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Peter Arner - One of the best experts on this subject based on the ideXlab platform.
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genome wide association study of adipocyte Lipolysis in the genetics of adipocyte Lipolysis genial cohort
Molecular metabolism, 2020Co-Authors: Agne Kulyte, Peter Arner, Veroniqa Lundback, Cecilia M Lindgren, Jianan Luan, Luca A Lotta, Claudia Langenberg, Rona J Strawbridge, Ingrid DahlmanAbstract:Abstract Objectives Lipolysis, hydrolysis of triglycerides to fatty acids in adipocytes, is tightly regulated, poorly understood, and, if perturbed, can lead to metabolic diseases including obesity and type 2 diabetes. The goal of this study was to identify the genetic regulators of Lipolysis and elucidate their molecular mechanisms. Methods Adipocytes from abdominal subcutaneous adipose tissue biopsies were isolated and were incubated without (spontaneous Lipolysis) or with a catecholamine (stimulated Lipolysis) to analyze Lipolysis. DNA was extracted and genome-wide genotyping and imputation conducted. After quality control, 939 samples with genetic and Lipolysis data were available. Genome-wide association studies of spontaneous and stimulated Lipolysis were conducted. Subsequent in vitro gene expression analyses were used to identify candidate genes and explore their regulation of adipose tissue biology. Results One locus on chromosome 19 demonstrated genome-wide significance with spontaneous Lipolysis. 60 loci showed suggestive associations with spontaneous or stimulated Lipolysis, of which many influenced both traits. In the chromosome 19 locus, only HIF3A was expressed in the adipocytes and displayed genotype-dependent gene expression. HIF3A knockdown in vitro increased Lipolysis and the expression of key Lipolysis-regulating genes. Conclusions In conclusion, we identified a genetic regulator of spontaneous Lipolysis and provided evidence of HIF3A as a novel key regulator of Lipolysis in subcutaneous adipocytes as the mechanism through which the locus influences adipose tissue biology.
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weight gain and impaired glucose metabolism in women are predicted by inefficient subcutaneous fat cell Lipolysis
Cell Metabolism, 2018Co-Authors: Peter Arner, Ingrid Dahlman, Daniel P Andersson, Jesper Backdahl, Mikael RydenAbstract:Summary Adipocyte mobilization of fatty acids (Lipolysis) is instrumental for energy expenditure. Lipolysis displays both spontaneous (basal) and hormone-stimulated activity. It is unknown if Lipolysis is important for future body weight gain and associated disturbed glucose metabolism, and this was presently investigated in subcutaneous adipocytes from two female cohorts before and after ≥10-year follow-up. High basal and low stimulated Lipolysis at baseline predicted future weight gain (odds ratios ≥4.6) as well as development of insulin resistance and impaired fasting glucose/type 2 diabetes (odds ratios ≥3.2). At baseline, weight gainers displayed lower adipose expression of several established Lipolysis-regulating genes. Thus, inefficient Lipolysis (high basal/low stimulated) involving altered gene expression is linked to future weight gain and impaired glucose metabolism and may constitute a treatment target. Finally, low stimulated Lipolysis could be accurately estimated in vivo by simple clinical/biochemical measures and may be used to identify risk individuals for intensified preventive measures.
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Subcutaneous Adipocyte Lipolysis Contributes to Circulating Lipid Levels.
Arteriosclerosis Thrombosis and Vascular Biology, 2017Co-Authors: Mikael Ryden, Peter ArnerAbstract:Objective— Fatty acids released via fat cell Lipolysis can affect circulating lipid levels. However, the contribution of different Lipolysis measures in adipose tissue is unknown and was presently examined in isolated subcutaneous adipocytes. Approach and Results— One thousand and sixty-six men and women were examined for Lipolysis regulation in subcutaneous abdominal fat cells. Results were compared with fasting plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol (HDL-C) and triglycerides. Spontaneous (basal) Lipolysis and the effects of the major hormones stimulating (catecholamines and natriuretic peptides) and inhibiting Lipolysis (insulin) were examined. Several statistically significant ( P r 2 ≥0.05) were only evident between basal or insulin-inhibited Lipolysis and plasma triglycerides or HDL-C. Together, these Lipolysis measures explained 14% of the variation in triglycerides or HDL-C, respectively. In comparison, a combination of established factors associated with variations in plasma lipids, that is, age; body mass index; waist circumference; waist-to-hip ratio; sex; nicotine use; fat cell volume; and pharmacotherapy against diabetes mellitus; hypertension; or hyperlipidemia explained 17% and 28%, respectively, of the variations in plasma triglycerides and HDL-C. Conclusions— Subcutaneous fat cell Lipolysis is an important independent contributor to interindividual variations in plasma lipids. High spontaneous Lipolysis activity and resistance to the antilipolytic effect of insulin associate with elevated triglyceride and low HDL-C concentrations. Thus, although several other factors also play a role, subcutaneous adipose tissue may have a causal influence on dyslipidemia.
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Epigenetic Regulation of PLIN 1 in Obese Women and its Relation to Lipolysis
Scientific Reports, 2017Co-Authors: Lucia Bialesova, Agné Kulyté, Karin Dahlman Wright, Jurga Laurencikiene, Indranil Sinha, Paul Petrus, Peter Arner, Chunyan Zhao, Ingrid DahlmanAbstract:© 2017 The Author(s). Increased adipocyte Lipolysis links obesity to insulin resistance. The lipid droplet coating-protein Perilipin participates in regulation of Lipolysis and is implicated in obesity. In the present study we investigate epigenetic regulation of the PLIN1 gene by correlating PLIN1 CpG methylation to gene expression and Lipolysis, and functionally evaluating PLIN1 promoter methylation. PLIN1 CpG methylation in adipocytes and gene expression in white adipose tissue (WAT) was quantified in two cohorts by array. Basal Lipolysis in WAT explants and adipocytes was quantified by measuring glycerol release. CpG-methylation of the PLIN1 promoter in adipocytes from obese women was higher as compared to never-obese women. PLIN1 promoter methylation was inversely correlated with PLIN1 mRNA expression and the lipolytic activity. Human mesenchymal stem cells (hMSCs) differentiated in vitro into adipocytes and harboring methylated PLIN1 promoter displayed decreased reporter gene activity as compared to hMSCs harboring unmethylated promoter. Treatment of hMSCs differentiated in vitro into adipocytes with a DNA methyltransferase inhibitor increased levels of PLIN1 mRNA and protein. In conclusion, the PLIN1 gene is epigenetically regulated and promoter methylation is inversely correlated with basal Lipolysis in women suggesting that epigenetic regulation of PLIN1 is important for increased adipocyte Lipolysis in insulin resistance states.
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Impaired atrial natriuretic peptide-mediated Lipolysis in obesity.
International Journal of Obesity, 2015Co-Authors: Mikael Ryden, Paul Petrus, Dominique Langin, Jesper Backdahl, Anders Thorell, Marine Coué, Cedric Moro, Peter ArnerAbstract:Catecholamines and natriuretic peptides (NPs) are the only hormones with pronounced lipolytic effects in human white adipose tissue. Although catecholamine-induced Lipolysis is well known to be impaired in obesity and insulin resistance, it is not known whether the effect of NPs is also altered. Catecholamine- and atrial NP (ANP)-induced Lipolysis was investigated in abdominal subcutaneous adipocytes in vitro and in situ by microdialysis. In a cohort of 122 women, both catecholamine- and ANP-induced Lipolysis in vitro was markedly attenuated in obesity (n=87), but normalized after substantial body weight loss (n=52). The impairment of Lipolysis differed between the two hormones when expressing Lipolysis per lipid weight, the ratio of stimulated over basal (spontaneous) Lipolysis rate or per number of adipocytes. Thus, while the response to catecholamines was lower when expressed as the former two measures, it was higher when expressed per cell number, a consequence of the significantly larger fat cell size in obesity. In contrast, although ANP-induced Lipolysis was also attenuated when expressed per lipid weight or the ratio stimulated/basal, it was similar between non-obese and obese subjects when expressed per cell number suggesting that the lipolytic effect of ANP may be even more sensitive to the effects of obesity than catecholamines. Obesity was characterized by a decrease in the protein expression of the signaling NP A receptor (NPRA) and a trend toward increased levels of the clearance receptor NPRC. The impairment in ANP-induced Lipolysis observed in vitro was corroborated by microdialysis experiments in situ in a smaller cohort of lean and overweight men. ANP- and catecholamine-induced Lipolysis is reversibly attenuated in obesity. The pro-lipolytic effects of ANP are relatively more impaired compared with that of catecholamines, which may in part be due to specific changes in NP receptor expression.
Dominique Langin - One of the best experts on this subject based on the ideXlab platform.
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Impaired atrial natriuretic peptide-mediated Lipolysis in obesity.
International Journal of Obesity, 2015Co-Authors: Mikael Ryden, Paul Petrus, Dominique Langin, Jesper Backdahl, Anders Thorell, Marine Coué, Cedric Moro, Peter ArnerAbstract:Catecholamines and natriuretic peptides (NPs) are the only hormones with pronounced lipolytic effects in human white adipose tissue. Although catecholamine-induced Lipolysis is well known to be impaired in obesity and insulin resistance, it is not known whether the effect of NPs is also altered. Catecholamine- and atrial NP (ANP)-induced Lipolysis was investigated in abdominal subcutaneous adipocytes in vitro and in situ by microdialysis. In a cohort of 122 women, both catecholamine- and ANP-induced Lipolysis in vitro was markedly attenuated in obesity (n=87), but normalized after substantial body weight loss (n=52). The impairment of Lipolysis differed between the two hormones when expressing Lipolysis per lipid weight, the ratio of stimulated over basal (spontaneous) Lipolysis rate or per number of adipocytes. Thus, while the response to catecholamines was lower when expressed as the former two measures, it was higher when expressed per cell number, a consequence of the significantly larger fat cell size in obesity. In contrast, although ANP-induced Lipolysis was also attenuated when expressed per lipid weight or the ratio stimulated/basal, it was similar between non-obese and obese subjects when expressed per cell number suggesting that the lipolytic effect of ANP may be even more sensitive to the effects of obesity than catecholamines. Obesity was characterized by a decrease in the protein expression of the signaling NP A receptor (NPRA) and a trend toward increased levels of the clearance receptor NPRC. The impairment in ANP-induced Lipolysis observed in vitro was corroborated by microdialysis experiments in situ in a smaller cohort of lean and overweight men. ANP- and catecholamine-induced Lipolysis is reversibly attenuated in obesity. The pro-lipolytic effects of ANP are relatively more impaired compared with that of catecholamines, which may in part be due to specific changes in NP receptor expression.
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Lipolysis in lipid turnover cancer cachexia and obesity induced insulin resistance
Trends in Endocrinology and Metabolism, 2014Co-Authors: Peter Arner, Dominique LanginAbstract:Triglycerides in adipose tissue are rapidly mobilized during times of energy needs via Lipolysis, a catabolic process that plays important role in whole body triglyceride turnover. Lipolysis is regulated through cell surface receptors via neurotransmitters, hormones, and paracrine factors that activate various intracellular pathways. These pathways converge on the lipid droplet, the site of action of lipases and cofactors. Fat cell Lipolysis is also involved in the pathogenesis of metabolic disorders, and recent human studies have underscored its role in disease states such as cancer cachexia and obesity-induced insulin resistance. We highlight here topics and findings with physiological and clinical relevance, namely lipid turnover in human fat cells and the role of Lipolysis in cancer cachexia and obesity-induced insulin resistance.
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Lipolysis and lipid mobilization in human adipose tissue
Progress in Lipid Research, 2009Co-Authors: Dominique Langin, Max LafontanAbstract:Triacylglycerol (TAG) stored in adipose tissue (AT) can be rapidly mobilized by the hydrolytic action of the three main lipases of the adipocyte. The non-esterified fatty acids (NEFA) released are used by other tissues during times of energy deprivation. Until recently hormone-sensitive lipase (HSL) was considered to be the key rate-limiting enzyme responsible for regulating TAG mobilization. A novel lipase named adipose triglyceride lipase/desnutrin (ATGL) has been identified as playing an important role in the control of fat cell Lipolysis. Additionally perilipin and other proteins of the surface of the lipid droplets protecting or exposing the TAG core of the droplets to lipases are also potent regulators of Lipolysis. Considerable progress has been made in understanding the mechanisms of activation of the various lipases. Lipolysis is under tight hormonal regulation. The best understood hormonal effects on AT Lipolysis concern the opposing regulation by insulin and catecholamines. Heart-derived natriuretic peptides (i.e., stored in granules in the atrial and ventricle cardiomyocytes and exerting stimulating effects on diuresis and natriuresis) and numerous autocrine/paracrine factors originating from adipocytes and other cells of the stroma-vascular fraction may also participate in the regulation of Lipolysis. Endocrine and autocrine/paracrine factors cooperate and lead to a fine regulation of Lipolysis in adipocytes. Age, anatomical site, sex, genotype and species differences all play a part in the regulation of Lipolysis. The manipulation of Lipolysis has therapeutic potential in the metabolic disorders frequently associated with obesity and probably in several inborn errors of metabolism.
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comparative studies of the role of hormone sensitive lipase and adipose triglyceride lipase in human fat cell Lipolysis
American Journal of Physiology-endocrinology and Metabolism, 2007Co-Authors: Mikael Ryden, Johan Jocken, Vanessa Van Harmelen, Johan Hoffstedt, Mikael Wiren, Lennart Blomqvist, Andrea Dicker, Aline Mairal, Dominique Langin, Ellen E. BlaakAbstract:Hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) regulate adipocyte Lipolysis in rodents. The purpose of this study was to compare the roles of these lipases for Lipolysis in h...
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adipose tissue Lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome
Pharmacological Research, 2006Co-Authors: Dominique LanginAbstract:Adipose tissue Lipolysis is the catabolic process leading to the breakdown of triglycerides stored in fat cells and release of fatty acids and glycerol. Recent work has revealed that Lipolysis is not a simple metabolic pathway stimulated by catecholamines and inhibited by insulin. There have been new discoveries on the endocrine and paracrine regulation of Lipolysis and on the molecular mechanisms of triglyceride hydrolysis. Catecholamines modulate Lipolysis through lipolytic beta-adrenoceptor and antilipolytic alpha2-adrenoceptor. Recent studies have allowed a better understanding of the relative contribution of the two types of receptors and provided evidence for the in vivo involvement of alpha2-adrenoceptors in the physiological control of subcutaneous adipose tissue Lipolysis. A puzzling observation is the characterization of a residual catecholamine-induced Lipolysis in mice deficient in beta-adrenoceptors. A novel lipolytic system has been characterized in human fat cells. Natriuretic peptides stimulate Lipolysis through a cGMP-dependent pathway. There are other lipolytic pathways active in human fat cells which importance is not fully understood. Forty years after the description of the antilipolytic effect of nicotinic acid, the receptors have been identified. Adrenomedullin which is produced by adipocytes exert an antilipolytic effect through an indirect mechanism involving nitric oxide. The molecular details of the lipolytic reaction are not fully understood. The role of the lipases has been re-evaluated with the cloning of adipose triglyceride lipase. Hormone-sensitive lipase appears as the major lipase for catecholamine and natriuretic peptide-stimulated Lipolysis whereas adipose triglyceride lipase mediates the hydrolysis of triglycerides during basal Lipolysis. Translocation of hormone-sensitive lipase bound to the adipocyte lipid binding protein to the lipid droplet seems to be an important step during lipolytic activation. Re-organization of the lipid droplet coating by perilipins facilitates the access of the enzyme. The role of other lipid-interacting proteins in Lipolysis is still unclear. The proteins involved in the lipolytic process constitute drug targets for the treatment of obesity and the metabolic syndrome. The oldest example is nicotinic acid (niacin) used as a hypolipidaemic drug. A first approach consists in molecules stimulating Lipolysis and oxidation of the released fatty acids to decrease fat stores. A second approach is a chronic inhibition of Lipolysis to diminish plasma fatty acid level which is a central feature of the metabolic syndrome.
Mikael Ryden - One of the best experts on this subject based on the ideXlab platform.
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weight gain and impaired glucose metabolism in women are predicted by inefficient subcutaneous fat cell Lipolysis
Cell Metabolism, 2018Co-Authors: Peter Arner, Ingrid Dahlman, Daniel P Andersson, Jesper Backdahl, Mikael RydenAbstract:Summary Adipocyte mobilization of fatty acids (Lipolysis) is instrumental for energy expenditure. Lipolysis displays both spontaneous (basal) and hormone-stimulated activity. It is unknown if Lipolysis is important for future body weight gain and associated disturbed glucose metabolism, and this was presently investigated in subcutaneous adipocytes from two female cohorts before and after ≥10-year follow-up. High basal and low stimulated Lipolysis at baseline predicted future weight gain (odds ratios ≥4.6) as well as development of insulin resistance and impaired fasting glucose/type 2 diabetes (odds ratios ≥3.2). At baseline, weight gainers displayed lower adipose expression of several established Lipolysis-regulating genes. Thus, inefficient Lipolysis (high basal/low stimulated) involving altered gene expression is linked to future weight gain and impaired glucose metabolism and may constitute a treatment target. Finally, low stimulated Lipolysis could be accurately estimated in vivo by simple clinical/biochemical measures and may be used to identify risk individuals for intensified preventive measures.
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Subcutaneous Adipocyte Lipolysis Contributes to Circulating Lipid Levels.
Arteriosclerosis Thrombosis and Vascular Biology, 2017Co-Authors: Mikael Ryden, Peter ArnerAbstract:Objective— Fatty acids released via fat cell Lipolysis can affect circulating lipid levels. However, the contribution of different Lipolysis measures in adipose tissue is unknown and was presently examined in isolated subcutaneous adipocytes. Approach and Results— One thousand and sixty-six men and women were examined for Lipolysis regulation in subcutaneous abdominal fat cells. Results were compared with fasting plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol (HDL-C) and triglycerides. Spontaneous (basal) Lipolysis and the effects of the major hormones stimulating (catecholamines and natriuretic peptides) and inhibiting Lipolysis (insulin) were examined. Several statistically significant ( P r 2 ≥0.05) were only evident between basal or insulin-inhibited Lipolysis and plasma triglycerides or HDL-C. Together, these Lipolysis measures explained 14% of the variation in triglycerides or HDL-C, respectively. In comparison, a combination of established factors associated with variations in plasma lipids, that is, age; body mass index; waist circumference; waist-to-hip ratio; sex; nicotine use; fat cell volume; and pharmacotherapy against diabetes mellitus; hypertension; or hyperlipidemia explained 17% and 28%, respectively, of the variations in plasma triglycerides and HDL-C. Conclusions— Subcutaneous fat cell Lipolysis is an important independent contributor to interindividual variations in plasma lipids. High spontaneous Lipolysis activity and resistance to the antilipolytic effect of insulin associate with elevated triglyceride and low HDL-C concentrations. Thus, although several other factors also play a role, subcutaneous adipose tissue may have a causal influence on dyslipidemia.
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Impaired atrial natriuretic peptide-mediated Lipolysis in obesity.
International Journal of Obesity, 2015Co-Authors: Mikael Ryden, Paul Petrus, Dominique Langin, Jesper Backdahl, Anders Thorell, Marine Coué, Cedric Moro, Peter ArnerAbstract:Catecholamines and natriuretic peptides (NPs) are the only hormones with pronounced lipolytic effects in human white adipose tissue. Although catecholamine-induced Lipolysis is well known to be impaired in obesity and insulin resistance, it is not known whether the effect of NPs is also altered. Catecholamine- and atrial NP (ANP)-induced Lipolysis was investigated in abdominal subcutaneous adipocytes in vitro and in situ by microdialysis. In a cohort of 122 women, both catecholamine- and ANP-induced Lipolysis in vitro was markedly attenuated in obesity (n=87), but normalized after substantial body weight loss (n=52). The impairment of Lipolysis differed between the two hormones when expressing Lipolysis per lipid weight, the ratio of stimulated over basal (spontaneous) Lipolysis rate or per number of adipocytes. Thus, while the response to catecholamines was lower when expressed as the former two measures, it was higher when expressed per cell number, a consequence of the significantly larger fat cell size in obesity. In contrast, although ANP-induced Lipolysis was also attenuated when expressed per lipid weight or the ratio stimulated/basal, it was similar between non-obese and obese subjects when expressed per cell number suggesting that the lipolytic effect of ANP may be even more sensitive to the effects of obesity than catecholamines. Obesity was characterized by a decrease in the protein expression of the signaling NP A receptor (NPRA) and a trend toward increased levels of the clearance receptor NPRC. The impairment in ANP-induced Lipolysis observed in vitro was corroborated by microdialysis experiments in situ in a smaller cohort of lean and overweight men. ANP- and catecholamine-induced Lipolysis is reversibly attenuated in obesity. The pro-lipolytic effects of ANP are relatively more impaired compared with that of catecholamines, which may in part be due to specific changes in NP receptor expression.
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Regulation of Lipolysis in small and large fat cells of the same subject.
The Journal of Clinical Endocrinology and Metabolism, 2011Co-Authors: Jurga Laurencikiene, T Skurk, Mikael Ryden, Hans Hauner, Agne Kulyte, Per Hedén, Gaby Åström, Eva Sjölin, Peter ArnerAbstract:Context: Large fat cell size is linked to type 2 diabetes risk and may involve an enhanced rate of adipocyte Lipolysis causing elevated levels of fatty acids. Objective: Our objective was to study the role of fat cell size in the regulation of Lipolysis within a subject. Design and Main Outcome Measures: Subcutaneous adipose tissue was obtained from 16 healthy subjects. Large and small adipocytes were isolated for each sample. Hormonal regulation of Lipolysis and expression of Lipolysis-regulating proteins were investigated. Results: No effect of cell size on the rate of Lipolysis was observed when Lipolysis was expressed per lipid weight of fat cells. However, when expressed per number of fat cells, the Lipolysis was significantly higher in large as compared with small adipocytes. This was observed in both the unstimulated (basal) state and in the presence of the major Lipolysis-regulating hormones such as catecholamines (stimulating), natriuretic peptides (stimulating), and insulin (inhibiting). The rec...
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Contribution of adipose triglyceride lipase and hormone-sensitive lipase to Lipolysis in hMADS adipocytes
Journal of Biological Chemistry, 2009Co-Authors: Véronic Bezaire, Carole Ribet, Corinne Lefort, Amandine Girousse, Johan Jocken, Anne Marie Rodriguez, Rodica Anesia, Jurga Laurencikiene, Aline Mairal, Mikael RydenAbstract:Lipolysis is the catabolic pathway by which triglycerides are hydrolyzed into fatty acids. Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) have the capacity to hydrolyze in vitro the first ester bond of triglycerides, but their respective contributions to whole cell Lipolysis in human adipocytes is unclear. Here, we have investigated the roles of HSL, ATGL, and its coactivator CGI-58 in basal and forskolin-stimulated Lipolysis in a human white adipocyte model, the hMADS cells. The hMADS adipocytes express the various components of fatty acid metabolism and show lipolytic capacity similar to primary cultured adipocytes. We show that Lipolysis and fatty acid esterification are tightly coupled except in conditions of stimulated Lipolysis. Immunocytochemistry experiments revealed that acute forskolin treatment promotes HSL translocation from the cytosol to small lipid droplets and redistribution of ATGL from the cytosol and large lipid droplets to small lipid droplets, resulting in enriched colocalization of the two lipases. HSL or ATGL overexpression resulted in increased triglyceride-specific hydrolase capacity, but only ATGL overexpression increased whole cell Lipolysis. HSL silencing had no effect on basal Lipolysis and only partially reduced forskolin-stimulated Lipolysis. Conversely, silencing of ATGL or CGI-58 significantly reduced basal Lipolysis and essentially abolished forskolin-stimulated Lipolysis. Altogether, these results suggest that ATGL/CGI-58 acts independently of HSL and precedes its action in the sequential hydrolysis of triglycerides in human hMADS adipocytes.
Ingrid Dahlman - One of the best experts on this subject based on the ideXlab platform.
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genome wide association study of adipocyte Lipolysis in the genetics of adipocyte Lipolysis genial cohort
Molecular metabolism, 2020Co-Authors: Agne Kulyte, Peter Arner, Veroniqa Lundback, Cecilia M Lindgren, Jianan Luan, Luca A Lotta, Claudia Langenberg, Rona J Strawbridge, Ingrid DahlmanAbstract:Abstract Objectives Lipolysis, hydrolysis of triglycerides to fatty acids in adipocytes, is tightly regulated, poorly understood, and, if perturbed, can lead to metabolic diseases including obesity and type 2 diabetes. The goal of this study was to identify the genetic regulators of Lipolysis and elucidate their molecular mechanisms. Methods Adipocytes from abdominal subcutaneous adipose tissue biopsies were isolated and were incubated without (spontaneous Lipolysis) or with a catecholamine (stimulated Lipolysis) to analyze Lipolysis. DNA was extracted and genome-wide genotyping and imputation conducted. After quality control, 939 samples with genetic and Lipolysis data were available. Genome-wide association studies of spontaneous and stimulated Lipolysis were conducted. Subsequent in vitro gene expression analyses were used to identify candidate genes and explore their regulation of adipose tissue biology. Results One locus on chromosome 19 demonstrated genome-wide significance with spontaneous Lipolysis. 60 loci showed suggestive associations with spontaneous or stimulated Lipolysis, of which many influenced both traits. In the chromosome 19 locus, only HIF3A was expressed in the adipocytes and displayed genotype-dependent gene expression. HIF3A knockdown in vitro increased Lipolysis and the expression of key Lipolysis-regulating genes. Conclusions In conclusion, we identified a genetic regulator of spontaneous Lipolysis and provided evidence of HIF3A as a novel key regulator of Lipolysis in subcutaneous adipocytes as the mechanism through which the locus influences adipose tissue biology.
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weight gain and impaired glucose metabolism in women are predicted by inefficient subcutaneous fat cell Lipolysis
Cell Metabolism, 2018Co-Authors: Peter Arner, Ingrid Dahlman, Daniel P Andersson, Jesper Backdahl, Mikael RydenAbstract:Summary Adipocyte mobilization of fatty acids (Lipolysis) is instrumental for energy expenditure. Lipolysis displays both spontaneous (basal) and hormone-stimulated activity. It is unknown if Lipolysis is important for future body weight gain and associated disturbed glucose metabolism, and this was presently investigated in subcutaneous adipocytes from two female cohorts before and after ≥10-year follow-up. High basal and low stimulated Lipolysis at baseline predicted future weight gain (odds ratios ≥4.6) as well as development of insulin resistance and impaired fasting glucose/type 2 diabetes (odds ratios ≥3.2). At baseline, weight gainers displayed lower adipose expression of several established Lipolysis-regulating genes. Thus, inefficient Lipolysis (high basal/low stimulated) involving altered gene expression is linked to future weight gain and impaired glucose metabolism and may constitute a treatment target. Finally, low stimulated Lipolysis could be accurately estimated in vivo by simple clinical/biochemical measures and may be used to identify risk individuals for intensified preventive measures.
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Epigenetic Regulation of PLIN 1 in Obese Women and its Relation to Lipolysis
Scientific Reports, 2017Co-Authors: Lucia Bialesova, Agné Kulyté, Karin Dahlman Wright, Jurga Laurencikiene, Indranil Sinha, Paul Petrus, Peter Arner, Chunyan Zhao, Ingrid DahlmanAbstract:© 2017 The Author(s). Increased adipocyte Lipolysis links obesity to insulin resistance. The lipid droplet coating-protein Perilipin participates in regulation of Lipolysis and is implicated in obesity. In the present study we investigate epigenetic regulation of the PLIN1 gene by correlating PLIN1 CpG methylation to gene expression and Lipolysis, and functionally evaluating PLIN1 promoter methylation. PLIN1 CpG methylation in adipocytes and gene expression in white adipose tissue (WAT) was quantified in two cohorts by array. Basal Lipolysis in WAT explants and adipocytes was quantified by measuring glycerol release. CpG-methylation of the PLIN1 promoter in adipocytes from obese women was higher as compared to never-obese women. PLIN1 promoter methylation was inversely correlated with PLIN1 mRNA expression and the lipolytic activity. Human mesenchymal stem cells (hMSCs) differentiated in vitro into adipocytes and harboring methylated PLIN1 promoter displayed decreased reporter gene activity as compared to hMSCs harboring unmethylated promoter. Treatment of hMSCs differentiated in vitro into adipocytes with a DNA methyltransferase inhibitor increased levels of PLIN1 mRNA and protein. In conclusion, the PLIN1 gene is epigenetically regulated and promoter methylation is inversely correlated with basal Lipolysis in women suggesting that epigenetic regulation of PLIN1 is important for increased adipocyte Lipolysis in insulin resistance states.
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Relationship between β-2 adrenoceptor gene haplotypes and adipocyte Lipolysis in women
International Journal of Obesity, 2004Co-Authors: P Eriksson, Ingrid Dahlman, Johan Hoffstedt, Mikael Ryden, Peter ArnerAbstract:BACKGROUND AND AIMS: The β _2-adrenergic receptors are important for adipocyte Lipolysis regulation by catecholamines in humans. The β _2-adrenoceptor gene is highly polymorphic. The role of these genetic variations for adipocyte Lipolysis was investigated. DESIGN AND METHODS: Six single-nucleotide polymorphisms (SNPs) in the promotor region and four SNPs in the coding region (leading to amino-acid substitution) of the β _2-adrenoceptor gene were determined in 141 overweight or obese, but otherwise healthy women. Lipolysis experiments were performed on isolated subcutaneous adipocytes. RESULTS: Three homozygous haplotypes (6/6, 4/4 and 2/2) were found that differed about 500-fold in noradrenaline sensitivity or β _2-adrenoceptor sensitivity (6/6>2/2>4/4, P =0.01). The haplotypes also differed by 100% in maximum noradrenaline-induced Lipolysis rates (6/6>2/2>4/4). However, there was no influence on β _1-, β _3- or α _2A-adrenoceptor sensitivity. Heterozygosity at one or several SNPs in the haplotypes influenced the β _2-adrenoceptor sensitivity significantly. CONCLUSION: Multiple SNPs in the β _2-adrenoceptor gene form several haplotypes that markedly influence β _2-receptor function- and catecholamine-induced Lipolysis in fat cells. These haplotypes may be important genetic factors behind impaired Lipolysis in obesity.
Sandra C Souza - One of the best experts on this subject based on the ideXlab platform.
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modulation of hormone sensitive lipase and protein kinase a mediated Lipolysis by perilipin a in an adenoviral reconstituted system
Journal of Biological Chemistry, 2002Co-Authors: Sandra C Souza, Mia T Yamamoto, Ping Lien, Kizito V Muliro, Fredric B Kraemer, Laura Liscum, Jean E Schaffer, Gerard E Dallal, Xinzhong Wang, Martin S ObinAbstract:Abstract Perilipin (Peri) A is a phosphoprotein located at the surface of intracellular lipid droplets in adipocytes. Activation of cyclic AMP-dependent protein kinase (PKA) results in the phosphorylation of Peri A and hormone-sensitive lipase (HSL), the predominant lipase in adipocytes, with concurrent stimulation of adipocyte Lipolysis. To investigate the relative contributions of Peri A and HSL in basal and PKA-mediated Lipolysis, we utilized NIH 3T3 fibroblasts lacking Peri A and HSL but stably overexpressing acyl-CoA synthetase 1 (ACS1) and fatty acid transport protein 1 (FATP1). When incubated with exogenous fatty acids, ACS1/FATP1 cells accumulated 5 times more triacylglycerol (TG) as compared with NIH 3T3 fibroblasts. Adenoviral-mediated expression of Peri A in ACS1/FATP1 cells enhanced TG accumulation and inhibited Lipolysis, whereas expression of HSL fused to green fluorescent protein (GFPHSL) reduced TG accumulation and enhanced Lipolysis. Forskolin treatment induced Peri A hyperphosphorylation and abrogated the inhibitory effect of Peri A on Lipolysis. Expression of a mutated Peri AΔ3 (Ser to Ala substitutions at PKA consensus sites Ser-81, Ser-222, and Ser-276) reduced Peri A hyperphosphorylation and blocked constitutive and forskolin-stimulated Lipolysis. Thus, perilipin expression and phosphorylation state are critical regulators of lipid storage and hydrolysis in ACS1/FATP1 cells.
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stimulation of Lipolysis and hormone sensitive lipase via the extracellular signal regulated kinase pathway
Journal of Biological Chemistry, 2001Co-Authors: Andrew S Greenberg, Sandra C Souza, Wenjun Shen, Kizito V Muliro, Shailja Patel, Richard A Roth, Fredric B KraemerAbstract:Abstract Hormonally stimulated Lipolysis occurs by activation of cyclic AMP-dependent protein kinase (PKA) which phosphorylates hormone-sensitive lipase (HSL) and increases adipocyte Lipolysis. Evidence suggests that catecholamines not only can activate PKA, but also the mitogen-activated protein kinase pathway and extracellular signal-regulated kinase (ERK). We now demonstrate that two different inhibitors of MEK, the upstream activator of ERK, block catecholamine- and β3-stimulated Lipolysis by ∼30%. Furthermore, treatment of adipocytes with dioctanoylglycerol, which activates ERK, increases Lipolysis, although MEK inhibitors decrease dioctanoylglycerol-stimulated activation of Lipolysis. Using a tamoxifen regulatable Raf system expressed in 3T3-L1 preadipocytes, exposure to tamoxifen causes a 14-fold activation of ERK within 15–30 min and results in ∼2-fold increase in HSL activity. In addition, when differentiated 3T3-L1 cells expressing the regulatable Raf were exposed to tamoxifen, a 2-fold increase in Lipolysis is observed. HSL is a substrate of activated ERK and site-directed mutagenesis of putative ERK consensus phosphorylation sites in HSL identified Ser600 as the site phosphorylated by active ERK. When S600A HSL was expressed in 3T3-L1 cells expressing the regulatable Raf, tamoxifen treatment fails to increase its activity. Thus, activation of the ERK pathway appears to be able to regulate adipocyte Lipolysis by phosphorylating HSL on Ser600 and increasing the activity of HSL.
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overexpression of perilipin a and b blocks the ability of tumor necrosis factor α to increase Lipolysis in 3t3 l1 adipocytes
Journal of Biological Chemistry, 1998Co-Authors: Sandra C Souza, Lina Moitoso De Vargas, Mia T Yamamoto, Ping Lien, Mark D Franciosa, Larry G Moss, Andrew S GreenbergAbstract:Abstract Perilipins, a family of phosphoproteins, are specifically located at the surface of intracellular lipid (triacylglycerol) droplets, the site of Lipolysis. Stimulation of Lipolysis in 3T3-L1 adipocytes by tumor necrosis factor α (TNF-α) is associated with a decrease in total cellular expression of perilipin A and B, consistent with the hypothesis that a decrease in perilipin protein expression is required for TNF-α-induced Lipolysis. Adenovirus-mediated overexpression of perilipin A or B maintains perilipin protein levels on the lipid droplet and blocks TNF-α-induced Lipolysis. In contrast, overexpression of perilipin A or perilipin B does not inhibit isoproterenol-stimulated Lipolysis and does not alter the isoproterenol-induced migration of perilipins from the lipid droplet. These results provide the first evidence of how perilipin functions and suggest that TNF-α regulates Lipolysis, in part, by decreasing perilipin protein levels at the lipid droplet surface.
