Asprosin, a novel glucogenic adipokine, is encoded by two exons (exon 65 and exon 66) of the gene Fibrillin 1 (FBN1) and mainly synthesized and released by white adipose tissue during fasting. Asprosin plays a complex role in the central nervous system (CNS), peripheral tissues, and organs. It is involved in appetite, glucose metabolism, insulin resistance (IR), cell apoptosis, etc. In this review, we will summarize the newly discovered roles of asprosin in metabolic diseases including diabetes, obesity, polycystic ovarian syndrome (PCOS), and cardiovascular disease (CVD), which may contribute to future clinical diagnosis and treatment.

Although diabetic peripheral neuropathy (DPN) has long been considered a disease of the peripheral nervous system, recent neuroimaging studies have shown that alterations in the central nervous system may play a crucial role in its pathogenesis. Here, we used surface‐based morphometry (SBM) and tract‐based spatial statistics (TBSS) to investigate gray matter (GM) and white matter (WM) differences between patients with DPN (n = 67, 44 painless and 23 painful) and healthy controls (HCs; n = 88). Compared with HCs, patients with DPN exhibited GM abnormalities in the pre‐ and postcentral gyrus and in several deep GM nuclei (caudate, putamen, medial pallidum, thalamus, and ventral nuclear). They also exhibited altered WM tracts (corticospinal tract, spinothalamic tract, and thalamocortical projecting fibers). These findings suggest impaired motor and somatosensory pathways in DPN. Further, patients with DPN (particularly painful DPN) exhibited morphological differences in the cingulate, insula, prefrontal cortex, and thalamus, as well as impaired WM integrity in periaqueductal WM and internal and external capsules. This suggests pain‐perception/modulation pathways are altered in painful DPN. Intermodal correlation analyses found that the morphological indices of the brain regions identified by the SBM analysis were significantly correlated with the fractional anisotropy of brain regions identified by the TBSS analysis, suggesting that the GM and WM alterations were tightly coupled. Overall, our study showed sensorimotor and pain‐related GM and WM alterations in patients with DPN, which might be involved in the development of DPN.

The accumulation of palmitic acid (PA), implicated in obesity, can induce apoptotic cell death and inflammation of astrocytes. Caveolin-1 (Cav-1), an essential protein for astrocytes survival, can be degraded by autophagy, which is a double-edge sword that can either promote cell survival or cell death. The aim of this study was to delineate whether the autophagic degradation of Cav-1 is involved in PA-induced apoptosis and inflammation in hippocampal astrocytes. In this study we found that: (1) PA caused apoptotic death and inflammation by autophagic induction; (2) Cav-1 was degraded by PA-induced autophagy and PA induced autophagy in a Cav-1-independent manner; (3) the degradation of Cav-1 was responsible for PA-induced autophagy-dependent apoptotic cell death and inflammation; (4) chronic high-fat diet (HFD) induced Cav-1 degradation, apoptosis, autophagy, and inflammation in the hippocampal astrocytes of rats. Our results suggest that the autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes. Therefore, Cav-1 may be a potential therapeutic target for central nervous system injuries caused by PA accumulation.

High glucose induces formation of tau hyperphosphorylation via Cav-1-mTOR pathway: A potential molecular mechanism for diabetes-induced cognitive dysfunction High glucose induces formation of tau hyperphosphorylation via Cav-1-mTOR pathway: A potential molecular mechanism for diabetes-induced cognitive dysfunction

Diabetes mellitus (DM) is a major risk factor for cognitive impairment. Previous studies have implicated hippocampal neuronal apoptosis in diabetes-related cognitive impairment. However, the underlying mechanism remains unclear. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, is indispensable in normal learning and memory. Whether SIRT1 is involved in diabetes-induced neuronal apoptosis and thus takes part in the development of diabetic cognitive impairment is unknown. To address this issue, we examined the possible role of SIRT1 in hippocampal neuronal apoptosis in streptozotocin-induced diabetic mice and SH-SY5Y cells. We found that downregulation of the activity and expression of SIRT1 was associated with increased hippocampal neuronal apoptosis in mice. Incubation of SH-SY5Y cells with high concentration of glucose induced cell apoptosis which was accompanied by a downregulation of SIRT1 and an increased acetylation of p53. On the contrary, activation of SIRT1 using its agonist resveratrol ameliorated cell apoptosis via deacetylating p53. Our data suggest that high concentration of glucose can induce neuronal apoptosis through downregulation of SIRT1 and increased acetylation of p53, which likely contributed to the development of cognitive impairment in diabetes.

Tau hyperphosphorylation in hippocampal neurons has an important pathogenetic role in the development of diabetic cognitive dysfunction. N⁶-methyladenosine (m⁶A) methylation is the most common modification of eukaryotic mRNA and is involved in regulating diverse biological processes. However, the role of m⁶A alteration in tau hyperphosphorylation of hippocampus neurons has not been reported. We found lower ALKBH5 expression in the hippocampus of diabetic rats and in HN-h cells with high-glucose intervention, accompanied by tau hyperphosphorylation. ALKBH5 overexpression significantly reversed tau hyperphosphorylation in high-glucose-stimulated HN-h cells. Furthermore, we found and confirmed by m⁶A–mRNA epitope transcriptome microarray and transcriptome RNA sequencing coupled with methylated RNA immunoprecipitation that ALKBH5 regulates the m⁶A modification of Dgkh mRNA. High glucose inhibited the demethylation modification of Dgkh by ALKBH5, resulting in decreases in Dgkh mRNA and protein levels. Overexpression of Dgkh reversed tau hyperphosphorylation in HN-h cells after high-glucose stimulation. Overexpression of Dgkh by adenovirus suspension injection into the bilateral hippocampus of diabetic rats significantly ameliorated tau hyperphosphorylation and diabetic cognitive dysfunction. In addition, ALKBH5 targeted Dgkh to activate PKC-α, leading to tau hyperphosphorylation under high-glucose conditions. The results of this study reveal that high glucose suppresses the demethylation modification of Dgkh by ALKBH5, which downregulates Dgkh and leads to tau hyperphosphorylation through activation of PKC-α in hippocampal neurons. These findings may indicate a new mechanism and a novel therapeutic target for diabetic cognitive dysfunction.