Asprosin in health and disease, a new glucose sensor with central and peripheral metabolic effects

Abstract

Adipose tissue malfunction leads to altered adipokine secretion which might consequently contribute to an array of metabolic diseases spectrum including obesity, diabetes mellitus, and cardiovascular disorders. Asprosin is a novel diabetogenic adipokine classified as a caudamin hormone protein. This adipokine is released from white adipose tissue during fasting and elicits glucogenic and orexigenic effects. Although white adipose tissue is the dominant source for this multitask adipokine, other tissues also may produce asprosin such as salivary glands, pancreatic B-cells, and cartilage. Significantly, plasma asprosin levels link to glucose metabolism, lipid profile, insulin resistance (IR), and β-cell function. Indeed, asprosin exhibits a potent role in the metabolic process, induces hepatic glucose production, and influences appetite behavior. Clinical and preclinical research showed dysregulated levels of circulating asprosin in several metabolic diseases including obesity, type 2 diabetes mellitus (T2DM), polycystic ovarian syndrome (PCOS), non-alcoholic fatty liver (NAFLD), and several types of cancer. This review provides a comprehensive overview of the asprosin role in the etiology and pathophysiological manifestations of these conditions. Asprosin could be a promising candidate for both novel pharmacological treatment strategies and diagnostic tools, although developing a better understanding of its function and signaling pathways is still needed.

Keywords: PCOS; adipokines; asprosin; diabetes; metabolic diseases; obesity.

Figure 1

Schematic diagram of the central effects of asprosin in hypothalamic nuclei. Asprosin exerts its appetite stimulating effect by acting mainly via Protein tyrosine phosphatase receptor δ (Ptprd) in; Hypothalamic arcuate nucleus (ARH) causing stimulation of agouti-related protein neurons (AgRP) and inhibition of Pro-opiomelanocortin neurons (POMC). In paraventricular nucleus (PVN), asprosin increases the sympathetic outflow, blood pressure, and heart rate via promoting the cyclic adenosine monophosphate (cAMP) level, adenylyl cyclase (AC), and protein kinase A (PKA) activity mediated by nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) activity and superoxide production (ROS). (The illustration was created using the software: PowerPoint).

Figure 2

Signaling pathways and reported peripheral effects of asprosin in different organs, tissues, cells in vivo and in vitro models. In the liver, asprosin increased glucose production via a G-protein coupled receptor OR4M1 in the human (OLFR734 the mouse orthologue) through activation of cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway. In pancreas, asprosin promotes inflammation, islet β-cells dysfunction and apoptosis via activation of toll-like receptor 4 (TLR4) expression and c-Jun N-terminal kinases (JNK) phosphorylation. In skeletal muscle caused insulin sensitivity impairment via activation of protein kinase C-delta (PKCδ)-associated endoplasmic reticulum (ER) stress/inflammation pathways. Overexpression of asprosin in adipocytes downregulated browning-specific markers (UCP1) and accelerated lipid deposition via inhibition of the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway. Asprosin regulates the function and survival of mesenchymal stromal cells (MSC) against ROS generation and apoptosis via upregulation of superoxide dismutase 2 (SOD2) protein expression and the activation of extracellular signal-regulated kinase 1/2 (ERK1/2)-SOD2 pathway. Asprosin alleviated the macrophage’s inflammatory response and atherosclerotic burden via upregulating ATP-binding cassette transporters A1 (ABCA1) and ABCG1 by the stimulation of the P38/ETS-like transcription factor (Elk-1) pathway. Additional abbreviations within the figure: Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA); Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). (The illustration was created using the software: PowerPoint).