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© Borgis - Postępy Nauk Medycznych 12/2017, s. 717-722 | DOI: 10.25121/PNM.2017.30.12.717
*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
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.
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.

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).

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otrzymano: 2017-11-10
zaakceptowano do druku: 2017-11-30

Adres do korespondencji:
*Agnieszka Baranowska-Bik
Klinika Endokrynologii Centrum Medyczne Kształcenia Podyplomowego Szpital Bielański
ul. Cegłowska 80, 01-809 Warszawa
tel. +48 (22) 834-31-31

Postępy Nauk Medycznych 12/2017
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