Adipose Tissue Hormone-sensitive Lipase Research Articles

Effects of Weight Loss and Aerobic Exercise Training on Adi-Pose Tissue Zinc α2-Glycoprotein and Associated Genes in Obesity.

Zinc α2-glycoprotein (ZAG) has been implicated in fatty acid metabolism and utilization and is lower in obese and higher in cachexic adults compared to those of normal weight. Previous studies suggest that ZAG binds to the beta3-adrenergic receptor (β3AR) to influence fatty acid metabolism in adipose tissue by regulating hormone sensitive lipase (HSL). The purpose of this study is to investigate the effects of a six-month weight loss (WL) or aerobic exercise (AEX) intervention on adipose tissue and skeletal muscle ZAG mRNA levels and protein expression, as well as the expression of β3AR, and HSL. Abdominal adipose tissue (AB) and gluteal adipose tissue (Glut) and vastus lateralis muscle biopsies were performed before and after WL (n = 13) or AEX (n = 13). ZAG, HSL, and β3AR expressions were determined by RT-PCR, and ZAG and HSL plasma levels by ELISA. Body weight decreased by 9.69% (p < 0.001) in WL and did not change with AEX. Maximal oxygen consumption (VO2max) increased by 7.1% (p < 0.005) after WL and by 16.69% (p < 0.001) after AEX. WL significantly decreased body weight with a reduction of percentage of fat, fat mass, fat-free mass (FFM). AEX decreased percent fat and increased VO2max, but did not change fat mass and FFM. Abdominal ZAG and HSL mRNA levels did not change significantly after WL or AEX. There were no changes in plasma ZAG, HSL and adipose tissue β3AR mRNA levels after WL and AEX. ZAG, HSL and β3AR mRNA expressions in adipose tissue are positively associated each other. Adipose tissue abdominal and gluteal HSL are negatively associated with HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), and both ZAG and HSL adipose tissue are negatively associated with fasting glucose and the glucose area under the curve. Further work is needed to elucidate the role of ZAG and HSL in the propensity for weight gain and the ability of exercise to mitigate these responses.

The Liver and Heart: How the Two Most Beloved “Babies” in the Human Body Communicate

The Liver and Heart: How the Two Most Beloved “Babies” in the Human Body Communicate

Hepatocyte‐specific Overexpression of Fatty Acid Desaturase 1 Improves Insulin Signaling and ameliorates hypertriglyceridemia in Male Rat

Objective Decreased fatty acid desaturase 1 (Fads1) activity results in the accumulation of saturated fat, which contributes to the development of nonalcoholic steatohepatitis (NASH). The aim of this study was to determine whether hepatic overexpression of Fads1 attenuates a dietary high-fat high-fructose (HFHF)-induced metabolic phenotype. Methods Hepatocyte-specific overexpression of Fads1 was achieved via the tail vein injection of recombinant adeno-associated virus (AAV) serotype 8 containing an albumin promoter with rat Fads1 sequence. Blank vectors served as controls. Male weanling Sprague-Dawley rats were assigned to five groups and fed with chow diet, low-fat high-fructose diet with AAV8 blank control (LFHF-AAV8-Blank), LFHF-AAV8-Fads1, high-fat high-fructose diet with AAV8 blank control (HFHF-AAV8-Blank), or HFHF-AAV8-Fads1 (n=8 rats/group) for 8 weeks. Metabolic phenotypes were characterized, including body weight, level of hepatic steatosis, glucose and insulin tolerance tests (GTT, ITT). Liver, skeletal muscle and adipose tissue insulin signaling were examined by western blot. Results Hepatocyte-specific overexpression of Fads1 significantly decreased body weight gain and improved glucose tolerance, but not hepatic steatosis, in LFHF-fed rats. These effects were not evident in HFHF-fed rats. On the contrary, white adipose tissue weight was markedly reduced in HFHF-AAV8-Fads1 rats compared to HFHF-AAV8-blank control rats, and to a lesser extent in LFHF rats. Both LFHF-AAV8-Fads1 and HFHF-AAV8-Fads1 rats displayed decreased fasting plasma triglycerides and increased plasma free fatty acids compared to their AAV8-blank control rats, and this was associated with upregulation of adipose tissue hormone sensitive lipase (HSL). While phosphorylated Akt (p-Akt) expression was downregulated, phosphorylated glycogen synthase kinase 3β (GSK-3β) was upregulated by both LFHF and HFHF diet in skeletal muscle, these alterations were not evident in the liver and adipose tissue. Moreover, decreased expression of p-Akt in skeletal muscle was partially restored in HFHF-AAV8-Fads1 rats, but not in LFHF-AAV8-Fads1 rats. Conclusion Our data demonstrated that hepatocyte-specific overexpression of Fads1 leads to the improvement of metabolic phenotypes in a diet- and tissue-specific manner, and this was associated with improved insulin signaling in skeletal muscle. The underlying mechanism(s) need further investigation.

Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis

The G protein–coupled receptor GPRC6A regulates various physiological processes in response to its interaction with multiple ligands, such as extracellular basic amino acids, divalent cations, testosterone, and the uncarboxylated form of osteocalcin (GluOC). Global ablation of GPRC6A increases the susceptibility of mice to diet-induced obesity and related metabolic disorders. However, given that GPRC6A is expressed in many tissues and responds to a variety of hormonal and nutritional signals, the cellular and molecular mechanisms underlying the development of metabolic disorders in conventional knockout mice have remained unclear. On the basis of our previous observation that long-term oral administration of GluOC markedly reduced adipocyte size and improved glucose tolerance in WT mice, we examined whether GPRC6A signaling in adipose tissue might be responsible for prevention of metabolic disorders. We thus generated adipocyte-specific GPRC6A knockout mice, and we found that these animals manifested increased adipose tissue weight, adipocyte hypertrophy, and adipose tissue inflammation when fed a high-fat and high-sucrose diet compared with control mice. These effects were associated with reduced lipolytic activity because of downregulation of lipolytic enzymes such as adipose triglyceride lipase and hormone-sensitive lipase in adipose tissue of the conditional knockout mice. Given that, among GPR6CA ligands tested, GluOC and ornithine increased the expression of adipose triglyceride lipase in cultured 3T3-L1 adipocytes in a manner dependent on GPRC6A, our results suggest that the constitutive activation of GPRC6A signaling in adipocytes by GluOC or ornithine plays a key role in adipose lipid handling and the prevention of obesity and related metabolic disorders.

Maternal Metabolic Alterations in Monosodium Glutamate Fed Rats during Gestation and Lactation Period

Background: Monosodium glutamate (MSG), an extensively used food additive, is claimed to cause many health problems, its use is still under debate. Aim: to explore the metabolic and hypertensive effect of MSG dietary administration in pregnant and lactating female rats, and its possible underlying mechanism. Methods: 16 adult female albino Wister rats were divided into 2 groups, control group; were fed standard rat chow, and MSG group; were fed 2% MSG supplemented rat chow throughout gestation and lactation period. Oral glucose tolerance test (OGTT) and arterial blood pressure (ABP) were measured at mid and late gestation, mid and late lactation periods. At mid lactation period, a retroorbital samples were analyzed for fasting glucose, lipid profile; triglycerides (TGs), total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C), hormonal assays; insulin, glucagon, prolactin, corticosterone and ACTH, as well as pancreatic lipase, amylase and malondialdehyde (MDA). By the end of lactation, adipose tissue was assessed for glucose transporter-4 (GLUT-4) and hormone sensitive lipase (HSL) relative expression. Results: MSG rats showed elevated ABP during pregnancy and lactation, with impaired OGTT at mid and late lactation period. Fasting serum glucose, TGs, TC, LDL-C, glucagon, corticosterone, pancreatic lipase and amylase, MDA as well as adipose tissue HSL expression were significantly elevated, while, fasting serum insulin, ACTH and adipose tissue GLUT-4 expression were significantly declined in MSG fed rats as compared to control group. Conclusion: MSG feeding during pregnancy and lactation induced hypertension and metabolic alterations that could be due to pancreatic and adrenal affection secondary oxidative stress.

Molecular mechanism of non-alcoholic fatty liver disease induced and aggravated by chronic stress through HSL/ATGL-FFA which promotes fat mobilization

Abstract Objective To study the effects of social stress (CS) and social stress combined with high-fat diet on fat mobilization as a candidate mechanism for the induction or aggravation of non-alcoholic fatty liver disease (NAFLD). Methods Thirty-two male Wistar rats (250 ± 10 g) were randomly allocated to a blank control group (BC), a high-fat diet group (HFD), a CS group, and a combined CS and high-fat diet group (CS + HFD). Rats were sacrificed and tissues were collected after 8 weeks. Liver and body mass were measured and used to calculate the liver index. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and free fatty acids (FFAs) were measured. Liver sections were examined microscopically after oil red O and hematoxylin and eosin staining. The relative mRNA expression of acetyl-CoA carboxylase (ACCase), hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase in liver, and hormone-sensitive lipase (HSL), and adipose triglyceride lipase (ATGL) in subcutaneous adipose tissue, were measured by real-time PCR. The liver concentrations of triglyceride, reactive oxygen species, and ACCase were measured by ELISA and HSL activity was determined using turbidimetry. Results NAFLD developed in the CS, HFD, and CS + HFD groups, with the most severe NAFLD being in the CS + HFD group. Serum AST, ALT, and FFA, liver index, and hepatic triglyceride, FFA, and tumor necrosis factor-α were significantly higher in both the CS and CS + HFD groups. However, food intake and ACCase mRNA expression were lower. The mRNA expression of HSL and ATGL in adipose tissue was much higher, and HSL activity was higher in the CS group than in the BC group, and in the CS + HFD group than in the HFD group. Conclusion We have successfully established two models of stress-induced NAFLD, suggesting stress can induce and aggravate NAFLD by promoting fat mobilization through upregulation of HSL and ATGL.

An Epistatic Interaction between Pnpla2 and Lipe Reveals New Pathways of Adipose Tissue Lipolysis.

White adipose tissue (WAT) lipolysis contributes to energy balance during fasting. Lipolysis can proceed by the sequential hydrolysis of triglycerides (TGs) by adipose triglyceride lipase (ATGL), then of diacylglycerols (DGs) by hormone-sensitive lipase (HSL). We showed that the combined genetic deficiency of ATGL and HSL in mouse adipose tissue produces a striking different phenotype from that of isolated ATGL deficiency, inconsistent with the linear model of lipolysis. We hypothesized that the mechanism might be functional redundancy between ATGL and HSL. To test this, the TG hydrolase activity of HSL was measured in WAT. HSL showed TG hydrolase activity. Then, to test ATGL for activity towards DGs, radiolabeled DGs were incubated with HSL-deficient lipid droplet fractions. The content of TG increased, suggesting DG-to-TG synthesis rather than DG hydrolysis. TG synthesis was abolished by a specific ATGL inhibitor, suggesting that ATGL functions as a transacylase when HSL is deficient, transferring an acyl group from one DG to another, forming a TG plus a monoglyceride (MG) that could be hydrolyzed by monoglyceride lipase. These results reveal a previously unknown physiological redundancy between ATGL and HSL, a mechanism for the epistatic interaction between Pnpla2 and Lipe. It provides an alternative lipolytic pathway, potentially important in patients with deficient lipolysis.

Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity.

Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency-mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL-ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.

Cholic Acid Supplementation of a High-Fat Obesogenic Diet Suppresses Hepatic Triacylglycerol Accumulation in Mice via a Fibroblast Growth Factor 21–Dependent Mechanism

BackgroundSupplementation of a high-fat obesogenic diet (HFD) with cholic acid (CA) suppresses the development of obesity, insulin resistance, and hepatic steatosis in mice. ObjectiveWe investigated the role of fibroblast growth factor 21 (FGF21) in mediating the beneficial actions of CA on metabolic syndrome. MethodsMale 7-wk-old wild-type (WT) mice and FGF21 knockout (FGF21KO) mice were fed an HFD for 12 wk followed by a 4-wk period in which the mice were fed the HFD alone or supplemented with 0.5% CA. Body composition, gross energy efficiency, glucose tolerance, homeostasis model assessment of insulin resistance (HOMA-IR), and hepatic triacylglycerol (TG) concentrations were measured. ResultsCA administration improved glucose tolerance and decreased total body fat accretion, gross energy efficiency, fasting blood glucose concentrations, and HOMA-IR in both WT mice and FGF21KO mice. The extent of the effect of CA on glucose tolerance, fasting blood glucose concentrations, and HOMA-IR was similar in both mouse strains, whereas the extent of the effect of CA on total body fat accretion and gross energy efficiency was 4.2- to 4.4-fold greater in FGF21KO mice than in WT mice. Further analyses showed that CA decreased hepatic TG concentrations in WT mice (49%) but had no effect on hepatic TG concentrations in FGF21KO mice. CA decreased the activation state of hepatic acetyl-CoA carboxylase 1 (ACC1) and adipose tissue hormone-sensitive lipase (HSL) in WT mice but was not effective in decreasing the activation of ACC1 and HSL in FGF21KO mice. ConclusionFGF21 signaling is required for the beneficial effect of CA on hepatic TG accumulation in mice fed an HFD. We propose that FGF21 signaling potentiates the ability of CA to decrease the activation of ACC1 and HSL, key enzymes controlling the supply of long-chain fatty acid precursors for hepatic TG synthesis.

Anti-hypertriglyceridemic Activity of Cornus Mas in Diabetic Rats

Introduction: Hypertriglyceridemia is among the multiple metabolic derangements seen in diabetes mellitus. Cornelian cherry (Cornus mas L.), belongs to the family Cornacea and has been shown to be helpful in treating hyperlipidemia. Aim: The study investigates mechanisms of action of dietary Cornelian Cherry fruit Dried Powder (CCDP) for ameliorating hypertriglyceridemia in diabetic rats. Materials and Methods: An experimental study with parallel controls was performed. Fifty six male adult rats were randomly assigned into 8 equal groups and treated as follows for 4 weeks. Negative control: Normal rats, basic diet; positive control: streptozotocin-induced diabetic rats, basic diet; T1 to T4 groups: diabetic rats fed with diets containing 0.25, 0.5, 1 and 2 g/ 100 g BW CCDP, respectively; T5: diabetic rats fed with basic diet plus 100 mg/kg BW of fenofibrate in drinking water and T6: normal rats fed with basic diet containing 1 g/100 g BW CCDP. Selected serum biochemical parameters, Lipoprotein Lipase (LPL) level as well as Adipose Tissue Hormone Sensitive Lipase (HSL) and Hepatic Peroxisome Proliferator-Activated Receptor Alpha (PPARα) levels were assayed. Analysis of data was performed by one-way ANOVA followed by Tukey’s test with p<0.05 as the significant level. Results: Treatment with CCDP at all dosages as well as fenofibrate decreased serum triglycerides and VLDL levels as compared to positive control. Serum AST significantly decreased in T1, T3 and T4 groups as compared to positive control rats. Serum LPL levels in the diabetic positive control group decreased significantly as compared to negative control. Rats in T1, T2, T4 and T5 groups showed increased serum LPL levels as compared to positive control. No significant difference was observed in hepatic PPARα levels among CCDP-treated and negative or positive controls. Positive control rats showed a significant decrease in adipose tissue HSL levels. Administration of CCDP in T3 group significantly increased HSL values as compared to positive control. CCDP in healthy rats did not change any of these parameters. Conclusion: Findings of the present study confirms positive effects of C. mas fruit on some liver function enzymes and hypertriglyceridemia and clarifies that increased serum LPL levels is at least partly responsible for hypotriglyceridemic effect of the fruit in rats with STZ-induced diabetes mellitus.

Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice.

Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency.

Impact of training state on fasting-induced regulation of adipose tissue metabolism in humans.

Recruitment of fatty acids from adipose tissue is increased during fasting. However, the molecular mechanisms behind fasting-induced metabolic regulation in human adipose tissue and the potential impact of training state in this are unknown. Therefore the aim of the present study was to investigate 1) fasting-induced regulation of lipolysis and glyceroneogenesis in human adipose tissue as well as 2) the impact of training state on basal oxidative capacity and fasting-induced metabolic regulation in human adipose tissue. Untrained [maximal oxygen uptake (V̇o2max) < 45 ml·min-1·kg-1] and trained subjects (V̇o2max > 55 ml·min-1·kg-1) fasted for 36 h, and abdominal subcutaneous adipose tissue biopsies were obtained 2, 12, 24, and 36 h after a standardized meal. Adipose tissue oxidative phosphorylation complexes, phosphoenolpyruvate carboxykinase, and pyruvate dehydrogenase (PDH)-E1α protein as well as PDH kinase (PDK) 2, PDK4, and PDH phosphatase 2 mRNA content were higher in trained subjects than in untrained subjects. In addition, trained subjects had higher adipose tissue hormone-sensitive lipase Ser660 phosphorylation and adipose triglyceride lipase protein content as well as higher plasma free fatty acid concentration than untrained subjects during fasting. Moreover, adipose tissue PDH phosphorylation increased with fasting only in trained subjects. Taken together, trained subjects seem to possess higher basal adipose tissue oxidative capacity as well as higher capacity for regulation of lipolysis and for providing substrate for glyceroneogenesis in adipose tissue during fasting than untrained subjects. NEW & NOTEWORTHY This study shows for the first time higher protein content of lipolytic enzymes and higher oxidative phosphorylation protein in adipose tissue from trained subjects than from untrained subjects during fasting. Furthermore, trained subjects had higher capacity for adipose tissue glyceroneogenesis than untrained subjects.

Leptin Gene Transfer Improves Symptoms of Type 2 Diabetic Mice by Regulating Leptin Signaling Pathway and Insulin Resistance of Peripheral Tissues.

The leptin gene was transferred into the liver of streptozocin- and high fat diet-induced type 2 diabetic (T2D) mice by hydrodynamic-based gene delivery. The food intake, water consumption, glucose concentration, and triglyceride and total cholesterol levels of T2D mice were significantly decreased. Meanwhile, plasma leptin was remarkably increased after gene transfer for 2, 3, 5, and 7 days, while plasma adiponectin was also significantly increased at day 2. To understand the mechanism of action of leptin on T2D mice, gene expressions related to glycometabolism and energy metabolism in the liver, epididymal adipose tissue, hypothalamus, and muscle were measured. The mRNA expression levels of adiponectin receptor 1 (ADR1), glucose transporter 4 (GLUT4), glucose-6-phosphase, and peroxisome proliferator-activated receptor γ in the liver, leptin, adiponectin, and hormone-sensitive lipase in adipose tissue, leptin, leptin-receptor, ADR1 in the hypothalamus, and ADR1, GLUT4, and insulin 1 in the gastrocnemius significantly increased. Moreover, the hepatic glycogen of the leptin-gene-treated group was significantly increased in comparison to the control group. Meanwhile, the significant decrease of forkhead box O1, adiponectin receptor 2, and peroxisome proliferator-activated receptor α in the liver, and agouti-related protein and proopiomelanocortin genes in the hypothalamus were also observed. In fat tissue and hypothalamus, leptin and adiponectin protein levels were also significantly increased, whereas the neuropeptide Y protein level was significantly decreased. These results indicated that the leptin gene transfer could improve the symptoms of T2D mice by regulating the leptin-hypothalamus signaling pathway and improving the insulin resistance of the peripheral tissues of T2D mice.

Adipose-Derived Mesenchymal Stem Cells Ameliorate Lipid Metabolic Disturbance in Mice.

: Adipose-derived mesenchymal stem cells (AD-MSCs) have been shown to ameliorate hyperglycemia in diabetic animals and individuals. However, little is known about whether AD-MSCs affect lipid metabolism. Here we have demonstrated for the first time that AD-MSC infusion can significantly suppress the increase in body weight and remarkably improve dyslipidemia in db/db obese mice and diet-induced obesity mice. Induction of white fat tissue "browning" and activation of adenosine monophosphate-activated protein kinase and its downstream hormone-sensitive lipase in adipose tissue contribute to the antiobesity and lipid-lowering effects. Thus, AD-MSC infusion holds great therapeutic potential for dyslipidemia and associated cardiovascular diseases. Mesenchymal stem cells (MSCs) are considered one of the most promising types of stem cells for translational application because of their rich tissue sources, multilineage differentiation capacity, and easy amplification in vitro and unique immunobiological properties. This study demonstrated that adipose-derived MSCs (AD-MSCs) infusion can significantly suppress the increase in body weight and remarkably improve dyslipidemia in obese mice. Induction of white fat tissue "browning" and activation of adenosine monophosphate-activated protein kinase and its downstream hormone-sensitive lipase in adipose tissue were demonstrated to contribute to the antiobesity and lipid-lowering effects. Thus, AD-MSC infusion holds great therapeutic potential for dyslipidemia.

Different effects of growth hormone and fasting on the induction patterns of two hormone-sensitive lipase genes in red seabream Pagrus major

Growth hormone (GH) increases phosphorylation and mRNA levels of hormone-sensitive lipase (HSL) in the livers of some marine teleosts. The hepatic GH-HSL axis appears to play important roles in fasting-induced lipolysis. However, it is not known whether GH exerts similar effects on HSL in fish adipose tissues. Functional differentiation of two fish-specific HSL isoforms (HSL1 and HSL2) also remains unclear. The present study seeks to address two unanswered questions about fish lipolysis using red seabream (Pagrus major): (1) Does GH increase phosphorylation and mRNA levels of HSL in adipose tissue? (2) How do GH and fasting affect mRNA levels of two HSL isoform genes in the liver and adipose tissue? To this end, we first cloned HSL1 and HSL2 cDNAs and investigated their tissue distribution. Transcripts of both HSLs and HSL1 proteins were abundant in the visceral adipose tissue, gonads, and liver, suggesting the important role of HSL in adipose tissue lipolysis. HSL2 transcript levels were 20–65% those of HSL1 except in the skin, and HSL2 proteins were not detected by our in-house antisera. Ex vivo administration of GH increased HSL1 phosphorylation, non-esterified fatty acid (NEFA) release, and levels of HSL1 and HSL2 mRNA in both the liver and visceral adipose tissue. Hepatic HSL2 mRNA was particularly sensitive to GH administration and sometimes exceeded HSL1 mRNA levels with up to 13-fold induction. In contrast, fasting for 4 and 7d increased HSL1 mRNA levels, but had only marginal effects on HSL2 mRNA levels in both adipose tissue or liver. We concluded that GH would increase HSL mRNAs during adipose tissue lipolysis in red seabream; however, GH and fasting result in different induction ratio of two HSL isoform genes, suggesting that other hormone(s) also contributes to fasting-induced lipolysis.

Phospholipase C-Related Catalytically Inactive Protein (PRIP) Regulates Lipolysis in Adipose Tissue by Modulating the Phosphorylation of Hormone-Sensitive Lipase

Phosphorylation of hormone-sensitive lipase (HSL) and perilipin by protein kinase A (PKA) promotes the hydrolysis of lipids in adipocytes. Although activation of lipolysis by PKA has been well studied, inactivation via protein phosphatases is poorly understood. Here, we investigated whether phospholipase C-related catalytically inactive protein (PRIP), a binding partner for protein phosphatase 1 and protein phosphatase 2A (PP2A), is involved in lipolysis by regulating phosphatase activity. PRIP knockout (PRIP-KO) mice displayed reduced body-fat mass as compared with wild-type mice fed with standard chow ad libitum. Most other organs appeared normal, suggesting that mutant mice had aberrant fat metabolism in adipocytes. HSL in PRIP-KO adipose tissue was highly phosphorylated compared to that in wild-type mice. Starvation of wild-type mice or stimulation of adipose tissue explants with the catabolic hormone, adrenaline, translocated both PRIP and PP2A from the cytosol to lipid droplets, but the translocation of PP2A was significantly reduced in PRIP-KO adipocytes. Consistently, the phosphatase activity associated with lipid droplet fraction in PRIP-KO adipocytes was significantly reduced and was independent of adrenaline stimulation. Lipolysis activity, as assessed by measurement of non-esterified fatty acids and glycerol, was higher in PRIP-KO adipocytes. When wild-type adipocytes were treated with a phosphatase inhibitor, they showed a high lipolysis activity at the similar level to PRIP-KO adipocytes. Collectively, these results suggest that PRIP promotes the translocation of phosphatases to lipid droplets to trigger the dephosphorylation of HSL and perilipin A, thus reducing PKA-mediated lipolysis.

Salacia reticulata has therapeutic effects on obesity.

Salacia reticulata Wight (S. reticulata) is a herbal medicine used for treatment of early diabetes in Ayurvedic medicine. In previous reports, the extract of S. reticulata showed preventive effects on obesity and various metabolic disorders and a suppressive effect on differentiation in premature adipocytes. The aim of this research was to elucidate the therapeutic efficacy of the extract of S. reticulata on obesity and various metabolic disorders in 12-week-old TSOD mice with obesity and metabolic disorders and in mature 3T3-L1 adipocytes. In TSOD mice, S. reticulata therapy produced a reduction in body weight and mesenteric fat accumulation, an improvement in abnormal glucose metabolism, and an increase in adiponectin level in plasma. In addition, the mRNA expressions of hormone-sensitive lipase (HSL) and adiponectin were increased in mesenteric fat. In in vitro experiments, S. reticulata therapy produced suppression of intracellular triacylglycerol accumulation and enhancement of glycerol release into the medium in mature 3T3-L1 cells. The mRNA expressions of lipogenesis factor (peroxisome proliferator-activated receptor γ, lipoprotein lipase, CD36, and fatty acid binding protein 4) were down-regulated, while the expressions of lipolysis factor (adipose tissue triacylglycerol lipase and HSL) and adiponectin were up-regulated. Moreover, the extract of S. reticulata enhanced the expression of total AMP-activated protein kinase α (AMPKα) and phosphorylated AMPKα in mature adipocytes. These findings demonstrate that the extract of S. reticulata has therapeutic effects on obesity and metabolic disorders by enhancing lipogenesis genes and suppressing lipolysis genes through the activation of AMPKα in adipocytes.

The ratio of estrogen receptor α to β is associated with the expression of lipoprotein lipase and hormone-sensitive lipase in human adipose tissue

Lipoprotein lipase (LPL) is a key enzyme regulating fat metabolism by catabolizing plasma triglyceride (TG) into free fatty acid (FFA) (lipogenesis). Hormone-sensitive lipase (HSL) is rate-limiting enzyme for lipolysis by hydrolysis of stored TG in fat into FFA and glycerol. Current evidence has suggested that estrogen have regulatory effect on determining the amount and distribution of adipose tissue, but the mechanism remains unclear. Estrogen performs its biological activities through binding to its two receptors, ER-alpha (ERα) and ER-beta (ERβ), which are expressed in adipocytes. In this study, we investigate the association between ER expression and LPL or HSL in human adipose tissue. Exploratory, pilot study. We obtained small pieces (5-10g) of subcutaneous and omental adipose tissue from thirty-eight women who have had a gynecologic surgery. Total RNA was extracted from the fat samples, and a real-time RT-PCR was performed to measure and quantify the mRNA expression of ER, LPL, and HSL. Correlation and regression tests were performed for the variables. All subjects were premenopausal women aged 20 to 50 (median age: 39.2 years-old). In subcutaneous fat, neither ERα nor ERβ showed a correlation with the mRNA levels of LPL or HSL. However, the ER ratio (α/β) showed a negative correlation with the HSL (r = -0.553, P < 0.001). In omental fat, the mRNA of ERα was significantly correlated with both LPL and HSL (P = 0.001 and P = 0.017). In addition, the ER ratio was positively correlated with LPL mRNA level (r = 0.471, P < 0.001). The results of present study showed that both subtypes of ER were associated with the expression of LPL or HSL. Our findings imply that the ratio of ERα to ERβ in human subcutaneous and omental adipose tissue is an important regulatory factor involved in fat metabolism by interacting with LPL and HSL.

Effect of exercise training intensity on adipose tissue hormone sensitive lipase gene expression in obese women under weight loss

BackgroundHormone sensitive lipase (HSL) is an enzyme that regulates adipose tissue lipolysis and plays an important role in chronic exercise-induced changes in adipose tissue metabolism. The purpose of this study was to determine whether aerobic exercise intensity influences abdominal adipose tissue HSL gene expression in obese women under weight loss. MethodsThirty women (body mass index (BMI) = 33.0 ± 0.7 kg/m2, age = 58 ± 1 years) completed one of three 20-week interventions: caloric restriction alone (CR only, n = 8), CR plus moderate-intensity exercise (CR + moderate-intensity, 45%–50% heart rate reserve (HRR), 3 day/week, n = 9), or CR plus vigorous-intensity exercise (CR + vigorous-intensity, 70%–75% HRR, 3 day/week, n = 13). Each group had a similar prescribed energy deficit comprised of underfeeding alone (2800 kcal/week for CR only) or underfeeding (2400 kcal/week) plus exercise (400 kcal/week). Body composition and maximal aerobic capacity (VO2max) were measured, and subcutaneous abdominal adipose tissue samples were collected before and after the interventions. Adipose tissue HSL gene expression was measured by real time reverse-transcriptase polymerase chain reaction. ResultsAll three interventions reduced body weight, fat mass, percent fat, and waist to a similar degree (all p < 0.01). In addition, all interventions did not change absolute VO2max, but increased relative VO2max (p < 0.05 to p < 0.01). Compared to pre-intervention, neither CR only nor CR + moderate-intensity changed adipose tissue HSL gene expression, but CR + vigorous-intensity significantly increased adipose tissue HSL gene expression (p < 0.01). The changes of HSL gene expression levels in the CR + vigorous-intensity group were significantly different from those in the CR only (p < 0.05) and CR + moderate-intensity (p < 0.01) groups. In the whole cohort, changes in adipose tissue HSL gene expression correlated positively to changes in absolute (r = 0.55, p < 0.01) and relative (r = 0.32, p = 0.09) VO2max. ConclusionThese results support a potential effect of aerobic exercise training intensity on hormone sensitive lipase pathway in adipose tissue metabolism in obese women under weight loss.

Altered Subcutaneous Adipose Tissue Response to Systemic LPS Administration in Patients with Type 2 Diabetes

Aim: Inflammation is thought to play a major role in impaired metabolism. However, the metabolic and inflammatory response of adipose tissue, to a pro-inflammatory stimulus is poorly defined in patients with Type 2 Diabetes Mellitus (T2DM). We therefore aimed to investigate whether adipose tissue in T2DM would display an altered response to E. coli LipoPolySaccharide (LPS). Materials and methods: Twelve patients with T2DM and 12 control subjects received an intravenous bolus injection of LPS (0.3 ng/kg). Abdominal subcutaneous adipose tissue biopsies, serum and plasma were obtained at 0, 2, 4, 6 and 8 hours after LPS. The gene expression of Tumour Necrosis Factor-α (TNF), InterLeukin-6 (IL-6), lipoprotein lipase (LPL), hormone sensitive lipase (HSL), fatty acid synthase (FASN), adiponectin and peroxisome proliferator-activated recptor γ (PPARγ) was analysed by real time reverse transcription Polymerase Chain Reaction (PCR). Results: The expression of TNF and IL-6 in adipose tissue increased after LPS administration without any difference between groups (2-way ANOVA, effect of time: p<0.001 and p=0.0001, respectively). In contrast, the expression of LPL, HSL and adiponectin in adipose tissue increased only in control subjects (2-way ANOVA, effect of time X group: p=0.03; p=0.02 and p=0.02, respectively). There was no effect of LPS on FASN or PPARγ in either group. Conclusion: Patients with T2DM demonstrate a resistance to LPS in terms of inducing important mediators of lipolysis and lipogenesis, although the expression of TNF and IL-6 in adipose tissue increased in both groups. And thus, adipose tissue may contribute to the acute inflammation-related metabolic complications seen in T2DM.