Hormone-sensitive Lipase Activity Research Articles

Citrullus mucosospermus Extract Exerts Protective Effects against Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Steatohepatitis in Mice.

In recent years, there has been increasing interest in exploring the potential therapeutic advantages of Citrullus mucosospermus extracts (CME) for nonalcoholic steatohepatitis (NASH). In this study, we investigated the therapeutic effects of CME on NASH using a mice model. High-performance liquid chromatography (HPLC) was employed to identify cucurbitacin E and cucurbitacin E-2-O-glucoside from the CME. Although CME did not significantly alter the serum lipid levels in methionine- and choline-deficient (MCD) mice, it demonstrated a protective effect against MCD diet-induced liver damage. CME reduced histological markers, reduced alanine transaminase (ALT) and aspartame transaminase (AST) levels, and modulated key NASH-related genes, including C/EBPα, PPARγ, Fas, and aP2. In addition, CME was found to restore hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) activity, both crucial for fat catabolism, and reduced the levels of pro-inflammatory cytokines. Furthermore, CME demonstrated the potential to mitigate oxidative stress by maintaining or enhancing the activation and expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and superoxide dismutase (SOD), both pivotal players in antioxidant defense mechanisms. These findings underscore the promising therapeutic potential of CME in ameliorating liver damage, inflammation, and oxidative stress associated with NASH.

Effect of finger millet (Eleusine coracana) flour and malt on sirtuin1 protein in hypercholesterolemic rats

Finger millets are consumed as flour and malt with both forms promoting good health. Sirtuin1 protein impact metabolic pathways and improves health. Hypercholesterolemia is leading cause of several degenerative disorders. Since effect of flour and malt on sirtuin1 protein remains elusive so present study was designed to explore potential of finger millet flour and malt in hypercholesterolemic rats. The results showed that high-cholesterol (H) fed animals lowered sirtuin1 protein by 19.4%, 23.8%, 11.8% in liver, heart and kidneys respectively. Sirtuin1 protein was enhanced by flour (16.6%, 13.7% in liver and heart respectively); malt (14.8% and 13.4% in liver and heart respectively). H-fed rats showed reduction in cholesterol (21.8%, 59%, 25.1% by flour; 28.2%, 35.7%, 20.2% by malt in liver, heart and kidneys respectively), triglycerides (11.5%, 34%, 16.7% by flour in liver heart, adipose respectively; 29.1% and 15.5% by malt in heart and adipose respectively). Elevation in lipid peroxidation due H was reduced (35.8%, 28.6%, 15.8% by flour and 16%, 22%, and 19.5% by malt in liver, heart and kidneys respectively) along with increase in phospholipids (2-fold, 2.5-fold, 2.3 fold by flour and 60.5%, 34.2%, 54.7% by malt in liver, heart and kidneys respectively), activity of hormone sensitive lipase (27.6% and 22.7% by flour and malt respectively in adipose), HMG CoA reductase (56.7%, 28.8%, 2-fold by flour in liver, heart and kidneys respectively; 48%, 2-fold by malt in liver and kidneys respectively). Finger millets normalized sirtuin1 and lipid profile. Potential of flour was greater than malt in favorably regulating biochemical parameters.

P2Y13 receptor deficiency favors adipose tissue lipolysis and worsens insulin resistance and fatty liver disease.

Excessive lipolysis in white adipose tissue (WAT) leads to insulin resistance (IR) and ectopic fat accumulation in insulin-sensitive tissues. However, the impact of Gi-coupled receptors in restraining adipocyte lipolysis through inhibition of cAMP production remained poorly elucidated. Given that the Gi-coupled P2Y13 receptor (P2Y13-R) is a purinergic receptor expressed in WAT, we investigated its role in adipocyte lipolysis and its effect on IR and metabolic dysfunction-associated steatotic liver disease (MASLD). In humans, mRNA expression of P2Y13-R in WAT was negatively correlated to adipocyte lipolysis. In mice, adipocytes lacking P2Y13-R displayed higher intracellular cAMP levels, indicating impaired Gi signaling. Consistently, the absence of P2Y13-R was linked to increased lipolysis in adipocytes and WAT explants via hormone-sensitive lipase activation. Metabolic studies indicated that mice lacking P2Y13-R showed a greater susceptibility to diet-induced IR, systemic inflammation, and MASLD compared with their wild-type counterparts. Assays conducted on precision-cut liver slices exposed to WAT conditioned medium and on liver-specific P2Y13-R-knockdown mice suggested that P2Y13-R activity in WAT protects from hepatic steatosis, independently of liver P2Y13-R expression. In conclusion, our findings support the idea that targeting adipose P2Y13-R activity may represent a pharmacological strategy to prevent obesity-associated disorders, including type 2 diabetes and MASLD.

P168 Specialized pro-resolving lipid mediator Resolvin D1 and omega 6 dihomo-γ-linolenic acid are unable to solve inflammation in the creeping fat of patients with severe postoperative recurrence in Crohn's disease

Abstract Background The ω3 derivate resolvin D1 (RvD1), and the ω6 dihomo-γ-linolenic acid (DGLA) prevent collateral damage by overcoming inflammation and enhancing microbial clearance. In Crohn's disease, the mesenteric adipose tissue becomes inflamed and hyperplasies due to transmural lesions and bacterial translocation, developing the so-called creeping fat. This tissue is unable to clear inflammation and has been linked to severer intestinal inflammation and post-operative recurrence (POR). Recently, we have described the presence of DGLA and the increase in the ω6/ω3 ratio together with pro-inflammatory mediators in the creeping fat at surgery. Our aims were study the mechanisms within the inflammatory resolution related to polyunsaturated fatty acids depending on POR severity. Methods Creeping fat samples were obtained in the intestinal resection of Crohn's disease patients and endoscopic POR was evaluated according to the Rutgeerts score: non recurrence (i0+i1; n=18), mild recurrence (i2; n=14) and severe recurrence (i3+i4; n=10). Mesenteric adipose tissue was also collected from patients with colorectal cancer (n=10) and severe obesity (n=11) as reference groups. RvD1 was evaluated by C18/ELISA, lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) activity by radioassay, and the free fatty acid receptor 1 (FFAR1) expression by qRT-PCR. Results RvD1 was increased in the creeping fat in comparison to the mesenteric adipose tissues of the reference groups (Graphical abstract A) and correlated antagonistically with pro-inflammatory mediators in non-recurrence versus severe recurrence (B). Specifically, factors such as TNF-α, CD14 or IL-18 showed significant positive correlations with RvD1 in severe recurrence while negative in non recurrence. The LPL/HSL ratio indicated greater storage of fatty acids in severe recurrence creeping fats (C), and only in these patients, DGLA negatively correlated with HSL (D) and FFAR1 (E), a receptor that was only detected in Crohn's disease (F). At the same time, this receptor antagonistically correlated with pro-inflammatory mediators such as IL-8 in the creeping fat, positively in non-recurrence and negatively in severe recurrence (G). Conclusion The RvD1 increase suggests a greater production of this factor from ω3, but that would be insufficient to resolve inflammation in severe recurrent creeping fat at surgery time. In this phenotype, HSL activity is linked to a lower presence of DGLA, the only anti-inflammatory ω6. In contrast, the presence of this ligand in severe recurrents seems to reduce the expression of the FFAR1, which acts on the neutrophil function. Thus, immune-inflammation derived from lipid metabolism is antagonistic among the most disparate cases of POR in the creeping fat at surgery.

Follistatin-like 1 is a myokine regulating lipid mobilization during endurance exercise and recovery.

The aim of this study was to investigate the role of the follistatin-like 1 (Fstl1) and disco-interacting protein 2 homolog A (DIP2a) axis in relation to lipid metabolism during and after endurance exercise and to elucidate the mechanisms underlying the metabolic effects of Fstl1 on adipocytes, considering its regulation by exercise and muscle mass and its link to obesity. Twenty-nine sedentary males participated in endurance exercise, and blood samples were collected during and after the exercise. Body composition, Fstl1, glycerol, epinephrine, growth hormone, and atrial natriuretic peptide were measured. 3T3-L1 adipocytes, with or without DIP2a knockdown, were treated with Fstl1 to assess glycerol release, cyclic AMP/cyclic GMP production, and hormone sensitive lipase phosphorylation. The association between DIP2a gene expression levels in human adipose tissues and exercise-induced lipolysis was examined. Fstl1 levels significantly increased during endurance exercise and following recovery, correlating with lean body mass and lipolysis. In 3T3-L1 adipocytes, Fstl1 increased glycerol release, cyclic GMP production, and hormone sensitive lipase activation, but these effects were attenuated by DIP2a knockdown. DIP2a gene expression in human adipose tissues correlated with serum glycerol concentrations during endurance exercise. Fstl1 is a myokine facilitating lipid mobilization during and after endurance exercise through DIP2a-mediated lipolytic effects in adipocytes.

Extracellular macrophage migration inhibitory factor (MIF) downregulates adipose hormone-sensitive lipase (HSL) and contributes to obesity

Attenuation of adipose hormone sensitive lipase (HSL) may impair lipolysis and exacerbate obesity. We investigate the role of cytokine, macrophage migration inhibitory factor (MIF) in regulating adipose HSL and adipocyte hypertrophy. Extracellular MIF downregulates HSL in an autocrine fashion, by activating the AMPK/JNK signaling pathway upon binding to its membrane receptor, CD74. WT mice fed high fat diet (HFD), as well as mice overexpressing MIF, both had high circulating MIF levels and showed suppression of HSL during the development of obesity. Blocking the extracellular action of MIF by a neutralizing MIF antibody significantly reduced obesity in HFD mice. Interestingly, intracellular MIF binds with COP9 signalosome subunit 5 (Csn5) and JNK, which leads to an opposing effect to inhibit JNK phosphorylation. With global MIF deletion, adipocyte JNK phosphorylation increased, resulting in decreased HSL expression, suggesting that the loss of MIF's intracellular inhibitory action on JNK was dominant in Mif−/− mice. Adipose tissue from Mif−/− mice also exhibited higher Akt and lower PKA phosphorylation following HFD feeding compared with WT, which may contribute to the downregulation of HSL activation during more severe obesity. Both intracellular and extracellular MIF have opposing effects to regulate HSL, but extracellular actions predominate to downregulate HSL and exacerbate the development of obesity during HFD.

Rabbit Meat Extract Induces Browning in 3T3-L1 Adipocytes via the AMP-Activated Protein Kinase Pathway.

The browning of white adipocytes may be an innovative approach to address obesity. This study investigated the effects of rabbit meat extract on 3T3-L1 adipocytes, with a specific emphasis on inducing browning. The browning effects of rabbit meat extract were evaluated by analyzing genes specifically expressed in 3T3-L1 adipocytes using quantitative PCR and immunoblotting. Rabbit meat extract increased the expression of brown adipocyte-specific markers, UCP1 and PGC1α, and mitochondrial biogenesis factors, TFAM and NRF1, without affecting cell viability in fully differentiated 3T3-L1 adipocytes. Moreover, adipocyte differentiation and the triglyceride content were decreased; hormone-sensitive lipase activity was promoted. Rabbit meat extract activated the AMPK pathway in the differentiated 3T3-L1 cells. However, in adipocytes treated with rabbit meat extract, the expression of genes related to browning was reduced by the AMP-activated protein kinase (AMPK) inhibitor, dorsomorphin dihydrochloride. To the best of our knowledge, this is the first study to demonstrate that rabbit meat extract induces the browning of white adipocytes via the activation of the AMPK pathway, thereby demonstrating its therapeutic potential in preventing obesity.

Habitual nappers and non-nappers differ in circadian rhythms of LIPE expression in abdominal adipose tissue explants.

Napping is a widespread practice worldwide and has in recent years been linked to increased abdominal adiposity. Lipase E or LIPE encodes the protein hormone-sensitive lipase (HSL), an enzyme that plays an important role in lipid mobilization and exhibits a circadian expression rhythm in human adipose tissue. We hypothesized that habitual napping may impact the circadian expression pattern of LIPE, which in turn may attenuate lipid mobilization and induce abdominal fat accumulation. Abdominal adipose tissue explants from participants with obesity (n = 17) were cultured for a 24-h duration and analyzed every 4 h. Habitual nappers (n = 8) were selected to match non-nappers (n = 9) in age, sex, BMI, adiposity, and metabolic syndrome traits. Circadian LIPE expression rhythmicity was analyzed using the cosinor method. Adipose tissue explants exhibited robust circadian rhythms in LIPE expression in non-nappers. In contrast, nappers had a flattened rhythm. LIPE amplitude was decreased in nappers as compared with non-nappers (71% lower). The decrease in amplitude among nappers was related to the frequency of napping (times per week) where a lower rhythm amplitude was associated with a higher napping frequency (r = -0.80; P = 0.018). Confirmatory analyses in the activity of LIPE's protein (i.e., HSL) also showed a significant rhythm in non-nappers, whereas significance in the activity of HSL was lost among nappers. Our results suggest that nappers display dysregulated circadian LIPE expression as well as dysregulated circadian HSL activity, which may alter lipid mobilization and contribute to increased abdominal obesity in habitual nappers.

Type 2 Immunity Regulates Dermal White Adipose Tissue Function

Type 2 immune responses have been increasingly linked with tissue maintenance, regeneration, and metabolic homeostasis. The molecular basis of regulator and effector mechanisms of type 2 immunity in skin regeneration and homeostasis is still lacking. In this study, we analyzed the role of IL-4Rα signaling in the regeneration of diverse cellular compartments in the skin. Mutants with global IL-4Rα deficiency showed two major phenotypes: first, a pronounced atrophy of the interfollicular epidermis, and second, a significant increase in dermal white adipose tissue thickness in mice aged 3 weeks (postnatal day 21) compared with littermate controls. Notably, IL-4Rα deficiency decreased the activation of hormone-sensitive lipase, a rate-limiting step in lipolysis. Immunohistochemical and FACS analysis in IL-4/enhanced GFP reporter mice showed that IL-4 expression peaked on postnatal day 21 and that eosinophils are the predominant IL-4-expressing cells. Eosinophil-deficient mice recapitulated the lipolytic-defective dermal white adipose tissue phenotype of Il4ra-deficient mice, showing that eosinophils are necessary for dermal white adipose tissue lipolysis. Collectively, we provide mechanistic insights into the regulation of interfollicular epidermis and hormone-sensitive lipase-mediated lipolysis in dermal white adipose tissue in early life by IL-4Rα, and our findings show that eosinophils play a critical role in this process.

A new graphene-based nanomaterial increases lipolysis and reduces body weight gain through integrin linked kinase (ILK).

GMC is a new graphene-based CNM that was tested for biocompatibility and functionality in cultured adipocytes. MTT, TG content, lipolysis quantification, and transcriptional changes were determined. Specific INTB1 blocking antibody and ILK depletion with specific siRNA were used to study the intracellular signalling. We complemented the study using subcutaneous WAT (scWAT) explants from transgenic ILK knockdown mice (cKD-ILK). GMC was topically administrated in the dorsal area of high fat diet-induced obese rats (HFD) for 5 consecutive days. The scWAT weights and some intracellular markers were analyzed after the treatment. graphene presence was characterized in GMC. It was non-toxic and effective in reducing TG content in vitro in a dose-dependent manner. GMC rapidly phosphorylated INTB1 and increased the expression and activity of hormone sensitive lipase (HSL), the lipolysis subproduct glycerol, and the expression of glycerol and fatty acid transporters. GMC also reduced the expression of adipogenesis markers. Pro-inflammatory cytokines were unaffected. ILK was overexpressed, and INTB1 or ILK blockade avoided functional GMC effects. Topical administration of GMC in HFD rats overexpressed ILK in scWAT, and their weight gains were reduced, while systemic (renal, hepatic) toxicity parameters were unaffected. GMC is safe and effective in reducing hypertrophied scWAT weight when topically applied and it can be considered of interest in anti-obesogenic strategies. GMC increases lipolysis and reduces adipogenesis inside adipocytes by mechanisms that imply the activation of INTB1, the overexpression of ILK, and changes in the expression and activity of several markers related to fat metabolism.

Alleviating effect of mulberry leaf 1-deoxynojirimycin on resistin-induced hepatic steatosis and insulin resistance in mice.

Resistin is upregulated in obese humans and mice, and elevated serum resistin induces insulin resistance and hepatic steatosis. Previous studies have revealed that mulberry 1-deoxynojirimycin (DNJ) is important for a variety of physiological processes, especially carbohydrate and lipid metabolism. However, it remains unclear whether DNJ has a positive effect on insulin resistance and hepatic steatosis, and what the exact mechanism is. Male C57BL/6J mice were treated with resistin with or without DNJ. DNJ reversed the homeostasis model assessment of insulin resistance (HOMA-IR)-induced by resistin and significantly decreased triglyceride levels both in the serum and liver. A histological analysis demonstrated that lipid accumulation significantly decreased in the DNJ group compared to the resistin group. A mechanistic analysis showed that DNJ significantly inhibited the resistin-induced decline in enzyme activities of hormone-sensitive lipase (HSL) and hepatic lipase (HL) in serum and lipoprotein lipase (LPL) in liver. FAS and Acox13α were significantly altered by resistin but restored by DNJ. Furthermore, DNJ partially but significantly restored insulin-stimulated glucose uptake compared with the resistin group, suggesting that DNJ reversed the insulin sensitivity impaired by hyperresistinemia. Treatment of AML12 cells with DNJ significantly restored the expression level and phosphorylation of Akt. The transcriptional levels of InsR and IRS1, as well as the protein levels of InsR and Glut4 and phosphorylation of PI3K and GSK3β, were also normalized in the DNJ-treated group. In conclusion: mulberry DNJ significantly alleviated liver steatosis and insulin resistance in hyperresistinemia.

Hydrocortisone-Containing Animal-Derived Food Intake Affects Lipid Nutrients Utilization.

As the tremendous increases in consumption of animal-derived food, endogenous hydrocortisone migrating along the food chain to organism arouses extensive attention. This study aims to investigate the cumulative impacts of dietary hydrocortisone intake and mechanistic understanding on metabolism of lipid nutrients. A total of 120 porcine muscles samples with different concentrations of hydrocortisone are collected at three time points. An operational food chain simulation framework is constructed and 175 lipid molecules are identified by UHPLC-Q-Orbitrap HRMS. Compared to the control group, 66 lipid molecules are significantly different, including 17 triglycerides and 31 glycerophospholipids. Integrated analyses of lipidomics and proteomics indicate that hydrocortisone promotes adipose triglyceride lipase and hormone sensitive lipase activity to precondition for triglycerides hydrolysis. Quantitative lipidomics analysis shows the presence of hydrocortisone decreases the concentration of docosahexaenoic acid (3.66 ± 0.15-3.09 ± 0.12mgkg-1 ) and eicosapentanoic acid (0.54 ± 0.09-0.48 ± 0.06mgkg-1 ). A noteworthy increase of most saturated triglycerides concentration with the prolonging of time is observed. Hydrocortisone originating from animal-derived food induces glycerophospholipids degradation and triglycerides hydrolysis through promoting adipose triglyceride lipase, hormone sensitive lipase, and phosphoglycerate kinase activity and further intervenes lipid nutrients utilization.

Improved liver lipid catabolism and utilization in growth hormone transgenic common carp (Cyprinus carpio L.) through enhanced lipolytic and fatty acid β-oxidation pathways

Growth hormone (GH) transgenic common carp (Cyprinus carpio L.) show desirable aquaculture traits. Their specific growth rate (SGR) and feed efficiency (FE) are approximately 12% and 17% higher than the wild-type (WT) common carp, respectively. However, the mechanisms of lipid catabolism (lipolysis and fatty acid β-oxidation) and utilization in GH transgenic common carp are still unclear. In this study, we firstly compared the lipid metabolism of GH transgenic (initial weight 3.72 ± 0.32 g) and WT (initial weight 3.30 ± 0.28 g) common carp fed with a normal fat level diet (6% lipid, 33% protein) for two months, then compared the growth performance of GH transgenic (initial weight 3.65 ± 0.33 g) and WT (initial weight 3.27 ± 0.26 g) common carp fed with different fat levels diets (6% lipid and 12% lipid, 33% protein) for two months. We found that the lipid content in serum, liver and whole body was significantly reduced in GH transgenic common carp, the hepatic activities of the lipolytic enzymes hormone-sensitive lipase and adipose triglyceride lipase were enhanced, and the hepatic expression level of hormone-sensitive lipase was upregulated. In addition, the mitochondrion numbers were increased, and the expression level of carnitine palmitoyltransferase-1a and carnitine palmitoyltransferase-1b was upregulated in the liver of GH transgenic common carp. GH transgenic common carp showed higher weight gain and SGR than that in WT carp when fed with a normal-fat diet as they did when fed with a high-fat diet, and GH transgenic common carp showed higher FE than that in WT carp when fed with a high-fat diet. These results suggested that the lipid catabolism and utilization was improved in the GH transgenic common carp liver through enhanced lipolytic and fatty acid β-oxidation pathways. Our study provides new insights into improving lipid utilization in some aquaculture fish species.

Walnut Meal Extracts Rich In Polyphenols Mitigate Insulin Resistance and Modulate Gut Microbiota in High Fat Diet-Fed Rats

Walnut kernel is a traditional Chinese herb recorded in the Chinese Pharmacopoeia with the efficacies of invigorating kidney, tonifying lung, and relaxing bowel. However, the potential mechanisms were unclear. This article aims to uncover the interdict mechanisms of walnut meal extracts (WMP) on high-fat diet (HFD) induced metabolic disorders in rats and reveal how the WMP benefits are associated with changes in the intestinal flora. Sprague-Dawley (SD) rats were fed a standard chow diet or an HFD for 18 weeks. After 6 weeks, the HFD rats were supplemented with 750 mg WMP/kg body weight or the vehicle for 12 weeks. The structure of gut microbiota was assessed by analyzing 16S rDNA sequences. WMP suppressed the weight gain and visceral obesity. WMP treatment also improved lipid profiles and increased antioxidative activities. WMP fully reversed hepatic steatosis with the upregulation of adipocytokines involved in lipid catabolism (e.g., adiponectin, PPAR-γ, visfatin, CEBPα) and the increased activities of lipoprotein lipase and hormone-sensitive lipase, which were associated with glucose tolerance improvement and insulin resistance (IR) mitigation. As revealed by 16S rDNA sequencing, WMP restored the diversity of intestinal flora reduced by HFD. WMP dramatically reduced the abundance of Gram-negative bacteria, especially Fusobacterium varium and Bacteroides vulgatus, and sharply increased the abundance of Lactobacillus animalis decreased by HFD. Our findings demonstrated that WMP suppressed the weight gain and adiposity in HFD-fed rats and fully reversed HFD induced IR and hepatic steatosis while dramatically reducing the abundance of Fusobacteriaceae and Enterobacteriaceae, underscoring the gut-liver axis as a primary target of walnut polyphenols.

Sulforaphane induces lipophagy through the activation of AMPK-mTOR-ULK1 pathway signaling in adipocytes

Lipophagy, a form of selective autophagy, degrades lipid droplet (LD) in adipose tissue and the liver. The chemotherapeutic isothiocyanate sulforaphane (SFN) contributes to lipolysis through the activation of hormone-sensitive lipase and the browning of white adipocytes. However, the details concerning the regulation of lipolysis in adipocytes by SFN-mediated autophagy remain unclear. In this study, we investigated the effects of SFN on autophagy in the epididymal fat of mice fed a high-fat diet (HFD) or control-fat diet and on the molecular mechanisms of autophagy in differentiated 3T3-L1 cells. Western blotting revealed that the protein expression of lipidated LC3 (LC3-II), an autophagic substrate, was induced after 3T3-L1 adipocytes treatment with SFN. In addition, SFN increased the LC3-II protein expression in the epididymal fat of mice fed an HFD. Immunofluorescence showed that the SFN-induced LC3 expression was co-localized with LDs in 3T3-L1 adipocytes and with perilipin, the most abundant adipocyte-specific protein, in adipocytes of mice fed an HFD. Next, we confirmed that SFN activates autophagy flux in differentiated 3T3-L1 cells using the mCherry-EGFP-LC3 and GFP-LC3-RFP-LC3ΔG probe. Furthermore, we examined the induction mechanisms of autophagy by SFN in 3T3-L1 adipocytes using western blotting. ATG5 knockdown partially blocked the SFN-induced release of fatty acids from LDs in mature 3T3-L1 adipocytes. SFN time-dependently elicited the phosphorylation of AMPK, the dephosphorylation of mTOR, and the phosphorylation of ULK1 in differentiated 3T3-L1 cells. Taken together, these results suggest that SFN may provoke lipophagy through AMPK-mTOR-ULK1 pathway signaling, resulting in partial lipolysis of adipocytes.

The Fibrinogen-like Domain of ANGPTL3 Facilitates Lipolysis in 3T3-L1 Cells by Activating the Intracellular Erk Pathway.

Background: ANGPTL3 stimulates lipolysis in adipocytes, but the underlying molecular mechanism is yet unknown. The C-terminal fibrinogen-like domain of ANGPTL3 (ANGPTL3-Fld) activates the AKT pathway in endothelial cells. Hence, we evaluated whether ANGPTL3-Fld stimulates lipolysis in adipocytes through the MAPK kinase pathway. Materials and Methods: 3T3-L1 adipocytes were treated with isoproterenol (ISO), ANGPTL3-Fld, or both. Lipolysis was evaluated through the release of free fatty acids (FFAs) in the culture medium. The activation status of intracellular kinases was evaluated with and without the inhibition of the BRAF–ERK arm of the MAPK pathway. Results: ANGPTL3-Fld alone was not able to activate lipolysis, while the combination of ANGPTL3-Fld and ISO determined a 10-fold enrichment of the FFA concentration in the culture medium with an incremental effect (twofold) when compared with ISO alone. ANGPTL3-Fld alone inhibited hormone-sensitive lipase (HSL), whereas the treatment with ISO induced the activation of HSL. The net balance of ANGPTL3-Fld and ISO cotreatment resulted in HSL activation. The results indicate that ANGPTL3-Fld generated an intracellular activation signal involving the MAPK–ERK pathway, possibly through the PDGFRβ—PLCγ-AMPK axis. Conclusion: ANGPTL3-Fld appears to act as a facilitator of lipolysis in adipocytes, and this effect was driven by a signal mediated by a pathway that is different from the canonical β-adrenergic stimulus.

Hormone-sensitive lipase is localized at synapses and is necessary for normal memory functioning in mice

Hormone-sensitive lipase (HSL) is mainly present in adipose tissue where it hydrolyzes diacylglycerol. Although expression of HSL has also been reported in the brain, its presence in different cellular compartments is uncertain, and its role in regulating brain lipid metabolism remains hitherto unexplored. We hypothesized that HSL might play a role in regulating the availability of bioactive lipids necessary for neuronal function and therefore investigated whether dampening HSL activity could lead to brain dysfunction. In mice, we found HSL protein and enzymatic activity throughout the brain, localized within neurons and enriched in synapses. HSL-null mice were then analyzed using a battery of behavioral tests. Relative to wild-type littermates, HSL-null mice showed impaired short-term and long-term memory, yet preserved exploratory behaviors. Molecular analysis of the cortex and hippocampus showed increased expression of genes involved in glucose utilization in the hippocampus, but not cortex, of HSL-null mice compared with controls. Furthermore, lipidomics analyses indicated an impact of HSL deletion on the profile of bioactive lipids, including a decrease in endocannabinoids and eicosanoids that are known to modulate neuronal activity, cerebral blood flow, and inflammation processes. Accordingly, mild increases in the expression of proinflammatory cytokines in HSL mice compared with littermates were suggestive of low-grade inflammation. We conclude that HSL has a homeostatic role in maintaining pools of lipids required for normal brain function. It remains to be tested, however, whether the recruitment of HSL for the synthesis of these lipids occurs during increased neuronal activity or whether HSL participates in neuroinflammatory responses.

Hormone-sensitive lipase protects adipose triglyceride lipase-deficient mice from lethal lipotoxic cardiomyopathy

Lipid droplets (LDs) are multifunctional organelles that regulate energy storage and cellular homeostasis. The first step of triacylglycerol hydrolysis in LDs is catalyzed by adipose triglyceride lipase (ATGL), deficiency of which results in lethal cardiac steatosis. Although hormone-sensitive lipase (HSL) functions as a diacylglycerol lipase in the heart, we hypothesized that activation of HSL might compensate for ATGL deficiency. To test this hypothesis, we crossed ATGL-KO (AKO) mice and cardiac-specific HSL-overexpressing mice (cHSL) to establish homozygous AKO mice and AKO mice with cardiac-specific HSL overexpression (AKO+cHSL). We found that cardiac triacylglycerol content was 160-fold higher in AKO relative to Wt mice, whereas that of AKO+cHSL mice was comparable to the latter. In addition, AKO cardiac tissues exhibited reduced mRNA expression of PPARα-regulated genes and upregulation of genes involved in inflammation, fibrosis, and cardiac stress. In contrast, AKO+cHSL cardiac tissues exhibited expression levels similar to those observed in Wt mice. AKO cardiac tissues also exhibited macrophage infiltration, apoptosis, interstitial fibrosis, impaired systolic function, and marked increases in ceramide and diacylglycerol contents, whereas no such pathological alterations were observed in AKO+cHSL tissues. Furthermore, electron microscopy revealed considerable LDs, damaged mitochondria, and disrupted intercalated discs in AKO cardiomyocytes, none of which were noted in AKO+cHSL cardiomyocytes. Importantly, the life span of AKO+cHSL mice was comparable to that of Wt mice. HSL overexpression normalizes lipotoxic cardiomyopathy in AKO mice and the findings highlight the applicability of cardiac HSL activation as a therapeutic strategy for ATGL deficiency-associated lipotoxic cardiomyopathies.

Effects of Different Supplemental Levels of Eucommia ulmoides Leaf Extract in the Diet on Carcass Traits and Lipid Metabolism in Growing-Finishing Pigs.

This study examined the effects of dietary Eucommia ulmoides leaf extract (ELE) supplements on carcass traits and lipid metabolism in growing–finishing pigs. A total of 144 crossbred (Duroc × Landrace × Yorkshire) piglets with an average initial weight of 10.11 ± 0.03 kg were randomly allotted to four treatment groups, each with six replicates and six piglets per replicate. Each group of pigs was fed a basal diet or a diet supplemented with increasing levels of ELE (0.1, 0.2, or 0.3%). The results showed that adding ELE had no negative effect on the growth performance of pigs. Dietary supplements of 0.1% ELE significantly increased carcass weight (p < 0.01), dressing percentage (p < 0.01), carcass length (p < 0.05), and eye muscle area (p < 0.05). Compared with the control group, a 0.2% ELE supplement significantly increased (p < 0.01) the levels of adiponectin, insulin-like growth factor 1, and hormone-sensitive lipase and lipoprotein lipase activity in the serum. Histological examination showed that ELE inhibited fat deposition in the backfat tissue. Lipid metabolism-related biochemical indices and mRNA expression levels were improved after supplementing diets with ELE. Moreover, all three levels of ELE dramatically upregulated (p < 0.05) the protein levels of p-AMPK-α and p-ACC. In summary, adding ELE to pig diets could improve the carcass traits of growing–finishing pigs and exert a lipid-lowering effect by activating the AMPK-ACC pathway and regulating mRNA expression levels related to lipid metabolism. Supplementing the diet with 0.1–0.2% ELE is the optimal range to reduce fat deposition in pig backfat tissue.

DECR1 directly activates HSL to promote lipolysis in cervical cancer cells

Fatty acids have a high turnover rate in cancer cells to supply energy for tumor growth and proliferation. Lipolysis is particularly important for the regulation of fatty acid homeostasis and in the maintenance of cancer cells. In the current study, we explored how 2,4-Dienoyl-CoA reductase (DECR1), a short-chain dehydrogenase/reductase associated with mitochondrial and cytoplasmic compartments, promotes cancer cell growth. We report that DECR1 overexpression significantly reduced the triglyceride (TAG) content in HeLa cells; conversely, DECR1 silencing increased intracellular TAG content. Subsequently, our experiments demonstrate that DECR1 promotes lipolysis via effects on hormone sensitive lipase (HSL). The direct interaction of DECR1 with HSL increases HSL phosphorylation and activity, facilitating the translocation of HSL to lipid droplets. The ensuing enhancement of lipolysis thus increases the release of free fatty acids. Downstream effects include the promotion of cervical cancer cell migration and growth, associated with the enhanced levels of p62 protein. In summary, high levels of DECR1 serves to enhance lipolysis and the release of fatty acid energy stores to support cervical cancer cell growth.