Adiponectin, the most abundant plasma adipokine, plays an important role in the regulation of glucose and lipid metabolism. Adiponectin also possesses insulin-sensitizing, anti-inflammatory, angiogenic, and vasodilatory properties which may influence central nervous system (CNS) disorders.
Although initially not thought to cross the blood-brain barrier, adiponectin enters the brain through peripheral circulation. In the brain, adiponectin signaling through its receptors, AdipoR1 and AdipoR2, directly influences important brain functions such as energy homeostasis, hippocampal neurogenesis, and synaptic plasticity.
Overall, based on its central and peripheral actions, recent evidence indicates that adiponectin has neuroprotective, antiatherogenic, and antidepressant effects. However, these findings are not without controversy as human observational studies report differing correlations between plasma adiponectin levels and incidence of CNS disorders.
Despite these controversies, adiponectin is gaining attention as a potential therapeutic target for diverse CNS disorders, such as stroke, Alzheimer’s disease, anxiety, and depression. Evidence regarding the emerging role for adiponectin in these disorders is discussed in the current review.
1. Introduction
Adiponectin, a hormone produced by adipocytes, regulates metabolic processes and improves insulin sensitivity. Adiponectin signaling has been widely studied in multisystem diseases, for example, obesity, diabetes, dyslipidemia, atherosclerosis, and comorbid metabolic dysfunction in the setting of cardiovascular disease such as hypertension.
Serum adiponectin levels appear to be inversely correlated with the presence and severity of metabolic dysfunction, that is, lower serum adiponectin is seen in patients with disease.
Serum adiponectin levels also appear to be altered in various neurological disorders in which the etiologies of these conditions involve both metabolic and inflammatory components.
Furthermore, adiponectin receptors are highly expressed in a number of brain regions, and adiponectin exerts neuroprotective and antidepressant properties, likely through specific adiponectin receptors expressed in the central nervous system (CNS).
Therefore, this review provides an overview of adiponectin and discusses recent evidence supporting adiponectin’s role in stroke, Alzheimer’s disease (AD), anxiety, and depression.
2. Overview of Adiponectin
2.1. Structure and Production of Adiponectin
Adiponectin is a 244-amino acid polypeptide protein which belongs to the complement 1q family. Adiponectin is produced in adipocytes, and its transcription is regulated by sirtuin 1/forkhead box O-1 and peroxisome proliferator-activated receptors (PPARs). It forms a characteristic homomultimer composed of an NH2-terminal collagenous region and a COOH-terminal globular domain. Usually, adiponectin exists as a full-length protein of 30 kDa (fAd) that circulates in trimeric, hexameric, and higher order complexes.
Adiponectin is further identified based on the molecular weight of these multimers as low (trimer), middle (hexameric), and high (higher order complexes). In the circulation, adiponectin is present as either these full-length forms or a smaller, globular fragment. Full-length adiponectin is cleaved by leukocyte esterase to form globular adiponectin (gAd). Both gAd and fAd mediate tissue-specific effects, as well as regulate distinct signaling pathways in the same tissue. Studies report that a sexual dimorphism exists in serum adiponectin levels.
Adiponectin serum levels are approximately 2.5-fold higher in female than in male mice, and this sexual dimorphism is also confirmed in humans. Furthermore, the associations between adiponectin and certain disease states appear to be sex specific . Because adiponectin may have sex-specific effects, differentiating the effects of altered adiponectin levels in both males and females is important, although the vast majority of rodent studies have only been performed in males.
It was initially thought that adiponectin does not cross the blood-brain barrier (BBB). However, adiponectin is observed in human cerebral spinal fluid (CSF), with evidence that the adiponectin trimer is the predominate form. In addition, studies in mice show that peripheral intravenous application of adiponectin leads to a concurrent rise in CSF adiponectin. Therefore, adiponectin does cross the BBB, although concentrations in the CSF are approximately 1000-fold lower than that in serum.