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BACKGROUND: Obesity is a worldwide epidemic characterized by adipose tissue (AT) inflammation. AT is also a source of extracellular vesicles (EVs) that have recently been implicated in disorders related to metabolic syndrome. However, our understanding of mechanistic aspect of obesitys impact on EV secretion from human AT remains limited. METHODS: We investigated EVs from human Simpson Golabi Behmel Syndrome (SGBS) adipocytes, and from AT as well as plasma of subjects undergoing bariatric surgery. SGBS cells were treated with TNFα, palmitic acid, and eicosapentaenoic acid. Various analyses, including nanoparticle tracking analysis, electron microscopy, high-resolution confocal microscopy, and gas chromatography-mass spectrometry, were utilized to study EVs. Plasma EVs were analyzed with imaging flow cytometry. RESULTS: EVs from mature SGBS cells differed significantly in size and quantity compared to preadipocytes, disagreeing with previous findings in mouse adipocytes and indicating that adipogenesis promotes EV secretion in human adipocytes. Inflammatory stimuli also induced EV secretion, and altered EV fatty acid (FA) profiles more than those of cells, suggesting the role of EVs as rapid responders to metabolic shifts. Visceral AT (VAT) exhibited higher EV secretion compared to subcutaneous AT (SAT), with VAT EV counts positively correlating with plasma triacylglycerol (TAG) levels. Notably, the plasma EVs of subjects with obesity contained a higher number of adiponectin-positive EVs than those of lean subjects, further demonstrating higher AT EV secretion in obesity. Moreover, plasma EV counts of people with obesity positively correlated with body mass index and TNF expression in SAT, connecting increased EV secretion with AT expansion and inflammation. Finally, EVs from SGBS adipocytes and AT contained TAGs, and EV secretion increased despite signs of less active lipolytic pathways, indicating that AT EVs could be involved in the mobilization of excess lipids into circulation. CONCLUSIONS: We are the first to provide detailed FA profiles of human AT EVs. We report that AT EV secretion increases in human obesity, implicating their role in TAG transport and association with adverse metabolic parameters, thereby emphasizing their role in metabolic disorders. These findings promote our understanding of the roles that EVs play in human AT biology and metabolic disorders.

OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent liver disease globally, yet no therapies are approved. The effects of Escherichia coli Nissle 1917 expressing aldafermin, an engineered analog of the intestinal hormone FGF19, in combination with dietary change were investigated as a potential treatment for MASLD. METHODS: MASLD was induced in C57BL/6J male mice by American lifestyle-induced obesity syndrome diet and then switched to a standard chow diet for seven weeks. In addition to the dietary change, the intervention group received genetically engineered E. coli Nissle expressing aldafermin, while control groups received either E. coli Nissle vehicle or no treatment. MASLD-related plasma biomarkers were measured using an automated clinical chemistry analyzer. The liver steatosis was assessed by histology and bioimaging analysis using Fiji (ImageJ) software. The effects of the intervention in the liver were also evaluated by RNA sequencing and liquid-chromatography-based non-targeted metabolomics analysis. Pathway enrichment studies were conducted by integrating the differentially expressed genes from the transcriptomics findings with the metabolites from the metabolomics results using Ingenuity pathway analysis. RESULTS: After the intervention, E. coli Nissle expressing aldafermin along with dietary changes reduced body weight, liver steatosis, plasma aspartate aminotransferase, and plasma cholesterol levels compared to the two control groups. The integration of transcriptomics with non-targeted metabolomics analysis revealed the downregulation of amino acid metabolism and related receptor signaling pathways potentially implicated in the reduction of hepatic steatosis and insulin resistance. Moreover, the downregulation of pathways linked to lipid metabolism and changes in amino acid-related pathways suggested an overall reduction of oxidative stress in the liver. CONCLUSIONS: These data support the potential for using engineered microbial therapeutics in combination with dietary changes for managing MASLD.

Objective Fatty acid (FA) composition affects obesity-associated low-grade inflammation. It has been shown that the fatty acid desaturase ( FADS) 2 gene polymorphism associates with FA metabolism and adipose tissue (AT) inflammation. This study aimed to investigate the relationship between FA metabolism and inflammation in different tissues and the possible interorgan cross talk. Methods Cross-sectional baseline data from 155 individuals with obesity (both male and female) participating in the Roux-en-Y gastric bypass operation in the ongoing Kuopio Obesity Surgery Study were used. Gas chromatograph for FA composition, liver histology, and targeted RNA expression for gene expression profile were performed. Results It was demonstrated that the saturated fatty acid (SFA) proportion in AT correlated positively with inflammation in subcutaneous AT (SAT) and visceral AT (VAT) but not in the liver, while the monounsaturated fatty acid (MUFA) proportion in SAT and VAT correlated negatively with AT inflammation. Notably, there was a positive correlation between AT n-6 polyunsaturated fatty acids (PUFAs), but not AT SFAs or MUFAs, and liver inflammation. This correlation was modified by the FADS2 genotype. Conclusions The AT FA profile relates with AT inflammation. Additionally, there seems to be a complex interaction, partly regulated by the FADS2 genotype, regulating the interaction between FAs in AT and liver inflammation. [ABSTRACT FROM AUTHOR]

Objective Low-grade inflammation is involved in adipose tissue (AT) and extracellular matrix (ECM) remodeling and induces deposition of ECM proteins in AT. We have previously shown that MFAP5 (microfibrillar-associated protein 5) expression decreases in AT after weight loss. The aim of this study was to investigate MFAP5 localization in human AT and gene expression in adipocytes and the role of MFAP5 in adipocyte metabolism and inflammation. Methods MFAP5 protein localization and gene expression were studied with immunohistochemistry and quantitative reverse transcriptase PCR (RT-qPCR) in human subcutaneous AT and cultured Simpson-Golabi-Behmel syndrome (SGBS) adipocytes, respectively. The effect of MFAP5 knock-down by siRNA on gene expression and insulin action was examined with RT-qPCR, western blot, and insulin-stimulated glucose uptake. The effect of different cytokines on MFAP5 gene and protein expression was investigated in cultured human SGBS preadipocytes. Results MFAP5 protein was highly expressed in AT, and gene expression decreased during adipocyte differentiation in SGBS cells. Treatment of preadipocytes with TNFα and TGFβ1 increased MFAP5 gene and protein expression. Furthermore, MFAP5 knock-down decreased the expression of genes involved in inflammation. Conclusions Our results demonstrate that factors involving low-grade inflammation modulate MFAP5 expression and that the modified expression of MFAP5 may further regulate AT inflammation. [ABSTRACT FROM AUTHOR]

Body fat accumulation, distribution, and metabolic activity are factors in the pathophysiology of obesity and type 2 diabetes (T2D). We investigated adipose blood flow, fatty acid uptake (FAU), and subcutaneous and visceral fat cellularity in obese patients with or without T2D. A total of 23 morbidly obese (mean body mass index = 42 kg/m 2 ) patients were studied before and 6 mo after bariatric surgery; 15 nonobese subjects served as controls. Positron emission tomography was used to measure tissue FAU (with 18 F-FTHA) and blood flow (with H 2 15 O); MRI was used for fat distribution and fat biopsy for adipocyte size. Obese subjects had subcutaneous hyperplasia and hypertrophy and lower blood flow; when expressed per cell, flow was similar to controls. FAU into subcutaneous and visceral depots was increased in the obese; per unit tissue mass, however, FAU was similar to controls but reduced in skeletal muscle. Fatty acid fractional extraction in subcutaneous fat and muscle was only increased in obese patients with T2D. We conclude that surgery reduces subcutaneous fat hyperplasia and hypertrophy; subcutaneous blood flow and FAU decrease in absolute terms and per cell while fractional FAU remains unchanged in T2D. In the obese, subcutaneous blood flow is a determinant of FAU and is coupled with cellularity; efficiency of FAU is enhanced in subcutaneous fat and muscle in T2D., (Copyright © 2017 the American Physiological Society.)