The multifaceted role of profilin-1 in adipose tissue inflammation and glucose homeostasis

Abstract

Profilin-1 (pfn) is a small ubiquitous protein that can bind to: (1) G-actin, (2) phosphatidylinositol 4,5-bisphosphate, and (3) a heterogeneous group of proteins harboring poly-l-proline stretches. Through these interactions, pfn integrates signaling from a diverse array of extracellular cues with actin cytoskeleton dynamics. Cumulating evidence indicates that changes in pfn levels are associated and may play a pathogenic role in such inflammatory diseases as atherosclerosis and glomerulonephritis. We recently demonstrated that high fat diet (HFD) increases pfn expression in the white adipose tissue (WAT), but not in the liver or the muscle. Pfn heterozygote mice (PfnHet) were protected against HFD-induced glucose intolerance, and WAT and systemic inflammation, when compared to pfn wild-type mice. In addition to blunted accumulation of macrophages and reduced "pro-inflammatory" cytokines, the WAT of PfnHet exhibited preserved frequency of regulatory T cells. These findings suggest that pfn levels in WAT-both adipocytes and hematopoietic-derived cells-can modulate immune homeostasis within the WAT and glucose tolerance systemically. Here, we review the interaction of pfn with his diverse array of binding partners and discuss mechanisms that may underlie the effects of pfn dosage on insulin sensitivity and metabolic inflammation. IntroductionIt is estimated that obesity affects more than one-third of the US adult population 1 with its prevalence steadily increasing also in children and adolescents.2 The worldwide social and economic burden of obesity has recently led the American Medical Association and other key medical societies to recognize obesity as an independent disease, rather than simply a risk factor for a growing list of ailments. These include, but are not limited to, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease, atherosclerosis, and obstructive sleep apnea.The hypothesis has been set forth that the low-grade chronic inflammation observed in experimental models of obesity and in obese individuals may represent a common pathophysiological trait of obesity-associated abnormalities. 3As discussed below, several lines of investigations have helped define a dynamic cross-talk and possibly interdependence between the changes in the immune system and metabolic processes occurring in obesity and insulin resistance (IR), both systemically and at the tissue level (reviewed in ref. 4).Tremendous progress has been attained in our understanding of the events fueling this "metabolic" inflammation, and the efficacy of therapies targeting candidate inflammatory pathways is being actively investigated in patients with obesity and T2DM. 5,6 Yet, the molecular mechanisms responsible for immune cell recruitment in the adipose tissue and vascular wall upon high fat diet (HFD) remain largely elusive. In this context, we addressed the effect of profilin-1 in HFD-induced IR and adipose tissue inflammation.The members of the profilin family (profilin-1, -2, and -3) are well conserved

Serum Proteomes Distinguish Children Developing Type 1 Diabetes in a Cohort With HLA-Conferred Susceptibility

“…ADIPO is involved both in the control of fat metabolism and in insulin sensitivity and has been positively correlated with insulin sensitivity in patients with type 1 diabetes (4,39). PFN1 has been associated with inflammation and insulin resistance (40), and notably, significant differences were detected both before and after seroconversion (decreasing in the latter). Further evaluation of this observation is needed.…”

Differential expression of genes identified by suppression subtractive hybridization in liver and adipose tissue of gerbils with diabetes

“…Another gene Pfn1 , the expression of which increased in diabetic gerbils, is recognized as a binding protein involved in a variety of cellular activities [ 19 ]. Munkyong et al [ 20 ]demonstrated that a high-fat diet (HFD) upregulates Pfn1 expression in white adipose tissue (WAT). Caglayan et al [ 21 ] reported that Pfn1 expression is significantly enhanced in human atherosclerotic plaques compared with normal vessel walls.…”

Proteomic Analysis of Differentially-Expressed Proteins in the Liver of Streptozotocin-Induced Diabetic Rats Treated with Parkia biglobosa Protein Isolate

“…Profilin-1 OS = Rattus norvegicus GN = Pfn1 PE = 1 SV = 2 (PROF1_RAT) was also identified to be differentially expressed in this study. Profilin-1 is a small ubiquitous actin-binding protein, (12 to 15 kD) widely distributed in various types of cells with highly conserved sequences [ 29 , 30 ]. It binds G-actin and motivates the exchange of ADP to ATP on G-actin, thus controlling the pool of ATP-actin within the cell [ 30 ].…”

“…Profilin-1 is a small ubiquitous actin-binding protein, (12 to 15 kD) widely distributed in various types of cells with highly conserved sequences [ 29 , 30 ]. It binds G-actin and motivates the exchange of ADP to ATP on G-actin, thus controlling the pool of ATP-actin within the cell [ 30 ]. Profilin-1 plays a significant role in endothelial dysfunction and atherosclerosis; and endothelial dysfunction has been identified and implicated as an underling factor preceding structural alterations in diabetic vascular disease, although its molecular basis is still poorly understood [ 31 ].…”