The Role of Angiopoietin-like Protein 4 in Obesity and Obesity-related Diseases

TY - BOOK

T1 - The Role of Angiopoietin-like Protein 4 in Obesity and Obesity-related Diseases

AU - Blædel, Trine

N1 - CURIS 2017 NEXS 087

PY - 2017

Y1 - 2017

N2 - The ability to appropriately metabolize and store lipids in the adipose tissue is crucial to maintainmetabolic health. This regulation can be disrupted in sustained obesity, where a reduced capacity toadapt to increased needs for vascularization and extracellular matrix remodeling in adipose tissuecan lead to inflammation. This has been linked to the risk of developing metabolic complications,such as insulin resistance. Lipid partitioning is also abrogated in dyslipidemia, which leads to anincreased risk of atherosclerosis and cardiovascular diseases.Angiopoietin-like protein 4 (ANGPTL4) is a lipoprotein lipase inhibitor involved in the regulationof several metabolic pathways, including angiogenesis, hypoxia, lipid and glucose metabolism andis upregulated in response to fasting and intracellular fatty acids in the fed state. ANGPTL4 isreleased into circulation in two fragments with distinct functions. In individuals with ANGPTL4loss-of-function mutations and ANGPTL4 knock-out mice, ANGPTL4 deficiency is associated withdecreased triacylglycerol plasma concentration, suggesting that the absence of the protein may havebeneficial effects on blood lipid profile. Animal studies have indicated a negative associationbetween ANGPTL4 and body weight and body fat, and cell studies have indicated that the proteinmay be associated with angiogenesis in adipose tissue, potentially modulating the capacity toaccommodate adipose tissue growth. ANGPTL4 expression and secretion has been suggested to beregulated through dietary components, possibly through peroxisome proliferator-activated receptorpathways or modification of the gut microbiome. This thesis investigates the potential of dietarymodulation of plasma ANGPTL4 and the role of ANGPTL4 in obesity in four intervention studies.We investigated the effect of a moderate dietary intervention with either a prebiotic or increased fatfrom dairy on plasma ANGPTL4 concentration and adipose tissue ANGPTL4 mRNA in arandomized, controlled cross-over study with 20 healthy and weight stable male participants (PaperI). The objective of the second study was to examine the association between plasma ANGPTL4and lipid metabolism during weight loss and weight maintenance. Data from two weight lossinterventions studies was used to assess the effect of energy availability on plasma ANGPTL4concentration and the associations with lipid profile (Paper II). Finally, data from a large,multicenter dietary intervention was used to investigate the role of ANGPTL4 in lipid metabolism8using data on genetic variation, gene-diet interactions, mRNA expression and plasma concentrationof ANGPTL4 during weight loss and weight loss maintenance (Paper III).We found that plasma ANGPTL4 concentration or adipose tissue ANGPTL4 mRNA expressionwas not changed by moderate dietary interventions in healthy, weight stable male participants andthat there was no association between plasma ANGPTL4 and free fatty acids (Paper I). In contrast,free fatty acid concentration was positively associated with plasma ANGPTL4 in three weight lossinterventions (Paper II and III) and with adipose tissue ANGPTL4 mRNA expression in adiposetissue (Paper III). Additionally, ANGPTL4 adipose tissue mRNA expression was positivelyassociated with markers of vascularization and inflammation (Paper III).In conclusion, the effects of ANGPTL4 are primarily acute and ANGPTL4 does not seem to affectweight regulation in human obesity. Furthermore, the adipose tissue is a relevant source ofANGPTL4 and is associated with proteins involved in vascularization and extracellular matrixremodeling, suggesting that ANGPTL4 could play a role in accommodating growth of adiposetissue. Furthermore, ANGPTL4 in adipose tissue seems to be differentially regulated by a networkof transcription factors and may play a role in adipose tissue inflammation. In order to moveANGPTL4 research forward fragment-specific antibodies should be commercialized.

AB - The ability to appropriately metabolize and store lipids in the adipose tissue is crucial to maintainmetabolic health. This regulation can be disrupted in sustained obesity, where a reduced capacity toadapt to increased needs for vascularization and extracellular matrix remodeling in adipose tissuecan lead to inflammation. This has been linked to the risk of developing metabolic complications,such as insulin resistance. Lipid partitioning is also abrogated in dyslipidemia, which leads to anincreased risk of atherosclerosis and cardiovascular diseases.Angiopoietin-like protein 4 (ANGPTL4) is a lipoprotein lipase inhibitor involved in the regulationof several metabolic pathways, including angiogenesis, hypoxia, lipid and glucose metabolism andis upregulated in response to fasting and intracellular fatty acids in the fed state. ANGPTL4 isreleased into circulation in two fragments with distinct functions. In individuals with ANGPTL4loss-of-function mutations and ANGPTL4 knock-out mice, ANGPTL4 deficiency is associated withdecreased triacylglycerol plasma concentration, suggesting that the absence of the protein may havebeneficial effects on blood lipid profile. Animal studies have indicated a negative associationbetween ANGPTL4 and body weight and body fat, and cell studies have indicated that the proteinmay be associated with angiogenesis in adipose tissue, potentially modulating the capacity toaccommodate adipose tissue growth. ANGPTL4 expression and secretion has been suggested to beregulated through dietary components, possibly through peroxisome proliferator-activated receptorpathways or modification of the gut microbiome. This thesis investigates the potential of dietarymodulation of plasma ANGPTL4 and the role of ANGPTL4 in obesity in four intervention studies.We investigated the effect of a moderate dietary intervention with either a prebiotic or increased fatfrom dairy on plasma ANGPTL4 concentration and adipose tissue ANGPTL4 mRNA in arandomized, controlled cross-over study with 20 healthy and weight stable male participants (PaperI). The objective of the second study was to examine the association between plasma ANGPTL4and lipid metabolism during weight loss and weight maintenance. Data from two weight lossinterventions studies was used to assess the effect of energy availability on plasma ANGPTL4concentration and the associations with lipid profile (Paper II). Finally, data from a large,multicenter dietary intervention was used to investigate the role of ANGPTL4 in lipid metabolism8using data on genetic variation, gene-diet interactions, mRNA expression and plasma concentrationof ANGPTL4 during weight loss and weight loss maintenance (Paper III).We found that plasma ANGPTL4 concentration or adipose tissue ANGPTL4 mRNA expressionwas not changed by moderate dietary interventions in healthy, weight stable male participants andthat there was no association between plasma ANGPTL4 and free fatty acids (Paper I). In contrast,free fatty acid concentration was positively associated with plasma ANGPTL4 in three weight lossinterventions (Paper II and III) and with adipose tissue ANGPTL4 mRNA expression in adiposetissue (Paper III). Additionally, ANGPTL4 adipose tissue mRNA expression was positivelyassociated with markers of vascularization and inflammation (Paper III).In conclusion, the effects of ANGPTL4 are primarily acute and ANGPTL4 does not seem to affectweight regulation in human obesity. Furthermore, the adipose tissue is a relevant source ofANGPTL4 and is associated with proteins involved in vascularization and extracellular matrixremodeling, suggesting that ANGPTL4 could play a role in accommodating growth of adiposetissue. Furthermore, ANGPTL4 in adipose tissue seems to be differentially regulated by a networkof transcription factors and may play a role in adipose tissue inflammation. In order to moveANGPTL4 research forward fragment-specific antibodies should be commercialized.

UR - https://rex.kb.dk/primo-explore/fulldisplay?docid=KGL01010311043&context=L&vid=NUI&search_scope=KGL&isFrbr=true&tab=default_tab&lang=da_DK

M3 - Ph.D. thesis

SN - 978-87-93476-87-5

BT - The Role of Angiopoietin-like Protein 4 in Obesity and Obesity-related Diseases

PB - Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen

CY - Copenhagen

ER -