Tkanka tłuszczowa wydziela wiele biologicznie czynnych substancji, nazywanych adipokinami. Adiponektyna, jedna z adipokin, posiada szerokie spektrum funkcji. Między innymi może wykazywać aktywność przeciwzapalną i antyapoptotyczną również w obrębie centralnego układu nerwowego.
Neuropeptyd może być zdefiniowany jako biologicznie czynna substancja wydzielana przez różnego typu komórki nerwowe, która wpływa na aktywność mózgu.
Pomimo że adiponektyna nie jest klasycznym neuropeptydem, to istnieją dowody na to, że może ona działać jako modulator niektórych funkcji mózgu.
W pracy prezentujemy aktualną wiedzę na temat interakcji pomiędzy adiponektyną a centralnym układem nerwowym. Poza tym omawiamy rolę adiponektyny w wybranych chorobach neurologicznych.
Wyniki badań eksperymentalnych i klinicznych wskazują, że adiponektyna może odgrywać istotną rolę w modyfikacji aktywności i funkcji centralnego układu nerwowego, jak również może wpływać na przebieg chorób neurologicznych. Niewykluczone, że lek oparty na adiponektynie może stać się obiecującą metodą terapeutyczną w chorobach neurologicznych.
Adiponektyna może stanowić również ogniwo łączące obwodową tkankę tłuszczową i centralny układ nerwowy.
Summary
Adipose tissue is able to secrete many biologically active substances, named adipokines. Adiponectin, an adipokine, possesses a wide spectrum of properties including anti-inflammatory and anti-apoptotic activity that could also be present within the central nervous system.
Neuropeptide could be defined as a biologically active substance secreted from the neuronal cells of different types that influences the activity of the brain. Although adiponectin is not a classical neuropeptide, there is some evidence that this peptide acts as a modulator of selected brain functions.
In this paper we present a general knowledge considering interactions between adiponectin and the central nervous system. Moreover, we discuss the role of adiponectin in selected neurological diseases.
Data from experimental and clinical studies indicate that adiponectin may play an important role in the modification of the central nervous activity and function, and may change neurological diseases course. Possibly, therapeutic agent based on adiponectin might be a promising treatment method of neurological diseases. Adiponectin could also be considered as a link between peripheral adipose tissue and the brain.
Introduction
Adipose tissue was originally recognized as an energy storage reservoir. Since the 1990s its endocrine activity has been evaluated as it is able to secrete many biologically active substances, named adipokines (1). Adipokines represent a wide spectrum of polypeptides and small molecules with different activity.
Adiponectin (ADPN) is an adipose-derived peptide that was discovered in 1995. Adiponectin is a 30 kD protein representing 0.01% of total serum proteins in humans (2). It circulates in the blood as complexes of trimers (low molecular weight – LMW), hexamers (medium molecular weight – MMW) or multimers (high molecular weight – HMW) or globular form (gADPN). It has been reported that HMW adiponectin is the most metabolically active form in the periphery. The presence of adiponectin has been also confirmed in the cerebrospinal fluid with concentrations much lower than in the periphery (2).
Adiponectin possesses insulin-sensitizing, anti-inflammatory, anti-apoptotic and anti-atherosclerotic properties. Therefore, this peptide promotes beneficial metabolic effects, including enhanced insulin sensitivity and decreased inflammation. It has ability to increase insulin sensitivity in the liver, resulting in decreased hepatic glucose production (3). Interestingly, adiponectin levels inversely correlate with adiposity and are decreased in obesity and diabetes mellitus type 2. It is widely accepted that adipose tissue secretes pro-inflammatory mediators to the periphery causing a systemic chronic low-grade inflammation (4). It is known that ADPN is systemic anti-inflammatory adipokine, with ability to macrophage polarization towards an anti-inflammatory M2 phenotype by inhibiting tumor necrosis factor (TNF) α, INFγ, monocyte chemoattractant protein 1 (MCP-1) and IL-6 production as well as increasing anti-inflammatory cytokine production (e.g. IL-10, IL-1Ra) (5).
Moreover, ADPN possesses anti-apoptotic ability which is carried out by the activation of the enzyme ceramidase (6).
Furthermore, it has been reported that decreased concentration of circulating adiponectin is associated with episodes of cardiovascular disease including cerebrovascular disease caused by atherosclerosis. Increased mortality rate after ischemic stroke was also correlated with low ADPN levels.
Neuropeptide could be defined as a biologically active substance secreted from the neuronal cells of different types that influences the activity of the brain. Although adiponectin is not a classical neuropeptide, there is some evidence that this peptide acts as a modulator of selected brain functions.
Herein, we aimed to present a general knowledge considering interactions between adiponectin and the central nervous system. Moreover, we discuss the role of adiponectin in selected neurological diseases.
Adiponectin in the central nervous system
Despite the fact that adiponectin in CSF is 1000 x lower in comparison of the results in serum or plasma, it has been established that these concentrations correlate with each other (7-9). It is worth to notice that LMW adiponectin have been found in the CSF of both humans and mice and LMW adiponectin might be the most active form of adiponectin in the CNS (2).
To date, the exact source of adiponectin in CSF has not been specified. However, it has been suggested that adiponectin is able to cross the blood brain barrier (BBB). The results of experimental studies may confirm this hypothesis. In details, Kadowaki et al. reported that peripheral administration of adiponectin caused a stimulation of AMPK in the mice hypothalamus being responsible for an increase of food intake and a decrease in energy expenditure (10). Nevertheless, the local synthesis within the central nervous system cannot be also excluded. Indeed, adiponectin mRNA has been detected in chicken and murine brain extracts (11, 12), but not in human brain extracts. However, an expression of ADPN mRNA has been reported in human pituitary gland. In the pituitary gland, adiponectin plays a putative role in the autocrine/paracrine control and regulation of the release of somatotrophs and gonadotrophs (13).
Adiponectin receptors
According to the literature, three ADPN receptors have been identified so far: AdipoR1, AdipoR2 and T-cadherin (T-cad). The first two receptors are highly structurally related and ubiquitously expressed, though they differ between each other with affinity to different isoforms and variable predominance in some tissues. Receptors for adiponectin (AdipoRs) are widely expressed with AdipoR1 expression being more pronounced. In the human brain, AdipoRs have been localized in the hypothalamus, pituitary gland, the nucleus basalis of Meynert and in the hippocampus (14). In mice, AdipoRs expressions have been detected in the hypothalamus, brainstem and endothelial cells, as well as in the whole brain and pituitary extracts (2, 12, 13) Moreover, mouse cortical neurons also express both AdipoR1 and AdipoR2, with AdipoR1 expression being more pronounced than AdipoR2 (14). The effect of adiponectin is mediated by ceramidase activity (6). Therefore, interaction between adiponectin and the receptor results in decreased intracellular ceramide concentrations. Subsequently, it has been reported that adiponectin receptors themselves may have ceramidase activity (15).
Adiponectin and Alzheimer’s disease
Alzheimer’s disease (AD) is a progressive central nervous system disease with clinical hallmark of dementia. From histopathological point of view, Alzheimer’s disease is characterized by deposition within the brain of pathological β-amyloid (Aβ) and tau hyperphosphorylation leading to neurodegeneration, neuroinflammation and apoptosis. Although all processes take place in the CNS, there is a growing evidence supporting the thesis that this neurodegenerative disorder coexists with metabolic dysfunction (16, 17). AD is characterized by cerebral glucose hypometabolism caused by insulin receptor impairment, insufficiency and/or resistance to insulin and insulin-like growth factor (IGF) (17, 18).
Adiponectin may influence neuropathological processes seen in AD in several ways. Firstly, ADPN due to its insulin-sensitizing, anti-inflammatory, anti-apoptotic and anti-atherosclerotic properties can indirectly modulate a course of disease (2). ADPN is regarded as systemic anti-inflammatory adipokine that can inhibit synthesis and secretion of pro-inflammatory cytokines, and it has ability to enhance production of anti-inflammatory factors. Secondly, ADPN anti-apoptotic properties include activation of the enzyme ceramidase, and enhancement of its metabolite, sphingosine-1-phosphate (S1p) (6). It has been found that S1p is involved in survival pathways (19). Moreover, growing evidence indicates that ADPN modulates the expression of endothelial adhesion molecules, stimulates eNOS phosphorylation and nitric oxide (NO) production, and regulates angiogenesis potentially protecting the brain against Aβ-induced vascular impairment (2).
Experimental study on APP transfected-neuroblastoma cells revealed that adiponectin protected cells against Aβ neurotoxicity. Therefore, it has been suggested that chronic ADPN deficiency may cause AD-like pathology (20). The group of Ng used ADPN-knockout mice model to assess how adiponectin deficiency influences cerebral insulin resistance, cognitive decline and Alzheimer’s-like pathology. Their study resulted in conclusion that chronic ADPN deficiency inactivated AMPK causing insulin desensitization and elicited AD-like pathogenesis in aged mice which also developed significant cognitive impairments and psychiatric symptoms (21).
Powyżej zamieściliśmy fragment artykułu, do którego możesz uzyskać pełny dostęp.
Mam kod dostępu
- Aby uzyskać płatny dostęp do pełnej treści powyższego artykułu albo wszystkich artykułów (w zależności od wybranej opcji), należy wprowadzić kod.
- Wprowadzając kod, akceptują Państwo treść Regulaminu oraz potwierdzają zapoznanie się z nim.
- Aby kupić kod proszę skorzystać z jednej z poniższych opcji.
Opcja #1
29 zł
Wybieram
- dostęp do tego artykułu
- dostęp na 7 dni
uzyskany kod musi być wprowadzony na stronie artykułu, do którego został wykupiony
Opcja #2
69 zł
Wybieram
- dostęp do tego i pozostałych ponad 7000 artykułów
- dostęp na 30 dni
- najpopularniejsza opcja
Opcja #3
129 zł
Wybieram
- dostęp do tego i pozostałych ponad 7000 artykułów
- dostęp na 90 dni
- oszczędzasz 78 zł
Piśmiennictwo
1. Choi CHJ, Cohen P: Adipose crosstalk with other cell types in health and disease. Exp Cell Res 2017; 360: 6-11.
2. Letra L, Rodrigues T, Matafome P et al.: Adiponectin and sporadic Alzheimer’s disease: clinical and molecular links. Front Neuroendocrinol 2017. DOI: 10.1016/j.yfrne.2017.10.002.
3. Berg AH, Combs TP, Du X et al.: The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001; 7: 947-953.
4. Gomez-Hernandez A, Beneit N, Diaz-Castroverde S et al.: Differential role of adipose tissues in obesity and related metabolic andvascular complications. Int J Endocrinol 2016; 2016: 1216783.
5. Turer AT, Scherer PE: Adiponectin: mechanistic insights and clinical implications. Diabetologia 2012; 55: 2319-2326.
6. Holland WL, Miller RA, Wang ZV et al.: Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 2011; 17: 55-63.
7. Hietaharju A, Kuusisto H, Nieminen R et al.: Elevated cerebrospinal fluid adiponectin and adipsin levels in patients with multiple sclerosis: a Finnish co-twin study. Eur J Neurol 2010; 17: 332-334.
8. Kusminski CM, McTernan PG, Schraw T et al.: Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum. Diabetologia 2007; 50: 634-642.
9. Une K, Takei YA, Tomita N et al.: Adiponectin in plasma and cerebrospinal fluid in MCI and Alzheimer’s disease. Eur J Neurol 2011; 18: 1006-1009.
10. Kadowaki T, Yamauchi T, Kubota N: The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS. FEBS Letters 2008; 582: 74-80.
11. Maddineni S, Metzger S, Ocon O et al.: Adiponectin gene is expressed in multiple tissues in the chicken: food deprivation influences adiponectin messenger ribonucleic acid expression. Endocrinology 2005; 146: 4250-4256.
12. Hoyda TD, Fry M, Ahima RS et al.: Adiponectin selectively inhibits oxytocin neurons of the paraventricular nucleus of the hypothalamus. J Physiol 2007; 585: 805-816.
13. Rodriguez-Pacheco F, Martinez-Fuentes AJ, Tovar S et al.: Regulation of pituitary cell function by adiponectin. Endocrinology 2007; 148: 401-410.
14. Thundyil J, Pavlovski D, Sobey CG et al.: Adiponectin receptor signalling in the brain. Br J Pharmacol 2012; 165: 313-327.
15. Vasiliauskaite-Brooks I, Sounier R, Rochaix P et al.: Structural insights into adiponectin receptors suggest ceramidase activity. Nature 2017; 544: 120-123.
16. Cai H, Cong WN, Ji S et al.: Metabolic dysfunction in Alzheimer’s disease and related neurodegenerative disorders. Curr Alzheimer Res 2012; 9: 5-17.
17. de la Monte SM, Wands JR: Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. J Alzheimers Dis 2005; 7: 45-61.
18. de la Monte SM, Tong M: Brain metabolic dysfunction at the core of Alzheimer’s disease. Biochem Pharmacol 2014; 88: 548-559.
19. Cuvillier O, Pirianov G, Kleuser B et al.: Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 1996; 381: 800-803.
20. Chan KH, Lam KS, Cheng OY et al.: Adiponectin is protective against oxidative stress induced cytotoxicity in amyloid-beta neurotoxicity. PLoS One 2012; 7: e52354.
21. Ng RC, Cheng OY, Jian M et al.: Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice. Mol Neurodegener 2016; 11: 71.
22. Waragai M, Adame A, Trinh I et al.: Possible involvement of adiponectin, the anti-diabetes molecule, in the pathogenesis of Alzheimer’s disease. J Alzheimers Dis 2016; 52: 1453-1459.
23. Khemka VK, Bagchi D, Bandyopadhyay K et al.: Altered serum levels of adipokines and insulin in probable Alzheimer’s disease. J Alzheimers Dis 2014; 41: 525-533.
24. Ma J, Zhang W, Wang HF W et al.: Peripheral blood adipokines and insulin levels in patients with Alzheimer’s disease: a replication study and meta-analysis. Curr Alzheimer Res 2016; 13: 223-233.
25. Warren MW, Hynan LS, Weiner MF: Lipids and adipokines as risk factors for Alzheimer’s disease. J Alzheimers Dis 2012; 29: 151-157.
26. Bigalke B, Schreitmuller B, Sopova K et al.: Adipocytokines and CD34 progenitor cells in Alzheimer’s disease. PLoS One 2011; 6: e20286.
27. Dukic L, Simundic AM, Martinic-Popovic I et al.: The role of human kallikrein 6, clusterin and adiponectin as potential blood biomarkers of dementia. Clin Biochem 2016; 49: 213-218.
28. Teixeira AL, Diniz BS, Campos AC et al.: Decreased levels of circulating adiponectin in mild cognitive impairment and Alzheimer’s disease. Neuromolecular Med 2013; 15: 115-121.
29. van Himbergen TM, Beiser AS, Ai M 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 Neurol 2012; 69: 594-600.
30. Rothman SM, Griffioen KJ, Fishbein KW et al.: Metabolic abnormalities and hypoleptinemia in alpha-synuclein A53T mutant mice. Neurobiol Aging 2014; 35: 1153-1161.
31. Sekiyama K, Waragai M, Akatsu H et al.: Disease-modifying effect of adiponectin in model of alpha-synucleinopathies. Ann Clin Transl Neurol 2014; 1: 479-489.
32. Rocha NP, Scalzo PL, Barbosa IG et al.: Circulating levels of adipokines in Parkinson’s disease. J Neurol Sci 2014; 339: 64-68.
33. Cassani E, Cancello R, Cavanna F et al.: Serum adiponectin levels in advanced-stage Parkinson’s disease patients. Parkinsons Dis 2011; 2011: 624764.
34. Li X, Geng J, Liu J: Adiponectin offers protection against L166P mutant DJ-1-induced neuronal cytotoxicity mediated by APPL1-dependent AMPK activation. Int J Neurosci 2014; 124: 350-361.
35. Gianfrancesco MA, Barcellos LF: Obesity and Multiple Sclerosis Susceptibility: A Review. J Neurol Neuromedicine 2016; 1: 1-5.
36. Matarese G, Carrieri PB, Montella S et al.: Leptin as a metabolic link to multiple sclerosis. Nat Rev Neurol 2010; 6: 455-461.
37. Kraszula L, Jasinska A, Eusebio M et al.: Evaluation of the relationship between leptin, resistin, adiponectin and natural regulatory T cells in relapsing-remitting multiple sclerosis. Neurol Neurochir Pol 2012; 46: 22-28.
38. Emamgholipour S, Eshaghi SM, Hossein-Nezhad A et al.: Adipocytokine profile, cytokine levels and foxp3 expression in multiple sclerosis: a possible link to susceptibility and clinical course of disease. PLoS One 2013; 8: e76555.
39. Guerrero-Garcia JJ, Carrera-Quintanar L, Lopez-Roa RI et al.: Multiple sclerosis and obesity: possible roles of adipokines. Mediators Inflamm 2016; 2016: 4036232.
40. Piccio L, Cantoni C, Henderson JG et al.: Lack of adiponectin leads to increased lymphocyte activation and increased disease severity in a mouse model of multiple sclerosis. Eur J Immunol 2013; 43: 2089-2100.
41. Zhang K, Guo Y, Ge Z et al.: Adiponectin suppress T helper 17 differentiation and limits autoimmune CNS inflammation via the SIRT1/PPARgamma/RORgammat pathway. Mol Neurobiol 2017; 54: 4908-4920.
42. Negrotto L, Farez MF, Correale J: Immunologic effects of metformin and pioglitazone treatment on metabolic syndrome andmultiple sclerosis. JAMA Neurol 2016; 73: 520-528.
43. Musabak U, Demirkaya S, Genc G et al.: Serum adiponectin, TNF-alpha, IL-12p70, and IL-13 levels in multiple sclerosis and the effects of different therapy regimens. Neuroimmunomodulation 2011; 18: 57-66.
44. Penesova A, Vlcek M, Imrich R et al.: Hyperinsulinemia in newly diagnosed patients with multiple sclerosis. Metab Brain Dis 2015; 30: 895-901.
45. Coban A, Duzel B, Tuzun E et al.: Investigation of the prognostic value of adipokines in multiple sclerosis. Mult Scler Relat Disord 2017; 15: 11-14.
46. Devorak J, Mokry LE, Morris JA et al.: Large differences in adiponectin levels have no clear effect on multiple sclerosis risk: a Mendelian randomization study. Mult Scler 2017; 23: 1461-1468.
