Highlights d RalA and PLD1 are necessary for starvation-induced lipid droplet (LD) formation d RalA recruits PLD1 to lysosomes to promote LD accumulation during starvation d Inhibition of RalA or PLD1 prevents PLIN3 redistribution to growing LDs d PLD1 activity and PA are required for LD accumulation and PLIN3 localization on LDs
Metabolic Syndrome (MetS) raises cardiovascular disease risk. Extracellular vesicles (EVs) have emerged as important mediators of insulin sensitivity, although few studies on vascular function exist in humans. We determined the effect of insulin on EVs in relation to vascular function. Adults with MetS ( n = 51, n = 9 M, 54.8 ± 1.0 years, 36.4 ± 0.7 kg/m 2 , ATPIII: 3.5 ± 0.1 a.u., VO 2 max: 22.1 ± 0.6 ml/kg/min) were enrolled in this cross‐sectional study. Peripheral insulin sensitivity (M‐value) was determined during a euglycemic clamp (40 mU/m 2 /min, 90 mg/dl), and blood was collected for EVs (CD105+, CD45+, CD41+, TX+, and CD31+; spectral flow cytometry), inflammation, insulin, and substrates. Central hemodynamics (applanation tonometry) was determined at 0 and 120 min via aortic waveforms. Pressure myography was used to assess insulin‐induced arterial vasodilation from mouse 3rd order mesenteric arteries (100–200 μm in diameter) at 0.2, 2 and 20 nM of insulin with EVs from healthy and MetS adults. Adults with MetS had low peripheral insulin sensitivity (2.6 ± 0.2 mg/kg/min) and high HOMA‐IR (4.7 ± 0.4 a.u.) plus Adipose‐IR (13.0 ± 1.3 a.u.). Insulin decreased total/particle counts ( p < 0.001), CD45+ EVs ( p = 0.002), AIx75 ( p = 0.005) and Pb ( p = 0.04), FFA ( p < 0.001), total adiponectin ( p = 0.006), ICAM ( p = 0.002), and VCAM ( p = 0.03). Higher M‐value related to lower fasted total EVs ( r = −0.40, p = 0.004) while higher Adipose‐IR associated with higher fasted EVs ( r = 0.42, p = 0.004) independent of VAT. Fasting CD105+ and CD45+ derived total EVs correlated with fasting AIx75 ( r = 0.29, p < 0.05) and Pb ( r = 0.30, p < 0.05). EVs from MetS participants blunted insulin‐induced vasodilation in mesenteric arteries compared with increases from healthy controls across insulin doses (all p < 0.005). These data highlight EVs as potentially novel mediators of vascular insulin sensitivity and disease risk.
: Endothelial dysfunction is hallmark of type 2 diabetes that can have severe consequences on vascular function, including hypertension and changes in blood flow, as well as exercise performance. Because endothelium is also the barrier for insulin movement into tissue, it acts as a gate keeper for transport and glucose uptake. For this reason, endothelial dysfunction is a tempting area for pharmacological and/or exercise intervention with insulin-based therapies. In this review we describe the current state of drugs that can be used to treat endothelial dysfunction in type 2 diabetes and diabetes related diseases (e.g., obesity) at the molecular levels, and also ascribe their role in exercise.
Adipose tissue is a critical regulator of energy balance that must rapidly shift its metabolism between fasting and feeding to maintain homeostasis. Adenosine has been characterized as an important regulator of adipocyte metabolism primarily through its actions on A1 adenosine receptors (A1R). We sought to understand the role A1R plays in adipocytes during fasting and feeding to regulate glucose and lipid metabolism by using an inducible, adiponectin-Cre with Adora1 floxed mice (FAdora1−/−), where F designates a fat-specific deletion. Fadora1−/− mice had impairments in the suppression of lipolysis by insulin on normal chow and impaired glucose tolerance on high-fat diet. FAdora1−/− mice also exhibited a higher lipolytic response to isoproterenol than WT controls when fasted, but not after a 4-hour refeeding period. We found that FOXO1 binds to the A1R promoter in adipocytes. Upon feeding, signaling along the insulin-Akt-FOXO1 axis leads to a rapid downregulation of A1R transcript and desensitization of adipocytes to A1R agonism. Obesity also desensitizes adipocyte A1R, and this is accompanied by a disruption of cyclical changes in A1R transcription between fasting and refeeding. We propose that FOXO1 drives high A1R expression under fasted conditions to limit excess lipolysis during stress and augment insulin action upon feeding. Subsequent downregulation of A1R under fed conditions facilitates reentrance into the catabolic state upon fasting.
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