In vitro SAR of (5-(2H)-isoxazolonyl) ureas, potent inhibitors of hormone-sensitive lipase

2004 ◽  
Vol 14 (12) ◽  
pp. 3155-3159 ◽  
Author(s):  
Derek B. Lowe ◽  
Steven Magnuson ◽  
Ning Qi ◽  
Ann-Marie Campbell ◽  
James Cook ◽  
...  
Keyword(s):  
Hormone Sensitive Lipase ◽  
Hormone Sensitive

Molecular mechanisms regulating hormone-sensitive lipase and lipolysis

2003 ◽  
Vol 31 (6) ◽  
pp. 1120-1124 ◽  
Author(s):  
C. Holm
Keyword(s):  
Lipid Droplet ◽  
Molecular Mechanisms ◽  
Hormone Sensitive Lipase ◽  
Glucose Disposal ◽  
Triacylglycerol Lipase ◽  
Insulin Resistant ◽  
Lipolytic Action ◽  
Key Enzyme ◽  
Hormone Sensitive

HSL (hormone-sensitive lipase) is a key enzyme in the mobilization of fatty acids from acylglycerols in adipocytes as well as non-adipocytes. In adipocytes, catecholamines stimulate lipolysis mainly through PKA (protein kinase A)-mediated phosphorylation of HSL and perilipin, a protein coating the lipid droplet. The anti-lipolytic action of insulin is mediated mainly via lowered cAMP levels, accomplished through activation of phosphodiesterase 3B. Phosphorylation of HSL by PKA occurs at three sites, the serines 563, 659 and 660, both in vitro and in primary rat adipocytes. Phosphorylation of Ser-659 and -660 is required for in vitro activation as well as translocation from the cytosol to the lipid droplet, whereas the role of the third PKA site remains elusive. Adipocytes isolated from homozygous HSL-null mice, generated in our laboratory, exhibit completely blunted catecholamine-induced glycerol release and reduced fatty acid release, suggesting the presence of additional, although not necessarily hormone-activatable, triacylglycerol lipase(s). Basal hyperinsulinaemia, release of exaggerated amounts of insulin during glucose challenges and retarded glucose disposal during insulin tolerance tests suggest that HSL-null mice are insulin resistant. Liver, adipose tissue and skeletal muscle appear all to be sites of impaired insulin sensitivity in HSL-null mice.

Endurance training changes in lipolytic responsiveness of obese adipose tissue

1998 ◽  
Vol 275 (6) ◽  
pp. E951-E956 ◽  
Author(s):  
I. De Glisezinski ◽  
F. Crampes ◽  
I. Harant ◽  
M. Berlan ◽  
J. Hejnova ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Physical Training ◽  
The Body ◽  
Hormone Sensitive Lipase ◽  
Aerobic Exercise Training ◽  
Adrenoceptor Agonist ◽  
Before And After ◽  
Hormone Sensitive ◽  
Obese Subjects

The aim of this study was to investigate the effect of aerobic exercise training on the lipolytic response of adipose tissue in obese subjects. Thirteen men (body mass index = 36.9 ± 1.3 kg/m2) were submitted to aerobic physical training on a cycloergometer (30–45 min, 4 days a wk) for 3 mo. Adipocyte sensitivity to the action of catecholamines and insulin was studied in vitro before and after training. Training induced a decrease in the percentage of fat mass ( P < 0.05) without changing the body weight. Basal lipolysis and hormone-sensitive lipase activity were significantly decreased after training ( P < 0.05). The lipolytic effects of epinephrine, isoprenaline (β-adrenoceptor agonist), and dobutamine (β1-adrenoceptor agonist) were significantly increased ( P < 0.05) but not those of procaterol (β2-adrenoceptor agonist). The antilipolytic effects of α2-adrenoceptor and insulin were significantly decreased ( P < 0.05). Lipolysis stimulation by agents acting at the postreceptor level was unchanged after training. In conclusion, aerobic physical training in obese male subjects modifies adipose tissue lipolysis through an enhancement of β-adrenergic response and a concomitant blunting of adipocyte antilipolytic activity.

Sex differences in hormone-sensitive lipase expression, activity, and phosphorylation in skeletal muscle at rest and during exercise

2006 ◽  
Vol 291 (5) ◽  
pp. E1106-E1114 ◽  
Author(s):  
Carsten Roepstorff ◽  
Morten Donsmark ◽  
Maja Thiele ◽  
Bodil Vistisen ◽  
Greg Stewart ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Content ◽  
Specific Activity ◽  
Exercise Bout ◽  
Total Activity ◽  
Hormone Sensitive Lipase ◽  
Expression Activity ◽  
Hormone Sensitive ◽  
Specific Regulation

Women have been shown to use more intramuscular triacylglycerol (IMTG) during exercise than men. To investigate whether this could be due to sex-specific regulation of hormone-sensitive lipase (HSL) and to use sex comparison as a model to gain further insight into HSL regulation, nine women and eight men performed bicycle exercise (90 min, 60% V̇o2peak), and skeletal muscle HSL expression, phosphorylation, and activity were determined. Supporting previous findings, basal IMTG content ( P < 0.001) and net IMTG decrease during exercise ( P < 0.01) were higher in women than in men and correlated significantly ( r = 0.72, P = 0.001). Muscle HSL mRNA (80%, P = 0.11) and protein content (50%, P < 0.05) were higher in women than in men. HSL total activity increased during exercise (47%, P < 0.05) but did not differ between sexes. Accordingly, HSL specific activity (HSL activity per HSL protein content) increased during exercise (62%, P < 0.05) and was generally higher in men than in women (82%, P < 0.05). A similar pattern was observed for HSL Ser659 phosphorylation, suggesting a role in regulation of HSL activity. Likewise, plasma epinephrine increased during exercise ( P < 0.05) and was higher in men than in women during the end of the exercise bout ( P < 0.05). We conclude that, although HSL expression and Ser659 phosphorylation in skeletal muscle during exercise is sex specific, total muscle HSL activity measured in vitro was similar between sexes. The higher basal IMTG content in women compared with men is therefore the best candidate to explain the higher IMTG net hydrolysis during exercise in women.

scholarly journals Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Madan Kumar Arumugam ◽  
Srinivas Chava ◽  
Karuna Rasineni ◽  
Matthew C. Paal ◽  
Terrence M. Donohue ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Liver Steatosis ◽  
Hormone Sensitive Lipase ◽  
Ethanol Administration ◽  
Droplet Sizes ◽  
Hormone Sensitive ◽  
Differentiation Status ◽  
Adipose Dysfunction ◽  
Methylation Defects

AbstractIt has been previously shown that chronic ethanol administration-induced increase in adipose tissue lipolysis and reduction in the secretion of protective adipokines collectively contribute to alcohol-associated liver disease (ALD) pathogenesis. Further studies have revealed that increased adipose S-adenosylhomocysteine (SAH) levels generate methylation defects that promote lipolysis. Here, we hypothesized that increased intracellular SAH alone causes additional related pathological changes in adipose tissue as seen with alcohol administration. To test this, we used 3-deazaadenosine (DZA), which selectively elevates intracellular SAH levels by blocking its hydrolysis. Fully differentiated 3T3-L1 adipocytes were treated in vitro for 48 h with DZA and analysed for lipolysis, adipokine release and differentiation status. DZA treatment enhanced adipocyte lipolysis, as judged by lower levels of intracellular triglycerides, reduced lipid droplet sizes and higher levels of glycerol and free fatty acids released into the culture medium. These findings coincided with activation of both adipose triglyceride lipase and hormone sensitive lipase. DZA treatment also significantly reduced adipocyte differentiation factors, impaired adiponectin and leptin secretion but increased release of pro-inflammatory cytokines, IL-6, TNF and MCP-1. Together, our results demonstrate that elevation of intracellular SAH alone by DZA treatment of 3T3-L1 adipocytes induces lipolysis and dysregulates adipokine secretion. Selective elevation of intracellular SAH by DZA treatment mimics ethanol’s effects and induces adipose dysfunction. We conclude that alcohol-induced elevations in adipose SAH levels contribute to the pathogenesis and progression of ALD.

Effect of Pitressin on lipolysis and on phosphorylase activity in rat adipose tissue

1964 ◽  
Vol 207 (5) ◽  
pp. 1166-1168 ◽  
Author(s):  
Martha Vaughan
Keyword(s):  
Hormone Sensitive Lipase ◽  
Prostaglandin E ◽  
Glycerol Release ◽  
Similar Concentration ◽  
Phosphorylase Activity ◽  
Hormone Sensitive ◽  
Rat Adipose Tissue ◽  
Release Of Glycerol ◽  
Synthetic Oxytocin

Pitressin, a mixture of arginine and lysine vasopressins, stimulates the release of glycerol and of free fatty acids from rat epididymal fat pads in vitro. This effect is inhibited by prostaglandin E1, which has previously been shown to interfere with the analogous effects of catecholamines, ACTH, TSH, and glucagon. Like these latter hormones, Pitressin, added for a few minutes after tissues have been incubated in the absence of hormones, significantly increases the activity of phosphorylase and of the hormone-sensitive lipase. (The activity of both of these enzymes declines during the period of incubation before the hormone is added.) No effects of synthetic oxytocin at similar concentration on glycerol release or on phosphorylase activity were demonstrated.

scholarly journals SIRT5 Inhibition Induces Brown Fat-Like Phenotype in 3T3-L1 Preadipocytes

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1126
Author(s):  
Francesca Molinari ◽  
Alessandra Feraco ◽  
Simone Mirabilii ◽  
Serena Saladini ◽  
Luigi Sansone ◽  
...  
Keyword(s):  
Hormone Sensitive Lipase ◽  
Brown Adipocyte ◽  
Brown Adipose ◽  
Hormone Sensitive ◽  
Lipid Droplet Size ◽  
And Function ◽  
Amp Activated Protein Kinase ◽  
Transcription Factor Expression

Brown adipose tissue (BAT) activity plays a key role in regulating systemic energy. The activation of BAT results in increased energy expenditure, making this tissue an attractive pharmacological target for therapies against obesity and type 2 diabetes. Sirtuin 5 (SIRT5) affects BAT function by regulating adipogenic transcription factor expression and mitochondrial respiration. We analyzed the expression of SIRT5 in the different adipose depots of mice. We treated 3T3-L1 preadipocytes and mouse primary preadipocyte cultures with the SIRT5 inhibitor MC3482 and investigated the effects of this compound on adipose differentiation and function. The administration of MC3482 during the early stages of differentiation promoted the expression of brown adipocyte and mitochondrial biogenesis markers. Upon treatment with MC3482, 3T3-L1 adipocytes showed an increased activation of the AMP-activated protein kinase (AMPK), which is known to stimulate brown adipocyte differentiation. This effect was paralleled by an increase in autophagic/mitophagic flux and a reduction in lipid droplet size, mediated by a higher lipolytic rate. Of note, MC3482 increased the expression and the activity of adipose triglyceride lipase, without modulating hormone-sensitive lipase. Our findings reveal that SIRT5 inhibition stimulates brown adipogenesis in vitro, supporting this approach as a strategy to stimulate BAT and counteract obesity.

Sign in / Sign up

Export Citation Format

Share Document