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1.
High-density lipoproteins (HDL): Novel function and therapeutic applications.
Darabi, M, Kontush, A
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2022;(1):159058
Abstract
The failure of high-density lipoprotein (HDL)-raising agents to reduce cardiovascular disease (CVD) together with recent findings of increased cardiovascular mortality in subjects with extremely high HDL-cholesterol levels provide new opportunities to revisit our view of HDL. The concept of HDL function developed to explain these contradictory findings has recently been expanded by a role played by HDL in the lipolysis of triglyceride-rich lipoproteins (TGRLs) by lipoprotein lipase. According to the reverse remnant-cholesterol transport (RRT) hypothesis, HDL critically contributes to TGRL lipolysis via acquirement of surface lipids, including free cholesterol, released from TGRL. Ensuing cholesterol transport to the liver with excretion into the bile may reduce cholesterol influx in the arterial wall by accelerating removal from circulation of atherogenic, cholesterol-rich TGRL remnants. Such novel function of HDL opens wide therapeutic applications to reduce CVD in statin-treated patients, which primarily involve activation of cholesterol flux upon lipolysis.
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2.
(-)-Epigallocatechin-3-O-gallate at a high concentration may induce lipolysis via ATP consumption by activation of stress defense mechanisms.
Suihara, S, Ishisaka, A, Murakami, A
Bioscience, biotechnology, and biochemistry. 2021;(2):411-420
Abstract
Green tea catechins have thus far been demonstrated to have antiobesity effects in a variety of experimental models. However, upstream molecular events triggering those phenomena remain to be identified. In this study, we found that (-)-epigallocatechin-3-O-gallate (EGCG) promoted lipolysis in lipid-loaded Huh7 human hepatoma cells. Notably, EGCG at a high concentration induced both oxidative stress and protein stress (proteo-stress), leading to activation of stress defense mechanisms, such as mRNA expressions of antioxidant and phase-2 detoxifying enzymes, and heat shock proteins. Furthermore, EGCG decreased the level of intracellular ATP, while glucose uptake from culture media was promoted possibly for energy homeostasis. EGCG also upregulated the expression of adipose triglyceride lipase, and activated AMP-activated protein kinase. Collectively, these results suggest that EGCG induces lipolysis to compensate for ATP reduction derived from activation of stress defense systems against its oxidative and proteo-stress properties.
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Leading the way in the nervous system: Lipid Droplets as new players in health and disease.
Teixeira, V, Maciel, P, Costa, V
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2021;(1):158820
Abstract
Lipid droplets (LDs) are ubiquitous fat storage organelles composed of a neutral lipid core, comprising triacylglycerols (TAG) and sterol esters (SEs), surrounded by a phospholipid monolayer membrane with several decorating proteins. Recently, LD biology has come to the foreground of research due to their importance for energy homeostasis and cellular stress response. As aberrant LD accumulation and lipid depletion are hallmarks of numerous diseases, addressing LD biogenesis and turnover provides a new framework for understanding disease-related mechanisms. Here we discuss the potential role of LDs in neurodegeneration, while making some predictions on how LD imbalance can contribute to pathophysiology in the brain.
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Effects of chronic decaffeinated green tea extract supplementation on lipolysis and substrate utilization during upper body exercise.
Blicher, S, Bartholomae, E, Kressler, J
Journal of sport and health science. 2021;(2):237-242
Abstract
BACKGROUND Decaffeinated green tea extract (dGTE) can increase fat oxidation during leg exercise, but dGTE is unsuitable for many people (e.g., those with injuries/disabilities), and its effects on arm exercise and women are unknown. METHODS Eight adults (23-37 years old, 4 women) performed an incremental arm cycle test to measure peak oxygen uptake (VO2peak), followed by four 1-h trials at 50% VO2peak. Subjects were randomly assigned to 650 mg of dGTE or placebo (PLA) for 4 weeks followed by a 4-week washout and crossover trial. Blood samples were obtained pre-exercise and post-exercise for glycerol and free fatty acid analysis. Respiratory gases were collected continuously. RESULTS VO2 showed no differences across trials ((0.83-0.89) ± (0.19-0.25) L/min, p = 0.460), neither did energy expenditure ((264-266) ± (59-77) kcal, p = 0.420) nor fat oxidation (dGTE = 0.11 to 0.12 g/min vs. PLA = 0.10 to 0.09 g/min, p = 0.220). Fat oxidation as percentage of energy expenditure was not different for dGTE vs. PLA (23% ± 12% to 25% ± 11% vs. 23% ± 10% to 21% ± 9%, p = 0.532). Glycerol concentration increased post-exercise in all trials, independent of treatments (pre = (3.4-5.1) ± (0.6-2.6) mg/dL vs. post = (7.9-9.8) ± (2.6-3.7) mg/dL, p = 0.867, η2 = 0.005 for interaction), as did free fatty acid ((3.5-4.8) ± (1.4-2.2) mg/dL vs. (7.2-9.1) ± (2.6-4.5) mg/dL, p = 0.981, η2 = 0.000). CONCLUSION Chronic dGTE supplementation had no effect on lipolysis and fat oxidation during arm cycle exercise in men and women.
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Oral 3-hydroxybutyrate ingestion decreases endogenous glucose production, lipolysis, and hormone-sensitive lipase phosphorylation in adipose tissue in men: a human randomized, controlled, crossover trial.
Svart, M, Rittig, N, Pedersen, SB, Jessen, N, Møller, N
Diabetic medicine : a journal of the British Diabetic Association. 2021;(2):e14385
Abstract
AIMS: To test whether oral administration of D/L-3-hydroxybutyrate as a sodium salt inhibits lipolysis and intracellular lipid signalling, in particular, hormone-sensitive lipase, and whether D/L-3-hydroxybutyrate alters endogenous glucose production. METHODS We studied six young men in a randomized, controlled, crossover study after ingestion of Na-D/L-3-hydroxybutyrate (hyperketotic condition) or saline (placebo control). We quantified lipolysis and endogenous glucose production using [9,10-3 H]-palmitate and [3-3H]glucose tracers, and adipose tissue biopsies were collected to investigate key lipolytic enzymes. RESULTS After ingestion, D/L-3-hydroxybutyrate increased by more than 2.5 mmol/l, free fatty acid concentrations decreased by >70%, and palmitate rate of appearance was halved. Protein kinase A phosphorylation of perilipin was reduced and hormone-sensitive lipase 660 phosphorylation in adipose tissue biopsies was 70-80% decreased in the hyperketotic condition and unchanged in the control. Compared to the control, endogenous glucose production was reduced by close to 20% (P<0.05) after 3-hydroxybutyrate ingestion. CONCLUSION We conclude that oral D/L-Na-3-hydroxybutyrate increases D/L-3-hydroxybutyrate concentrations within half an hour, decreases free fatty acid concentrations, lowers lipolysis and endogenous glucose production, and dephosphorylates hormone-sensitive lipase. Collectively these phenomena may be viewed as an orchestrated feedback loop, controlling endogenous glucose production, lipolysis and ketogenesis. Such effects would be beneficial in insulin-resistant states. (www.clinicaltrials.gov ID number: NCT02917252).
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6.
Leptin-Mediated Changes in the Human Metabolome.
Lawler, K, Huang-Doran, I, Sonoyama, T, Collet, TH, Keogh, JM, Henning, E, O'Rahilly, S, Bottolo, L, Farooqi, IS
The Journal of clinical endocrinology and metabolism. 2020;(8):2541-52
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Abstract
CONTEXT While severe obesity due to congenital leptin deficiency is rare, studies in patients before and after treatment with leptin can provide unique insights into the role that leptin plays in metabolic and endocrine function. OBJECTIVE The aim of this study was to characterize changes in peripheral metabolism in people with congenital leptin deficiency undergoing leptin replacement therapy, and to investigate the extent to which these changes are explained by reduced caloric intake. DESIGN Ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) was used to measure 661 metabolites in 6 severely obese people with congenital leptin deficiency before, and within 1 month after, treatment with recombinant leptin. Data were analyzed using unsupervised and hypothesis-driven computational approaches and compared with data from a study of acute caloric restriction in healthy volunteers. RESULTS Leptin replacement was associated with class-wide increased levels of fatty acids and acylcarnitines and decreased phospholipids, consistent with enhanced lipolysis and fatty acid oxidation. Primary and secondary bile acids increased after leptin treatment. Comparable changes were observed after acute caloric restriction. Branched-chain amino acids and steroid metabolites decreased after leptin, but not after acute caloric restriction. Individuals with severe obesity due to leptin deficiency and other genetic obesity syndromes shared a metabolomic signature associated with increased BMI. CONCLUSION Leptin replacement was associated with changes in lipolysis and substrate utilization that were consistent with negative energy balance. However, leptin's effects on branched-chain amino acids and steroid metabolites were independent of reduced caloric intake and require further exploration.
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Short-Term Effects of Growth Hormone on Lipolysis, Glucose and Amino Acid Metabolism Assessed in Serum and Microdialysate of Healthy Young Men.
Krebs, A, Baum, A, Doerfer, J, Gempel, K, Wurm, M, Brichta, C, Sass, JO, Winkler, K, Schwab, KO
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2020;(12):819-826
Abstract
OBJECTIVE We investigated direct effects of a therapeutic growth hormone dose on lipolysis, glucose and amino acid metabolism. METHODS This crossover microdialysis trial involved six healthy male volunteers receiving single subcutaneous injections of both growth hormone (0.035 mg/kg) and placebo (0.9% sodium chloride). The investigation comprised three test days with standard diet. The first day served for adaptation, the second and third one for determining study data during 9 night hours with or without growth hormone. Abdominal subcutaneous microdialysate and blood were continuously collected and forwarded to a separate room next door where hourly taken samples were centrifuged and frozen until analysed. RESULTS Growth hormone achieved the peak serum level after 3 h followed by a plateau-like course for the next 6 h. Glycerol in microdialysate started to rise 2 h following growth hormone injection achieving significance compared to placebo after 9 h (P<0.05). Serum glycerol increased 4 h after growth hormone administration achieving significance after 6 h (P<0.05). Glucose and amino acid concentrations showed neither in microdialysate nor in serum significant differences between growth hormone and placebo. Serum values of insulin and C-peptide revealed no significant difference between growth hormone and placebo. SUMMARY AND CONCLUSION As the result of a high single subcutaneous dose of GH, persistent lipolysis can be shown in continuously collected microdialysate and blood, but no indication for gluconeogenesis or protein anabolism.
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8.
Sex Differences in Adipose Tissue Function.
Gavin, KM, Bessesen, DH
Endocrinology and metabolism clinics of North America. 2020;(2):215-228
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Abstract
Regional adipose tissue distribution differs between men and women. Differences in the accumulation of adipose tissue as well as the regulation of secretion of a number of products from adipose tissue are under the control of sex steroids, which act through a wide variety of mechanisms, both direct and indirect, to tailor metabolism to the unique needs of each sex. A fuller understanding of sex-based differences in adipose tissue function may help with tailored strategies for disease prevention and treatment and provide insights into fundamental differences in the processes that regulate nutrient homeostasis and body weight.
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Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans.
Laurens, C, Parmar, A, Murphy, E, Carper, D, Lair, B, Maes, P, Vion, J, Boulet, N, Fontaine, C, Marquès, M, et al
JCI insight. 2020;(6)
Abstract
We hypothesized that skeletal muscle contraction produces a cellular stress signal, triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying exercise-regulated myokines, also known as exerkines, able to promote lipolysis. Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. CM and human plasma samples were analyzed using unbiased proteomic screening and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples. CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes. Growth and differentiation factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was upregulated in CM from both acute and chronic exercise-stimulated myotubes. We further showed that physiological concentrations of recombinant GDF15 protein increased lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogated EPS CM-mediated lipolysis. We herein provide the first evidence to our knowledge that GDF15 is a potentially novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.
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Liver-Oriented Acute Metabolic Effects of A Low Dose of L-Carnitine under Fat-Mobilizing Conditions: Pilot Human Clinical Trial.
Odo, S, Tanabe, K, Yohda, M, Yamauchi, M
Journal of nutritional science and vitaminology. 2020;(2):136-149
Abstract
The acute metabolic effect of low dosages of L-carnitine under fat-mobilizing conditions was investigated. Healthy subjects (Study 1: n=5; Study 2: n=6) were asked to fast overnight. Then, 30 min of aerobic exercise on a cycle ergometer was performed after supplementation, followed by a 3.5-h sedentary recovery phase. The following ingestion patterns were used: Study 1 (i) noningestion, (ii) 750 mg of L-carnitine (LC), and (iii) 750 mg of LC+50 g of carbohydrate (CHO); Study 2 (iv) noningestion, (v) 500 mg of LC, (vi) 30 mg of CoQ10, and (vii) 500 mg of LC+30 mg of CoQ10. The energy expenditure (EE) and nonprotein respiratory quotient (npRQ) were measured during the pre-exercise, postexercise, and recovery periods. Serum free carnitine, acetylcarnitine, total carnitine (Study 1 and 2), and ketone bodies (Study 2) were measured. The 750 mg LC treatment significantly facilitated fat oxidation during the recovery phases (p<0.05) without elevating EE. The higher fat oxidation associated with LC was completely suppressed by CHO. CoQ10 affected neither npRQ nor EE. npRQ was significantly correlated with the serum total ketone bodies (R=-0.68, p<0.001) and acetylcarnitine (R=-0.61--0.70, p<0.001). The highest correlation was found between acetylcarnitine and total ketone bodies immediately after exercise (R=0.85, p<0.001). In conclusion, LC enhanced liver fat utilization and ketogenesis in an acute manner without stimulating EE under fat-mobilizing conditions.