ABSTRACT
BACKGROUND: This study aimed to elucidate the molecular mechanism through which C1q/tumor necrosis factor (TNF)-related protein 9 (CTRP9) acts in the formation and differentiation of brown adipose tissue (BAT). METHODS: Adenovirus particles encoding CTRP9 and green fluorescent protein were inoculated into the scapula of C57BL/6J mice and fed a high-fat diet for 8 weeks; the body weight, lipid droplet morphology, glucose tolerance, insulin tolerance, and protein expression levels were analyzed. In addition, CTRP9 adenovirus was transfected into brown preadipocytes, and differentiation was induced to identify the effect of CTRP9 overexpression on adipocyte differentiation. RESULTS: CTRP9 overexpression significantly increased the weight gain of mice. Additionally, the CTRP9 overexpression group exhibited significantly increased adipose tissue weight and glucose clearance rates and decreased insulin sensitivity and serum triglyceride levels compared to the control group. Furthermore, CTRP9 overexpression significantly upregulated the adipose triglyceride lipase (ATGL) and perilipin 1 protein expression levels in BAT. The cell experiment results confirmed that CTRP9 overexpression significantly inhibited the adipogenesis of brown adipocytes as evidenced by the downregulation of uncoupling protein 1, beta-3 adrenergic receptor, ATGL, and hormone-sensitive lipase mRNA levels and the significant suppression of uncoupling protein 1, ATGL, and perilipin 1 protein levels in brown adipocytes. CONCLUSIONS: The finding of this study demonstrated that CTRP9 promotes lipolysis by upregulating ATGL expression in vivo and inhibits the differentiation of brown preadipocytes in vitro.
Subject(s)
Adiponectin , Adipose Tissue, Brown , Diet, High-Fat , Glycoproteins , Lipolysis , Animals , Male , Mice , Acyltransferases , Adipogenesis , Adiponectin/metabolism , Adiponectin/genetics , Adipose Tissue, Brown/metabolism , Cell Differentiation , Diet, High-Fat/adverse effects , Glycoproteins/metabolism , Insulin Resistance , Lipase/metabolism , Lipase/genetics , Mice, Inbred C57BL , Perilipin-1/metabolism , Perilipin-1/geneticsABSTRACT
BACKGROUND: Pathogenic variants in PLIN1-encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1-related FPL. METHODS: We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1-mutated FPL and 3 controls. RESULTS: Patients with PLIN1-mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P=0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P<0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P=0.006). Compared with controls, patients with PLIN1-related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P=0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P=0.005). VLDL-apoB100 production was not different between patients with PLIN1-related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1-related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 (P=0.031) and IDL-apoB100 (P=0.031). Plasma LPL mass was significantly lower in patients with PLIN1-related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P<0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass. CONCLUSIONS: We show that hypertriglyceridemia associated with PLIN1-related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass.
Subject(s)
Diabetes Mellitus, Type 2 , Hypertriglyceridemia , Insulin Resistance , Lipodystrophy, Familial Partial , Lipoprotein Lipase , Lipoproteins , Perilipin-1 , Triglycerides , Humans , Male , Perilipin-1/genetics , Perilipin-1/metabolism , Perilipin-1/blood , Triglycerides/blood , Hypertriglyceridemia/blood , Hypertriglyceridemia/genetics , Female , Adult , Middle Aged , Case-Control Studies , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/complications , Lipoproteins/blood , Lipoprotein Lipase/blood , Lipoprotein Lipase/metabolism , Lipoprotein Lipase/genetics , Lipodystrophy, Familial Partial/genetics , Lipodystrophy, Familial Partial/blood , Lipodystrophy, Familial Partial/metabolism , Mutation , Blood Glucose/metabolism , Lipoproteins, VLDL/blood , Lipoproteins, VLDL/metabolism , Biomarkers/blood , Phenotype , Genetic Predisposition to Disease , Lipolysis , RNA, Messenger/metabolism , RNA, Messenger/geneticsABSTRACT
Lipid droplets (LD) are highly dynamic organelles specialized for the regulation of energy storage and cellular homeostasis. LD consist of a neutral lipid core surrounded by a phospholipid monolayer membrane with embedded proteins, most of which are involved in lipid homeostasis. In this study, we focused on one of the major LD proteins, sterol C24-methyltransferase, encoded by ERG6. We found that the absence of Erg6p resulted in an increased accumulation of yeast perilipin Pet10p in LD, while the disruption of PET10 was accompanied by Erg6p LD over-accumulation. An observed reciprocal enrichment of Erg6p and Pet10p in pet10Δ and erg6Δ mutants in LD, respectively, was related to specific functional changes in the LD and was not due to regulation on the expression level. The involvement of Pet10p in neutral lipid homeostasis was observed in experiments that focused on the dynamics of neutral lipid mobilization as time-dependent changes in the triacylglycerols (TAG) and steryl esters (SE) content. We found that the kinetics of SE hydrolysis was reduced in erg6Δ cells and the mobilization of SE was completely lost in mutants that lacked both Erg6p and Pet10p. In addition, we observed that decreased levels of SE in erg6Δpet10Δ was linked to an overexpression of steryl ester hydrolase Yeh1p. Lipid analysis of erg6Δpet10Δ showed that PET10 deletion altered the composition of ergosterol intermediates which had accumulated in erg6Δ. In conclusion, yeast perilipin Pet10p functionally interacts with Erg6p during the metabolism of ergosterol.
Subject(s)
Ergosterol , Saccharomyces cerevisiae Proteins , Saccharomyces cerevisiae , Ergosterol/metabolism , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae Proteins/genetics , Perilipin-1/metabolism , Perilipin-1/genetics , Lipid Droplets/metabolism , Methyltransferases/metabolism , Methyltransferases/genetics , Lipid Metabolism/genetics , Triglycerides/metabolismABSTRACT
Lipid droplets (LDs) are dynamic organelles that participate in the regulation of lipid metabolism and cellular homeostasis inside of cells. LD-associated proteins, also known as perilipins (PLINs), are a family of proteins found on the surface of LDs that regulate lipid metabolism, immunity, and other functions. In silkworms, pébrine disease caused by infection by the microsporidian Nosema bombycis (Nb) is a severe threat to the sericultural industry. Although we found that Nb relies on lipids from silkworms to facilitate its proliferation, the relationship between PLINs and Nb proliferation remains unknown. Here, we found Nb infection caused the accumulation of LDs in the fat bodies of silkworm larvae. The characterized perilipin1 gene (plin1) promotes the accumulation of intracellular LDs and is involved in Nb proliferation. plin1 is similar to perilipin1 in humans and is conserved in all insects. The expression of plin1 was mostly enriched in the fat body rather than in other tissues. Knockdown of plin1 enhanced Nb proliferation, whereas overexpression of plin1 inhibited its proliferation. Furthermore, we confirmed that plin1 increased the expression of the Domeless and Hop in the JAK-STAT immune pathway and inhibited Nb proliferation. Taken together, our current findings demonstrate that plin1 inhibits Nb proliferation by promoting the JAK-STAT pathway through increased expression of Domeless and Hop. This study provides new insights into the complicated connections among microsporidia pathogens, LD surface proteins, and insect immunity.IMPORTANCELipid droplets (LDs) are lipid storage sites in cells and are present in almost all animals. Many studies have found that LDs may play a role in host resistance to pathogens and are closely related to innate immunity. The present study found that a surface protein of insect lipid droplets could not only regulate the morphological changes of lipid droplets but also inhibit the proliferation of a microsporidian pathogen Nosema bombycis (Nb) by activating the JAK-STAT signaling pathway. This is the first discovery of the relationship between microsporidian pathogen and insect lipid surface protein perilipin and insect immunity.
Subject(s)
Bombyx , Insect Proteins , Janus Kinases , Lipid Droplets , Nosema , Perilipin-1 , Signal Transduction , Bombyx/microbiology , Bombyx/metabolism , Bombyx/genetics , Animals , Nosema/metabolism , Nosema/genetics , Insect Proteins/metabolism , Insect Proteins/genetics , Lipid Droplets/metabolism , Janus Kinases/metabolism , Janus Kinases/genetics , Perilipin-1/metabolism , Perilipin-1/genetics , STAT Transcription Factors/metabolism , STAT Transcription Factors/genetics , Fat Body/metabolism , Larva/microbiology , Larva/metabolism , Lipid MetabolismABSTRACT
Adipose tissue stores triacylglycerol (TAG) in lipid droplets (LD) and release fatty acids upon lipolysis during energy shortage. We identify ApoL6 as a LD-associated protein mainly found in adipose tissue, specifically in adipocytes. ApoL6 expression is low during fasting but induced upon feeding. ApoL6 knockdown results in smaller LD with lower TAG content in adipocytes, while ApoL6 overexpression causes larger LD with higher TAG content. We show that the ApoL6 affects adipocytes through inhibition of lipolysis. While ApoL6, Perilipin 1 (Plin1), and HSL can form a complex on LD, C-terminal ApoL6 directly interacts with N-terminal Plin1 to prevent Plin1 binding to HSL, to inhibit lipolysis. Thus, ApoL6 ablation decreases white adipose tissue mass, protecting mice from diet-induced obesity, while ApoL6 overexpression in adipose brings obesity and insulin resistance, making ApoL6 a potential future target against obesity and diabetes.
Subject(s)
Lipid Droplets , Lipolysis , Animals , Mice , Lipid Droplets/metabolism , Adipose Tissue/metabolism , Adipocytes/metabolism , Obesity/genetics , Obesity/metabolism , Perilipin-1/genetics , Perilipin-1/metabolismABSTRACT
The function of perilipin 1 in human metabolism was recently highlighted by the description of PLIN1 variants associated with various pathologies. These include severe familial partial lipodystrophy and early onset acute coronary syndrome. Additionally, certain variants have been reported to have a protective effect on cardiovascular diseases. The role of this protein remains controversial in mice and variant interpretation in humans is still conflicting. This literature review has two primary objectives (i) to clarify the function of the PLIN1 gene in lipid metabolism and atherosclerosis by examining functional studies performed in cells (adipocytes) and mice and (ii) to understand the impact of PLIN1 variants identified in humans based on the variant's location within the protein and the type of variant (missense or frameshift). To achieve these objectives, we conducted an extensive analysis of the relevant literature on perilipin 1, its function in cellular models and mice, and the consequences of its mutations in humans. We also utilized bioinformatics tools and consulted the Human Genetics Cardiovascular Disease Knowledge Portal to enhance the pathogenicity assessment of PLIN1 missense variants.
Subject(s)
Atherosclerosis , Lipodystrophy, Familial Partial , Animals , Humans , Mice , Atherosclerosis/genetics , Lipid Metabolism/genetics , Lipodystrophy, Familial Partial/genetics , Mutation , Perilipin-1/genetics , Perilipin-1/metabolism , Perilipin-2/genetics , Perilipin-2/metabolism , Phosphoproteins/genetics , Phosphoproteins/metabolismABSTRACT
Perilipins are abundant lipid droplet (LD) proteins present in all metazoans and also in Amoebozoa and fungi. Humans express five perilipins, which share a similar domain organization: an amino-terminal PAT domain and an 11-mer repeat region, which can fold into amphipathic helices that interact with LDs, followed by a structured carboxy-terminal domain. Variations of this organization that arose during vertebrate evolution allow for functional specialization between perilipins in relation to the metabolic needs of different tissues. We discuss how different features of perilipins influence their interaction with LDs and their cellular targeting. PLIN1 and PLIN5 play a direct role in lipolysis by regulating the recruitment of lipases to LDs and LD interaction with mitochondria. Other perilipins, particularly PLIN2, appear to protect LDs from lipolysis, but the molecular mechanism is not clear. PLIN4 stands out with its long repetitive region, whereas PLIN3 is most widely expressed and is used as a nascent LD marker. Finally, we discuss the genetic variability in perilipins in connection with metabolic disease, prominent for PLIN1 and PLIN4, underlying the importance of understanding the molecular function of perilipins.
Subject(s)
Lipid Droplets , Perilipins , Humans , Lipid Droplets/metabolism , Animals , Perilipins/metabolism , Perilipins/genetics , Lipid Metabolism , Lipolysis , Perilipin-1/metabolism , Perilipin-1/geneticsABSTRACT
OBJECTIVE: The PERILIPIN1 (PLIN1) gene encodes an adipocyte-associated protein that modulates weight. The objective was to evaluate the role of the rs2289487 genetic variant of the PLIN1 gene on weight loss and glucose metabolism secondary to a partial meal replacement (pMR) hypocaloric diet. PATIENTS AND METHODS: We conducted an interventional study in 111 postmenopausal obese females with body mass index (BMI) > 35 kg/m2. The subjects received two intakes per day of a normocaloric hyperproteic formula for 12 weeks. RESULTS: After the pMR diet, body weight, (BMI), fat mass, waist circumference, fasting insulin levels and HOMA-IR decreased in both genotype groups. The improvements in these parameters were higher in C allele carriers than in subjects with TT genotype. The percentage of patients who achieved 7.5% weight loss was higher in the C carriers (57.4% vs. 27.6%), (adjusted Odds Ratio 2.14, 95% CI = 1.33-9.40; p = 0.02). The decrease in the percentage of diabetes mellitus or impaired fasting glucose decrease was statistically significant in C allele carriers (30.2% vs. 18.9%; p = 0.01) (OR 0.54, 95% CI = 0.22-0.78; p = 0.02). CONCLUSIONS: The C allele of rs2289487 predicts the magnitude of weight loss resulting from a pMR diet. These adiposity improvements produce a better improvement in insulin resistance and the percentage of impaired glucose metabolism.
Subject(s)
Insulin Resistance , Obesity , Female , Humans , Diet, Reducing/methods , Glucose , Insulin Resistance/genetics , Obesity/metabolism , Perilipin-1/genetics , Polymorphism, Single Nucleotide , Postmenopause , Weight Loss/geneticsABSTRACT
Body size is an important biological phenotypic trait that has attracted substantial attention. Small domestic pigs can serve as excellent animal models for biomedicine and also help meet sacrificial culture needs in human societies. Although the mechanisms underlying vertebral development regulating body size variation in domestic pigs during the embryonic period have been well described, few studies have examined the genetic basis of body size variation in post embryonic developmental stages. In this study, seven candidate genes-PLIN1, LIPE, PNPLA1, SCD, FABP5, KRT10 and IVL-significantly associated with body size were identified in Min pigs, on the basis of weighted gene co-expression network analysis (WGCNA), and most of their functions were found to be associated with lipid deposition. Six candidate genes except for IVL were found to have been subjected to purifying selection. PLIN1 had the lowest ω value (0.139) and showed heterogeneous selective pressure among domestic pig lineages with different body sizes (p < 0.05). These results suggested that PLIN1 is an important genetic factor regulating lipid deposition and consequently affecting body size variation in pigs. The culture of whole pig sacrifice in Manchu during the Qing Dynasty in China might have contributed to the strong artificial domestication and selection of Hebao pigs.
Subject(s)
Body Size , Perilipin-1 , Selection, Genetic , Swine, Miniature , Transcriptome , Animals , Humans , Acyltransferases/genetics , Perilipin-1/genetics , Perilipin-1/physiology , Phospholipases , Body Size/genetics , Lipid Metabolism/genetics , Swine, Miniature/genetics , Swine, Miniature/growth & developmentABSTRACT
AIM: Perilipins (PLINs), peripheral lipid droplet (LD) proteins, play important roles in lipid accumulation and maturation in adipocytes. The relationship between PLIN family proteins and macrophage polarization in atherosclerosis has not been elucidated. METHODS: The experiments used tissues from human arteries of 65 patients who had undergone a carotid endarterectomy, and cultured macrophages generated from healthy human peripheral blood mononuclear cells. RESULTS: Plaque immunohistochemistry demonstrated co-expression of PLIN1 and PLIN2 in both symptomatic (n=31) and asymptomatic patients (n=34). PLIN2 mRNA expression increased 3.38-fold in the symptomatic group compared with those from asymptomatic. PLIN1 was not expressed on small LDs at a shorter incubation but was on large LDs at longer incubation with oxidized LDL and VLDL, while PLIN2 was observed after 24 h and increased with a longer incubation in cultured M1 macrophage. In M2 macrophages, PLIN1 was seen as early as 24 h following incubation with VLDL, and LD size increased with longer incubation. PLIN1 overexpression increased the size of LDs in M1 macrophages, even after a short incubation, and reduced the RNA expression of TNFA, MMP2, ABCA1, and ABCG1 versus the M1 control. Conversely, silencing of PLIN1 in M2 macrophages had the opposite effects on LD size and RNA expression. CONCLUSION: There was a relationship between macrophage polarity, cytosolic LD size, and PLIN1/PLIN2 expression levels. PLIN2 was mainly expressed in arterial plaques in symptomatic stroke patients, and associated with the inflammatory phenotype of human macrophages, while PLIN1 expression is closely associated with plaque stability and the anti-inflammatory phenotype.
Subject(s)
Plaque, Atherosclerotic , Humans , Plaque, Atherosclerotic/metabolism , Lipid Droplets/metabolism , Leukocytes, Mononuclear/metabolism , Macrophages/metabolism , Perilipin-2/genetics , Perilipin-2/metabolism , Lipids , RNA/metabolism , Perilipin-1/genetics , Perilipin-1/metabolismABSTRACT
Variations in the perilipin (PLIN) gene have been suggested to be associated with obesity and its related alterations, but a different nutritional status seems to contribute to differences in these associations. In our study, we examined the association of several polymorphisms at the PLIN locus with obesity and lipid profile in children, and then analyzed the mediation of plasma leptin levels on these associations. The single-nucleotide polymorphisms (SNPs) rs894160, rs1052700, and rs2304795 in PLIN1, and rs35568725 in PLIN2, were analyzed by RT-PCR in 1264 children aged 6-8 years. Our results showed a contrasting association of PLIN1 rs1052700 with apolipoprotein (Apo) A-I levels in boys and girls, with genotype TT carriers showing significantly higher Apo A-I levels in boys and significantly lower Apo A-I levels in girls. Significant associations of the SNP PLIN2 rs35568725 with high-density lipoprotein cholesterol (HDL-cholesterol), Apo A-I, and non-esterified fatty acids (NEFA) were observed in boys but not in girls. The associations of the SNPs studied with body mass index (BMI), NEFA, and Apo A-I in boys and girls were different depending on leptin concentration. In conclusion, we describe the mediation of plasma leptin levels in the association of SNPs in PLIN1 and PLIN2 with BMI, Apo A-I, and NEFA. Different leptin levels by sex may contribute to explain the sex-dependent association of the PLIN SNPs with these variables.
Subject(s)
Apolipoprotein A-I , Body Mass Index , Leptin , Perilipin-1 , Perilipin-2 , Apolipoprotein A-I/blood , Child , Cholesterol, HDL/blood , Fatty Acids, Nonesterified/blood , Female , Humans , Leptin/blood , Male , Pediatric Obesity/genetics , Perilipin-1/genetics , Perilipin-2/genetics , Polymorphism, Single Nucleotide , Sex FactorsABSTRACT
Type 2 diabetes mellitus (T2DM) is a multifactorial disease with a high global incidence. Hypertriglyceridemia is a major risk factor for both cardiovascular disease and T2DM. In this study, we determined the allele and genotype frequencies of apolipoprotein A5 (APOA5) single nucleotide polymorphism (SNP) rs662799 and perilipin 1 (PLIN1) SNPs rs894160, rs6496589, and rs1052700 and evaluated their association with T2DM risk in western Saudis. Only rs6496589 was found to be significantly associated with T2DM risk. We determined the risk allele for each SNP based on relative risk, and found that the G allele of rs662799, T allele of rs894160, G allele of r6496589, and T allele of rs1052700 correlated with T2DM risk. The effect of each SNP on T2DM risk and five of its clinical phenotypes was explored using multiple logistic regression. We found significant correlations between the C/G and G/G genotypes of rs6496589 and T2DM risk in the unadjusted model, whereas G/G was the only genotype that correlated with the risk of T2DM in the adjusted model. There was no significant correlation between rs662799, rs894160, and rs1052700 genotypes and T2DM risk. In conclusion, we have identified novel risk alleles and genotypes that contribute to genetic risk for T2DM in the western Saudi population.
Subject(s)
Diabetes Mellitus, Type 2 , Apolipoprotein A-V/genetics , Case-Control Studies , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Genetic Predisposition to Disease , Humans , Perilipin-1/genetics , Saudi Arabia/epidemiologyABSTRACT
BACKGROUND: Perilipin 1 (PLIN1) is a lipid droplet scaffolding protein that plays a regulatory role in fat decomposition and mitochondrial function. OBJECTIVE: In this study, the effects of PLIN1 gene knockout (PLIN1-KO) and PLIN1 gene overexpression (PLIN1-EX) on cell metabolism and mitochondrial function in porcine skeletal muscle satellite cells were assessed. METHODS: Porcine skeletal muscle satellite cells were used as the control group (NC). The expression of mitochondrial function-related proteins was detected by western blot. Apoptosis, cell cycle, mitochondrial function-related indices, mitochondrial structure, and morphology were measured by flow cytometry. RESULTS: Our results demonstrated that stable expression of the PLIN1 gene in skeletal muscle satellite cells is critical to maintaining cell metabolism and mitochondrial function. After knockout and overexpression of the PLIN1 gene, the anti-apoptotic ability of cells was enhanced, and the metabolic activity of the cells was accelerated, but at the cost of mitochondrial structural damage, reduction in the number of mitochondria, and decreased mitochondrial function. CONCLUSION: This study explored the effect of the PLIN1 gene on the mitochondria and metabolism of porcine skeletal muscle satellite cells and provided a theoretical basis for the subsequent study of the effects of PLIN1 on muscle tissue development and meat quality.
Subject(s)
Satellite Cells, Skeletal Muscle , Animals , Swine , Perilipin-1/genetics , Mitochondria/genetics , Lipid Metabolism , ProteinsABSTRACT
CONTEXT: PLIN1 encodes perilipin-1, which coats lipid droplets in adipocytes and is involved in droplet formation, triglyceride storage, and lipolysis. Rare PLIN1 frameshift variants that extend the translated protein have been described to cause lipodystrophy. OBJECTIVE: This work aimed to test whether PLIN1 protein-truncating variants (PTVs) cause lipodystrophy in a large population-based cohort. METHODS: We identified individuals with PLIN1 PTVs in individuals with exome data in the UK Biobank. We performed gene-burden testing for individuals with PLIN1 PTVs. We replicated the associations using data from the T2D Knowledge portal. We performed a phenome-wide association study using publicly available association statistics. A total of 362 791 individuals in the UK Biobank, a population-based cohort, and 43 125 individuals in the T2D Knowledge portal, a type 2 diabetes (T2D) case-control study, were included in the analyses. Main outcome measures included 22 diseases and traits relevant to lipodystrophy. RESULTS: The 735 individuals with PLIN1 PTVs had a favorable metabolic profile. These individuals had increased high-density lipoprotein cholesterol (0.12 mmol/L; 95% CI, 0.09 to 0.14, Pâ =â 2â ×â 10-18), reduced triglycerides (-0.22 mmol/L; 95% CI, -0.29 to -0.14, Pâ =â 3â ×â 10-11), reduced waist-to-hip ratio (-0.02; 95% CI, -0.02 to -0.01, Pâ =â 9â ×â 10-12), and reduced systolic blood pressure (-1.67 mm Hg; 95% CI, -3.25 to -0.09, Pâ =â .05). These associations were consistent in the smaller T2D Knowledge portal cohort. In the UK Biobank, PLIN1 PTVs were associated with reduced risk of myocardial infarction (odds ratio [OR]â =â 0.59; 95% CI, 0.35 to 0.93, Pâ =â .02) and hypertension (ORâ =â 0.85; 95% CI, 0.73 to 0.98, Pâ =â .03), but not T2D (ORâ =â 0.99; 95% CI, 0.63-1.51, Pâ =â .99). CONCLUSION: Our study suggests that PLIN1 haploinsufficiency causes a favorable metabolic profile and may protect against cardiovascular disease.
Subject(s)
Diabetes Mellitus, Type 2 , Lipodystrophy , Case-Control Studies , Diabetes Mellitus, Type 2/genetics , Haploinsufficiency , Humans , Metabolome , Perilipin-1/geneticsABSTRACT
Aquaporins play a crucial role in water homeostasis in the human body, and recently the physiological importance of aquaporins as glycerol channels have been demonstrated. The aquaglyceroporins (AQP3, AQP7, AQP9 and AQP10) represent key glycerol channels, enabling glycerol flux across the membranes of cells. Adipocytes are the major source of glycerol and during lipolysis, glycerol is released to be metabolized by other tissues through a well-orchestrated process. Here we show that both AQP3 and AQP7 bind to the lipid droplet protein perilipin 1 (PLIN1), suggesting that PLIN1 is involved in the coordination of the subcellular translocation of aquaglyceroporins in human adipocytes. Moreover, in addition to aquaglyceroporins, we discovered by transcriptome sequencing that AQP1 is expressed in human primary adipocytes. AQP1 is mainly a water channel and thus is thought to be involved in the response to hyper-osmotic stress by efflux of water during hyperglycemia. Thus, this data suggests a contribution of both orthodox aquaporin and aquaglyceroporin in human adipocytes to maintain the homeostasis of glycerol and water during fasting and feeding.
Subject(s)
Aquaporin 1/genetics , Aquaporin 3/genetics , Aquaporins/genetics , Hyperglycemia/genetics , Perilipin-1/genetics , Adipocytes/metabolism , Aquaglyceroporins/genetics , Aquaglyceroporins/metabolism , Aquaporin 3/metabolism , Aquaporins/metabolism , Gene Expression Regulation/genetics , Glycerol/metabolism , Homeostasis/genetics , Humans , Hyperglycemia/metabolism , Hyperglycemia/pathology , Transcriptome/genetics , Water/metabolismABSTRACT
An excessive fat diet induces intramuscular fat deposition that accumulates as a form of lipid droplet (LD) and leads to lipotoxicity, including muscle atrophy or decreasing muscle strength. Lipotoxicity depends on the number of LDs, subcellular distribution (intermyofibrillar, IMF, LDs or subsarcolemmal, SS), and fiber type-specific differences (type I or type II fiber) as well as the size of LD. Ecklonia cava extracts (ECE), which is known to increase peroxisome proliferator-activated receptor alpha (PPAR-α), which leads to decreasing expression level of perilipin2 (PLIN2). PLIN2 is involved in modulating the size of LDs. This study shows that ECE and dieckol could decrease PLIN2 expression and decrease the size and number of LDs in the muscle of high-fat diet (HF)-fed animals and lead to attenuating muscle atrophy. Expression level of PPAR-α was decreased, and PLIN2 was increased by HF. ECE and dieckol increased PPAR-α expression and decreased PLIN2. The diameter of LDs was increased in high-fat diet condition, and it was decreased by ECE or dieckol treatment. The number of LDs in type II fibers/total LDs was increased by HF and it was decreased by ECE or dieckol. The SS LDs were increased, and IMF LDs were decreased by HF. ECE or dieckol decreased SS LDs and increased IMF LDs. The ECE or dieckol attenuated the upregulation of muscle atrophy-related genes including Murf1, Atrogin-1, and p53 by HF. ECE or dieckol increased the cross-sectional area of the muscle fibers and grip strength, which were decreased by HF. In conclusion, ECE or dieckol decreased the size of LDs and modulated the contribution of LDs to less toxic ones by decreasing PLIN2 expression and thus attenuated muscle atrophy and strength, which were induced by HF.
Subject(s)
Benzofurans/pharmacology , Diet, High-Fat/adverse effects , Lipid Droplets/metabolism , Muscle, Skeletal/physiology , Muscular Atrophy/chemically induced , Animals , Dietary Fats , Gene Expression Regulation/drug effects , Lipid Metabolism , Male , Mice , Mice, Inbred C57BL , Muscle Strength , PPAR alpha , Perilipin-1/genetics , Perilipin-1/metabolism , Phaeophyceae/chemistryABSTRACT
Lipid droplets (LDs), the highly dynamic intracellular organelles, are critical for lipid metabolism. Dynamic alterations in the configurations and functions of LDs during innate immune responses to bacterial infections and the underlying mechanisms, however, remain largely unknown. In this study, we trace the time-course morphology of LDs in fat bodies of Drosophila after transient bacterial infection. Detailed analysis shows that perilipin1 (plin1), a core gene involved in the regulation of LDs, is suppressed by the immune deficiency signaling, one major innate immune pathway in Drosophila During immune activation, downregulated plin1 promotes the enlargement of LDs, which in turn alleviates immune reaction-associated reactive oxygen species stress. Thus, the growth of LDs is likely an active adaptation to maintain redox homeostasis in response to immune deficiency activation. Therefore, our study provides evidence that plin1 serves as a modulator on LDs' reconfiguration in regulating infection-induced pathogenesis, and plin1 might be a potential therapeutic target for coordinating inflammation resolution and lipid metabolism.
Subject(s)
Drosophila Proteins/metabolism , Drosophila/immunology , Escherichia coli Infections/immunology , Escherichia coli/physiology , Lipid Droplets/metabolism , Perilipin-1/metabolism , Salmonella Infections/immunology , Salmonella typhimurium/physiology , Animals , Drosophila Proteins/genetics , Immunity, Innate , Inflammation , Oxidation-Reduction , Perilipin-1/genetics , Reactive Oxygen Species/metabolismABSTRACT
Amber-the fossilized resin of trees-is rich in terpenoids and rosin acids. The physiological effects, such as antipyretic, sedative, and anti-inflammatory, were used in traditional medicine. This study aims to clarify the physiological effects of amber extract on lipid metabolism in mouse 3T3-L1 cells. Mature adipocytes are used to evaluate the effect of amber extract on lipolysis by measuring the triglyceride content, glucose uptake, glycerol release, and lipolysis-related gene expression. Our results show that the amount of triacylglycerol, which is stored in lipid droplets in mature adipocytes, decreases following 96 h of treatment with different concentrations of amber extract. Amber extract treatment also decreases glucose uptake and increases the release of glycerol from the cells. Moreover, amber extract increases the expression of lipolysis-related genes encoding perilipin and hormone-sensitive lipase (HSL) and promotes the activity of HSL (by increasing HSL phosphorylation). Amber extract treatment also regulates the expression of other adipocytokines in mature adipocytes, such as adiponectin and leptin. Overall, our results indicate that amber extract increases the expression of lipolysis-related genes to induce lipolysis in 3T3-L1 cells, highlighting its potential for treating various obesity-related diseases.
Subject(s)
Adipocytes/drug effects , Amber/pharmacology , Complex Mixtures/pharmacology , Gene Expression Regulation/drug effects , Hypolipidemic Agents/pharmacology , Lipolysis/drug effects , 3T3-L1 Cells , Adipocytes/cytology , Adipocytes/metabolism , Adiponectin/genetics , Adiponectin/metabolism , Amber/chemistry , Animals , Cell Differentiation , Complex Mixtures/chemistry , Ethanol/chemistry , Glucose/metabolism , Glycerol/metabolism , Hypolipidemic Agents/chemistry , Leptin/genetics , Leptin/metabolism , Lipid Droplets/chemistry , Lipid Droplets/drug effects , Lipid Droplets/metabolism , Mice , Perilipin-1/genetics , Perilipin-1/metabolism , Phosphorylation/drug effects , Sterol Esterase/genetics , Sterol Esterase/metabolism , Triglycerides/metabolismABSTRACT
The role of post-therapeutic support after weight loss in obesity treatment is not fully understood. Therefore, weight maintenance after a successful weight loss intervention is not very common, especially in obese individuals. This randomized controlled study was conducted to explore the efficacy of following dietary and psychological support in a group of 36 obese individuals. Participants (22 women, 14 men aged 35.58 ± 9.85 years, BMI 35.04 ± 3.80 kg/m2) who completed a 12-month weight loss phase (balanced energy-restricted diet) were randomly allocated to receive 18-month support (SG) or no additional care (CG). The support phase included some elements of Ten Top Tips (TTT), cognitive behavioral therapy (CBT), motivational interviewing (MI) in combination with nutritional education and assessment of the level of physical activity. The primary outcome was the maintenance of anthropometric parameters at an 18-month follow-up. The secondary outcomes included evaluation of biochemical parameters and single nucleotide polymorphisms (SNPs) in genes connected with obesity. A comparison of SG vs. CG after a 30-month period of the study revealed significant differences in weight changes (-3.83 ± 6.09 vs. 2.48 ± 6.24 kg), Body Mass Index (-1.27 ± 2.02 vs. 0.72 ± 2.12 kg/m2), visceral adipose tissue (-0.58 ± 0.63 vs. 0.45 ± 0.74 L), and waist circumference (-4.83 ± 4.05 vs. 1.83 ± 5.97 cm). Analysis of SNPs (rs9939609 FTO, rs987237 TFAP2B, and rs894160 PLIN1) provided further insight into the potential modulating effect of certain genotypes on weight loss and maintenance and extended the knowledge of the potential benefits of personalized medicine. Post-therapeutical support in current clinical practice may increase the chances of long-term weight loss maintenance in obesity treatment even in patients with a genetic predisposition to excessive weight.