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Cell Reports. Medicine Apr 2020Heart failure is one of the leading causes of death worldwide. New therapeutic concepts are urgently required to lower the burden of heart failure with reduced ejection... (Review)
Review
Heart failure is one of the leading causes of death worldwide. New therapeutic concepts are urgently required to lower the burden of heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), the two major forms of heart failure. Lipolytic processes are induced during the development of heart failure and occur in adipose tissue and multiple organs, including the heart. Increasing evidence suggests that cellular lipolysis, in particular, adipose triglyceride lipase (ATGL) activity, has an important function in cardiac (patho)physiology. This review summarizes the crucial role of cellular lipolysis for normal cardiac function and for the development of HFrEF and HFpEF. We discuss the most relevant pre-clinical studies and elaborate on the cardiac consequences of non-myocardial and myocardial lipolysis modulation. Finally, we critically analyze the therapeutic importance of pharmacological ATGL inhibition as a potential treatment option for HFrEF and/or HFpEF in the future.
Topics: Acyltransferases; Cytosol; Heart; Heart Failure; Humans; Lipolysis; Myocardium; Stroke Volume
PubMed: 33205054
DOI: 10.1016/j.xcrm.2020.100001 -
Scientific Reports Mar 2022Total body fat and central fat distribution are heritable traits and well-established predictors of adverse metabolic outcomes. Lipolysis is the process responsible for...
Total body fat and central fat distribution are heritable traits and well-established predictors of adverse metabolic outcomes. Lipolysis is the process responsible for the hydrolysis of triacylglycerols stored in adipocytes. To increase our understanding of the genetic regulation of body fat distribution and total body fat, we set out to determine if genetic variants associated with body mass index (BMI) or waist-hip-ratio adjusted for BMI (WHRadjBMI) in genome-wide association studies (GWAS) mediate their effect by influencing adipocyte lipolysis. We utilized data from the recent GWAS of spontaneous and isoprenaline-stimulated lipolysis in the unique GENetics of Adipocyte Lipolysis (GENiAL) cohort. GENiAL consists of 939 participants who have undergone abdominal subcutaneous adipose biopsy for the determination of spontaneous and isoprenaline-stimulated lipolysis in adipocytes. We report 11 BMI and 15 WHRadjBMI loci with SNPs displaying nominal association with lipolysis and allele-dependent gene expression in adipose tissue according to in silico analysis. Functional evaluation of candidate genes in these loci by small interfering RNAs (siRNA)-mediated knock-down in adipose-derived stem cells identified ZNF436 and NUP85 as intrinsic regulators of lipolysis consistent with the associations observed in the clinical cohorts. Furthermore, candidate genes in another BMI-locus (STX17) and two more WHRadjBMI loci (NID2, GGA3, GRB2) control lipolysis alone, or in conjunction with lipid storage, and may hereby be involved in genetic control of body fat. The findings expand our understanding of how genetic variants mediate their impact on the complex traits of fat storage and distribution.
Topics: Adipocytes; Adipose Tissue; Genetic Loci; Genome-Wide Association Study; Humans; Isoproterenol; Lipolysis; Transcription Factors
PubMed: 35256633
DOI: 10.1038/s41598-022-07291-4 -
European Journal of Preventive... Oct 2020Low concentrations of high-density lipoprotein cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels...
Free cholesterol transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis underlies the U-shape relationship between HDL-cholesterol and cardiovascular disease.
BACKGROUND
Low concentrations of high-density lipoprotein cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels are equally associated with elevated cardiovascular risk, resulting in the U-shape relationship of HDL-C with cardiovascular disease. Mechanisms underlying this association are presently unknown. We hypothesised that the capacity of high-density lipoprotein (HDL) to acquire free cholesterol upon triglyceride-rich lipoprotein (TGRL) lipolysis by lipoprotein lipase underlies the non-linear relationship between HDL-C and cardiovascular risk.
METHODS
To assess our hypothesis, we developed a novel assay to evaluate the capacity of HDL to acquire free cholesterol (as fluorescent TopFluor® cholesterol) from TGRL upon in vitro lipolysis by lipoprotein lipase.
RESULTS
When the assay was applied to several populations markedly differing in plasma HDL-C levels, transfer of free cholesterol was significantly decreased in low HDL-C patients with acute myocardial infarction (-45%) and type 2 diabetes (-25%), and in subjects with extremely high HDL-C of >2.59 mmol/L (>100 mg/dL) (-20%) versus healthy normolipidaemic controls. When these data were combined and plotted against HDL-C concentrations, an inverse U-shape relationship was observed. Consistent with these findings, animal studies revealed that the capacity of HDL to acquire cholesterol upon lipolysis was reduced in low HDL-C apolipoprotein A-I knock-out mice and was negatively correlated with aortic accumulation of [H]-cholesterol after oral gavage, attesting this functional characteristic as a negative metric of postprandial atherosclerosis.
CONCLUSIONS
Free cholesterol transfer to HDL upon TGRL lipolysis may underlie the U-shape relationship between HDL-C and cardiovascular disease, linking HDL-C to triglyceride metabolism and atherosclerosis.
Topics: Animals; Aorta, Thoracic; Biomarkers; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Disease Models, Animal; Female; Humans; Lipolysis; Lipoprotein Lipase; Lipoproteins, HDL; Male; Mice; Mice, Transgenic; Postprandial Period; Triglycerides
PubMed: 31840535
DOI: 10.1177/2047487319894114 -
The Journal of Cell Biology Jun 2003Successful adaptation to starvation in mammals depends heavily on the regulated mobilization of fatty acids from triacylglycerols stored in adipose tissue. Although it... (Review)
Review
Successful adaptation to starvation in mammals depends heavily on the regulated mobilization of fatty acids from triacylglycerols stored in adipose tissue. Although it has long been recognized that cyclic AMP represents the critical second messenger and hormone-sensitive lipase (HSL)**Abbreviations used in this paper: ADRP, adipocyte differentiation-related protein; HSL, hormone-sensitive lipase; PKA, protein kinase A; TAG, triacylglycerol. the rate-determining enzyme for lipolysis, simple activation of the enzyme has failed to account for the robust augmentation of fatty release in response to physiological agonists. In this issue, Sztalryd et al. (2003) provide convincing support to the notion that the subcellular compartmentalization of lipase also regulates lipolysis, and, more importantly, that proteins other than HSL are localized to the lipid droplet and are indispensable for its optimal hydrolysis.
Topics: Adipose Tissue; Animals; Cell Compartmentation; Humans; Lipid Metabolism; Lipolysis; Protein Transport; Sterol Esterase
PubMed: 12810703
DOI: 10.1083/jcb.200306008 -
Molecular Metabolism Aug 2023Glucocorticoids are one of the most commonly prescribed classes of anti-inflammatory drugs; however, chronic treatment promotes iatrogenic (drug-induced) diabetes. As...
OBJECTIVE
Glucocorticoids are one of the most commonly prescribed classes of anti-inflammatory drugs; however, chronic treatment promotes iatrogenic (drug-induced) diabetes. As part of their physiological role, glucocorticoids stimulate lipolysis to spare glucose. We hypothesized that persistent stimulation of lipolysis during glucocorticoid therapy plays a causative role in the development of iatrogenic diabetes.
METHODS
Male C57BL/6J mice were given 100 μg/mL corticosterone (Cort) in the drinking water for two weeks and were fed either normal chow (TekLad 8640) or the same diet supplemented with an adipose triglyceride lipase inhibitor (Atglistatin - 2 g/kg diet) to inhibit the first step of lipolysis.
RESULTS
Herein, we report for the first time that glucocorticoid administration promotes a unique state of substrate excess and energetic overload in skeletal muscle that primarily results from the rampant mobilization of endogenous fuels. Inhibiting lipolysis protected mice from Cort-induced gains in fat mass, excess ectopic lipid accrual, hyperinsulinemia, and hyperglycemia. The role lipolysis plays in Cort-mediated pathology appears to differ between tissues. Within skeletal muscle, Cort-induced lipolysis facilitated diversion of glucose-derived carbons toward the pentose phosphate and hexosamine biosynthesis pathways but contributed to <3% of the Cort-induced genomic adaptations. In contrast, Cort stimulation of lipolysis accounted for ∼35% of the genomic changes in the liver but had minimal impact on hepatic metabolites reported.
CONCLUSIONS
These data support the idea that activation of lipolysis plays a causal role in the progression toward iatrogenic diabetes during glucocorticoid therapy with differential impact on skeletal muscle and liver.
Topics: Male; Mice; Animals; Glucocorticoids; Lipolysis; Insulin Resistance; Mice, Inbred C57BL; Corticosterone; Glucose; Iatrogenic Disease
PubMed: 37295745
DOI: 10.1016/j.molmet.2023.101751 -
Nature Microbiology Nov 2023Trypanosoma brucei causes African trypanosomiasis, colonizing adipose tissue and inducing weight loss. Here we investigated the molecular mechanisms responsible for...
Trypanosoma brucei causes African trypanosomiasis, colonizing adipose tissue and inducing weight loss. Here we investigated the molecular mechanisms responsible for adipose mass loss and its impact on disease pathology. We found that lipolysis is activated early in infection. Mice lacking B and T lymphocytes fail to upregulate adipocyte lipolysis, resulting in higher fat mass retention. Genetic ablation of the rate-limiting adipose triglyceride lipase specifically from adipocytes (Adipoq-Atgl) prevented the stimulation of adipocyte lipolysis during infection, reducing fat mass loss. Surprisingly, these mice succumbed earlier and presented a higher parasite burden in the gonadal adipose tissue, indicating that host lipolysis limits parasite growth. Consistently, free fatty acids comparable with those of adipose interstitial fluid induced loss of parasite viability. Adipocyte lipolysis emerges as a mechanism controlling local parasite burden and affecting the loss of fat mass in African trypanosomiasis.
Topics: Animals; Mice; Lipolysis; Trypanosoma brucei brucei; Trypanosomiasis, African; Lipase; Adipocytes; Obesity
PubMed: 37828246
DOI: 10.1038/s41564-023-01496-7 -
Molecular Metabolism Jul 2019Insulin suppresses adipose tissue lipolysis after a meal, playing a key role in metabolic homeostasis. This is mediated via the kinase Akt and its substrate...
OBJECTIVE
Insulin suppresses adipose tissue lipolysis after a meal, playing a key role in metabolic homeostasis. This is mediated via the kinase Akt and its substrate phosphodiesterase 3B (PDE3B). Once phosphorylated and activated, PDE3B hydrolyses cAMP leading to the inactivation of cAMP-dependent protein kinase (PKA) and suppression of lipolysis. However, several gaps have emerged in this model. Here we investigated the role of the PDE3B-interacting protein, α/β-hydrolase ABHD15 in this process.
METHODS
Lipolysis, glucose uptake, and signaling were assessed in ABHD15 knock down and knock out adipocytes and fat explants in response to insulin and/or β-adrenergic receptor agonist. Glucose and fatty acid metabolism were determined in wild type and ABHD15 littermate mice.
RESULTS
Deletion of ABHD15 in adipocytes resulted in a significant defect in insulin-mediated suppression of lipolysis with no effect on insulin-mediated glucose uptake. ABHD15 played a role in suppressing PKA signaling as phosphorylation of the PKA substrate Perilipin-1 remained elevated in response to insulin upon ABHD15 deletion. ABHD15 mice had normal glucose metabolism but defective fatty acid metabolism: plasma fatty acids were elevated upon fasting and in response to insulin, and this was accompanied by elevated liver triglycerides upon β-adrenergic receptor activation. This is likely due to hyperactive lipolysis as evident by the larger triglyceride depletion in brown adipose tissue in these mice. Finally, ABHD15 protein levels were reduced in adipocytes from mice fed a Western diet, further implicating this protein in metabolic homeostasis.
CONCLUSIONS
Collectively, ABHD15 regulates adipocyte lipolysis and liver lipid accumulation, providing novel therapeutic opportunities for modulating lipid homeostasis in disease.
Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Animals; Carbohydrate Metabolism; Carboxylic Ester Hydrolases; Cyclic AMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 3; Fasting; Fatty Acids; Glucose; Homeostasis; Insulin; Lipid Accumulation Product; Lipid Metabolism; Lipolysis; Liver; Male; Membrane Proteins; Mice; Mice, Knockout; Perilipin-1; Phosphorylation; Signal Transduction; Triglycerides
PubMed: 31105056
DOI: 10.1016/j.molmet.2019.05.002 -
Trends in Endocrinology and Metabolism:... Nov 2009Lipolysis for the provision of fatty acids (FA) for other organs during times of energy demand occurs uniquely in white adipose tissue (WAT). Recent findings have... (Review)
Review
Lipolysis for the provision of fatty acids (FA) for other organs during times of energy demand occurs uniquely in white adipose tissue (WAT). Recent findings have identified a bona fide TAG hydrolase and the major adipose phospholipase A(2), AdPLA. By controlling PGE(2) levels, AdPLA dominantly regulates lipolysis in an autocrine/paracrine manner. Moreover, recent findings demonstrate that, surprisingly, increasing lipolysis in adipose tissue does not necessarily increase serum FA levels, which are usually correlated with insulin resistance. Rather, increasing lipolysis in adipose tissue causes a shift within adipocytes towards increased FA utilization and energy expenditure and thus protects against obesity. Here, we discuss the regulation of lipolysis and its effects on FA utilization within WAT and on insulin resistance.
Topics: Adipocytes; Adipose Tissue; Animals; Energy Metabolism; Fatty Acids; Humans; Insulin Resistance; Lipolysis; Models, Biological
PubMed: 19796963
DOI: 10.1016/j.tem.2009.06.002 -
JCI Insight Jul 2023Fatty acid binding protein 4 (FABP4) is a lipid chaperone secreted from adipocytes upon stimulation of lipolysis. Circulating FABP4 levels strongly correlate with...
Fatty acid binding protein 4 (FABP4) is a lipid chaperone secreted from adipocytes upon stimulation of lipolysis. Circulating FABP4 levels strongly correlate with obesity and metabolic pathologies in experimental models and humans. While adipocytes have been presumed to be the major source of hormonal FABP4, this question has not been addressed definitively in vivo. We generated mice with Fabp4 deletion in cells known to express the gene - adipocytes (Adipo-KO), endothelial cells (Endo-KO), myeloid cells (Myeloid-KO), and the whole body (Total-KO) - to examine the contribution of these cell types to basal and stimulated plasma FABP4 levels. Unexpectedly, baseline plasma FABP4 was not significantly reduced in Adipo-KO mice, whereas Endo-KO mice showed ~87% reduction versus WT controls. In contrast, Adipo-KO mice exhibited ~62% decreased induction of FABP4 responses to lipolysis, while Endo-KO mice showed only mildly decreased induction, indicating that adipocytes are the main source of increases in FABP4 during lipolysis. We did not detect any myeloid contribution to circulating FABP4. Surprisingly, despite the nearly intact induction of FABP4, Endo-KO mice showed blunted lipolysis-induced insulin secretion, identical to Total-KO mice. We conclude that the endothelium is the major source of baseline hormonal FABP4 and is required for the insulin response to lipolysis.
Topics: Humans; Animals; Mice; Lipolysis; Insulin Secretion; Endothelial Cells; Mice, Knockout; Insulin; Endothelium; Fatty Acid-Binding Proteins
PubMed: 37279064
DOI: 10.1172/jci.insight.164642 -
Frontiers in Neuroendocrinology Oct 2014White adipose tissue (WAT) is innervated by the sympathetic nervous system (SNS) and its activation is necessary for lipolysis. WAT parasympathetic innervation is not... (Review)
Review
White adipose tissue (WAT) is innervated by the sympathetic nervous system (SNS) and its activation is necessary for lipolysis. WAT parasympathetic innervation is not supported. Fully-executed SNS-norepinephrine (NE)-mediated WAT lipolysis is dependent on β-adrenoceptor stimulation ultimately hinging on hormone sensitive lipase and perilipin A phosphorylation. WAT sympathetic drive is appropriately measured electrophysiologically and neurochemically (NE turnover) in non-human animals and this drive is fat pad-specific preventing generalizations among WAT depots and non-WAT organs. Leptin-triggered SNS-mediated lipolysis is weakly supported, whereas insulin or adenosine inhibition of SNS/NE-mediated lipolysis is strongly supported. In addition to lipolysis control, increases or decreases in WAT SNS drive/NE inhibit and stimulate white adipocyte proliferation, respectively. WAT sensory nerves are of spinal-origin and sensitive to local leptin and increases in sympathetic drive, the latter implicating lipolysis. Transsynaptic viral tract tracers revealed WAT central sympathetic and sensory circuits including SNS-sensory feedback loops that may control lipolysis.
Topics: Adipose Tissue, White; Animals; Humans; Insulin; Lipid Metabolism; Lipolysis; Norepinephrine; Sympathetic Nervous System
PubMed: 24736043
DOI: 10.1016/j.yfrne.2014.04.001