Association of the PNPLA2, SCD1 and Leptin Expression with Fat
                    Distribution in Liver and Adipose Tissue From Obese Subjects

AbstractThe expansion of adipose tissue is regulated by insulin and leptin through sterol regulatory element-binding protein-1c (SREBP-1c), up-regulating lipogenesis in tissues by Stearoylcoenzyme A desaturase 1 (SCD1) enzyme, while adipose triglyceride lipase (ATGL) enzyme is key in lipolysis. The research objective was to evaluate the expression of Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1), SCD1, Patatin Like Phospholipase Domain Containing 2 (PNPLA2), and leptin (LEP) genes in hepatic-adipose tissue, and related them with the increment and distribution of fat depots of individuals without insulin resistance. Thirty-eight subjects undergoing elective cholecystectomy with liver and adipose tissue biopsies (subcutaneous-omental) are included. Tissue gene expression was assessed by qPCR and biochemical parameters determined. Individuals are classified according to the body mass index, classified as lean (control group, n=12), overweight (n=11) and obesity (n=15). Abdominal adiposity was determined by anthropometric and histopathological study of the liver. Increased SCD1 expression in omental adipose tissue (p=0.005) and PNPLA2 in liver (p=0.01) were found in the obesity group. PNPLA2 decreased expression in subcutaneous adipose tissue was significant in individuals with abdominal adiposity (p=0.017). Anthropometric parameters positively correlated with liver PNPLA2 and the expression of liver PNPLA2 with serum leptin. SCD1 increased levels may represent lipid storage activity in omental adipose tissue. Liver PNPLA2 increased expression could function as a primary compensatory event of visceral fat deposits associated to the leptin hormone related to the increase of adipose tissue.

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Association of genes with physiological functions by comparative analysis of pooled expression microarray data

Physiological Genomics ◽

10.1152/physiolgenomics.00116.2012 ◽

2013 ◽

Vol 45 (2) ◽

pp. 69-78 ◽

Cited By ~ 6

Author(s):

Iuan-bor D. Chen ◽

Vinay K. Rathi ◽

Diana S. DeAndrade ◽

Patrick Y. Jay

Keyword(s):

Transcription Factor ◽

Adipose Tissue ◽

Regulatory Element ◽

The Body ◽

Accurate Identification ◽

Physiological Functions ◽

Microarray Expression Data ◽

Multiple Organs ◽

Brown Adipose ◽

Sterol Regulatory Element

The physiological functions of a tissue in the body are carried out by its complement of expressed genes. Genes that execute a particular function should be more specifically expressed in tissues that perform the function. Given this premise, we mined public microarray expression data to build a database of genes ranked by their specificity of expression in multiple organs. The database permitted the accurate identification of genes and functions known to be specific to individual organs. Next, we used the database to predict transcriptional regulators of brown adipose tissue (BAT) and validated two candidate genes. Based upon hypotheses regarding pathways shared between combinations of BAT or white adipose tissue (WAT) and other organs, we identified genes that met threshold criteria for specific or counterspecific expression in each tissue. By contrasting WAT to the heart and BAT, the two most mitochondria-rich tissues in the body, we discovered a novel function for the transcription factor ESRRG in the induction of BAT genes in white adipocytes. Because the heart and other estrogen-related receptor gamma (ESRRG)-rich tissues do not express BAT markers, we hypothesized that an adipocyte co-regulator acts with ESRRG. By comparing WAT and BAT to the heart, brain, kidney and skeletal muscle, we discovered that an isoform of the transcription factor sterol regulatory element binding transcription factor 1 (SREBF1) induces BAT markers in C2C12 myocytes in the presence of ESRRG. The results demonstrate a straightforward bioinformatic strategy to associate genes with functions. The database upon which the strategy is based is provided so that investigators can perform their own screens.

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Central Leptin Regulates Total Ceramide Content and Sterol Regulatory Element Binding Protein-1C Proteolytic Maturation in Rat White Adipose Tissue

Endocrinology ◽

10.1210/en.2008-0505 ◽

2008 ◽

Vol 150 (1) ◽

pp. 169-178 ◽

Cited By ~ 36

Author(s):

Elena Bonzón-Kulichenko ◽

Dominik Schwudke ◽

Nilda Gallardo ◽

Eduardo Moltó ◽

Teresa Fernández-Agulló ◽

...

Keyword(s):

Nervous System ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

White Adipose Tissue ◽

Binding Protein ◽

Regulatory Element ◽

Mrna Levels ◽

Element Binding Protein ◽

Ceramide Content ◽

Sterol Regulatory Element

Obesity and type 2 diabetes are associated with insulin and leptin resistance, and increased ceramide contents in target tissues. Because the adipose tissue has become a central focus in these diseases, and leptin-induced increases in insulin sensitivity may be related to effects of leptin on lipid metabolism, we investigated herein whether central leptin was able to regulate total ceramide levels and the expression of enzymes involved in ceramide metabolism in rat white adipose tissue (WAT). After 7 d central leptin treatment, the total content of ceramides was analyzed by quantitative shotgun lipidomics mass spectrometry. The effects of leptin on the expression of several enzymes of the sphingolipid metabolism, sterol regulatory element binding protein (SREBP)-1c, and insulin-induced gene 1 (INSIG-1) in this tissue were studied. Total ceramide levels were also determined after surgical WAT denervation. Central leptin infusion significantly decreased both total ceramide content and the long-chain fatty acid ceramide species in WAT. Concomitant with these results, leptin decreased the mRNA levels of enzymes involved in de novo ceramide synthesis (SPT-1, LASS2, LASS4) and ceramide production from sphingomyelin (SMPD-1/2). The mRNA levels of enzymes of ceramide degradation (Asah1/2) and utilization (sphingomyelin synthase, ceramide kinase, glycosyl-ceramide synthase, GM3 synthase) were also down-regulated. Ceramide-lowering effects of central leptin were prevented by local autonomic nervous system denervation of WAT. Finally, central leptin treatment markedly increased INSIG-1 mRNA expression and impaired SREBP-1c activation in epididymal WAT. These observations indicate that in vivo central leptin, acting through the autonomic nervous system, regulates total ceramide levels and SREBP-1c proteolytic maturation in WAT, probably contributing to improve the overall insulin sensitivity. Central leptin decreases total ceramide levels and prevents sterol regulatory element binding protein (SREBP-1C) proteolytic maturation in white adipose tissue, and probably, in this way, contributes to improve the overall insulin sensitivity.

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The in vitro secretion of human leptin is gender-dependent but independent of the body mass index of the donors

Acta Endocrinologica ◽

10.1530/eje.0.1430711 ◽

2000 ◽

pp. 711-714 ◽

Cited By ~ 14

Author(s):

C Menendez ◽

R Baldelli ◽

M Lage ◽

X Casabiell ◽

V Pinero ◽

...

Keyword(s):

Body Mass Index ◽

Adipose Tissue ◽

Body Mass ◽

Tissue Sample ◽

Secretory Activity ◽

The Body ◽

Secretory Rate ◽

Omental Adipose Tissue

OBJECTIVE: Leptin is an adipocyte-secreted hormone acting as a signal to the central nervous system, where it regulates energy homeostasis and neuroendocrine processes. Leptin plasma levels are mainly regulated by the percentage of body fat, but are also controlled by several metabolic and nutritional variables. Data regarding leptin secretion suggest that it is gender regulated, and higher levels are present in women than men; however, the biological basis for this sex-related difference is unknown. To clarify those points, a systematic study with tissue cultures from human omental adipose tissue was performed. DESIGN AND METHODS: Surgically obtained samples from 137 patients (68 women, 69 men) were evaluated. The assay was standardized in periods of 24 h ending at 96 h. Each adipose tissue sample from a single donor was incubated in triplicate and leptin results expressed as the mean of the integrated secretion into the medium (nanograms of leptin/g tissue per time). RESULTS: Tissue adipose cultures showed a steady leptin secretion throughout the 96 h studied, with the peak of secretory activity reached at 48 h; afterwards, the in vitro secretion reached a plateau state. Spontaneous leptin secretion in the 24 h and 48 h period, as well as the area under the curve analyzed in the 0-48 h period, showed a gender-based difference that was significantly (P<0. 05) higher in women than in men. When data of spontaneous leptin secretion were correlated with the body mass index (BMI) of the donors, no correlation was found. This suggests that in vivo leptin levels are dependent on the total amount of fat of the individual, but independent of the leptin secretory rate by the adipose tissue of the donor. CONCLUSIONS: Leptin secretion from omental adipose tissue in vitro is: (i) significantly higher in samples from women than in samples from men; and (ii) not correlated with the BMI, showing that in vitro leptin secretion is not related to the adiposity of the donor.

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Enhanced nutritionally induced adipose tissue development in mice with stromelysin-1 gene inactivation

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613586 ◽

2003 ◽

Vol 89 (04) ◽

pp. 696-704 ◽

Cited By ~ 41

Author(s):

Erik Maquoi ◽

Diego Demeulemeester ◽

Gabor Vörös ◽

Désire Collen ◽

H. Lijnen

Keyword(s):

Adipose Tissue ◽

Research Society ◽

The Body ◽

Tissue Development ◽

Cholesterol Levels ◽

Fat Deposits ◽

Adipose Tissue Development ◽

Adipocyte Hypertrophy ◽

Deficient Mice

SummaryTo investigate a potential role of stromelysin-1 (MMP-3) in development of adipose tissue, 5 week old male MMP-3 deficient mice (MMP-3-/-) and wild-type (MMP-3+/+) controls were kept on a high fat diet (HFD) for 15 weeks. MMP-3-/- mice were hyperphagic and gained more weight than the MMP-3+/+ mice. At the time of sacrifice, the body weight of the MMP-3-/- mice was significantly higher than that of the MMP-3+/+ mice, as was the weight of the isolated subcutaneous (SC) and gonadal (GON) fat deposits. Significant adipocyte hypertrophy was observed in the GON but not in the SC adipose tissue of MMP-3-/- mice. Fasting plasma glucose and cholesterol levels were comparable in both genotypes, whereas triglyceride levels were significantly lower in MMP-3-/- mice. Staining with an endothelial cell specific lectin revealed a significantly higher blood vessel density and larger total stained area in the GON adipose tissues of MMP-3-/- mice. Thus, in a murine model of nutritionally induced obesity, MMP-3 impairs adipose tissue development, possibly by affecting food intake and/or adipose tissue-related angiogenesis.Theme paper: Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.

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Sterol regulatory element binding proteins: relationship of adipose tissue gene expression with obesity in humans

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression ◽

10.1016/s0167-4781(02)00279-8 ◽

2002 ◽

Vol 1575 (1-3) ◽

pp. 75-81 ◽

Cited By ~ 30

Author(s):

Hannes Oberkofler ◽

Noriko Fukushima ◽

Harald Esterbauer ◽

Franz Krempler ◽

Wolfgang Patsch

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Binding Proteins ◽

Regulatory Element ◽

Sterol Regulatory Element ◽

Adipose Tissue Gene Expression ◽

Relationship Of ◽

Tissue Gene Expression

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ON BODY FAT AND BODY WATER IN RATS

Canadian Journal of Biochemistry and Physiology ◽

10.1139/y55-117 ◽

1955 ◽

Vol 33 (1) ◽

pp. 970-979 ◽

Cited By ~ 6

Author(s):

Louis-Marie Babineau ◽

Edouard Pagé

Keyword(s):

Adipose Tissue ◽

Body Fat ◽

Dry Matter ◽

The Body ◽

Energy Reserves ◽

Experimental Conditions ◽

Fat Depots ◽

Excess Water ◽

Fat Stores ◽

Free Body

Under our experimental conditions, water represented 72% of the fat-free body mass. This constant was found to be completely independent of the magnitude of the fat depots. Consideration of the composition of various samples of adipose tissue suggests that the water to fat-free dry matter ratio is the same as in the body as a whole or that any "excess" water contributed by adipose tissue is so small in absolute amounts as to leave the global ratio essentially undisturbed. Rats exposed to cold had to draw on their fat stores during the first month of exposure but later replenished their energy reserves. The water to fat-free dry matter ratio was not affected.

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Tissue-Specific Effects of Central Leptin on the Expression of Genes Involved in Lipid Metabolism in Liver and White Adipose Tissue

Endocrinology ◽

10.1210/en.2007-0933 ◽

2007 ◽

Vol 148 (12) ◽

pp. 5604-5610 ◽

Cited By ~ 74

Author(s):

Nilda Gallardo ◽

Elena Bonzón-Kulichenko ◽

Teresa Fernández-Agulló ◽

Eduardo Moltó ◽

Sergio Gómez-Alonso ◽

...

Keyword(s):

Adipose Tissue ◽

Lipid Metabolism ◽

White Adipose Tissue ◽

Binding Protein ◽

Regulatory Element ◽

Epididymal Adipose Tissue ◽

Key Enzymes ◽

Specific Effects ◽

Element Binding Protein ◽

Sterol Regulatory Element

Leptin reduces adiposity and exerts antisteatotic effects on nonadipose tissues. However, the mechanisms underlying leptin effects on lipid metabolism in liver and white adipose tissue have not been fully clarified. Here, we have studied the effects of central leptin administration on key enzymes and transcription factors involved in lipid metabolism in liver and epididymal adipose tissue. Intracerebroventricular leptin infusion for 7 d did not change leptin plasma levels but decreased triacylglyceride content in liver, epididymal adipose tissue, and plasma. In both tissues this treatment markedly decreased the expression of key enzymes of the de novo fatty acid (FA) synthesis such as acetyl-coenzyme A-carboxylase, FA synthase, and stearoyl-coenzyme A desaturase-1, in parallel with a reduction in mRNA expression of sterol regulatory element binding protein-1c in liver and carbohydrate regulatory element binding protein in adipose tissue. In addition, leptin also decreased phosphoenol-pyruvate carboxykinase-C expression in adipose tissue, an enzyme involved in glyceroneogenesis in this tissue. Central leptin administration down-regulates delta-6-desaturase expression in liver and adipose tissue, in parallel with the decrease of the expression of sterol regulatory element binding protein-1c in liver and peroxisome proliferator activated receptor α in adipose tissue. Finally, leptin treatment, by regulating adipose triglyceride lipase/hormone sensitive lipase/diacylglycerol transferase 1 expression, also established a new partitioning in the FA-triacylglyceride cycling in adipose tissue, increasing lipolysis and probably the FA efflux from this tissue, and favoring in parallel the FA uptake and oxidation in the liver. These results suggest that leptin, acting at central level, exerts tissue-specific effects in limiting fat tissue mass and lipid accumulation in nonadipose tissues, preventing the development of obesity and type 2 diabetes.

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Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00572.2004 ◽

2006 ◽

Vol 290 (6) ◽

pp. E1253-E1261 ◽

Cited By ~ 465

Author(s):

Rong-Ze Yang ◽

Mi-Jeong Lee ◽

Hong Hu ◽

Jessica Pray ◽

Hai-Bin Wu ◽

...

Keyword(s):

Adipose Tissue ◽

Cdna Library ◽

Insulin Action ◽

Signal Sequence ◽

Visceral Obesity ◽

Northern Analysis ◽

Protein Sequence Analysis ◽

Omental Adipose Tissue ◽

Fat Depots

Central (visceral) obesity is more closely associated with insulin resistance, type 2 diabetes, and cardiovascular disease than is peripheral [subcutaneous (sc)] obesity, but the underlying mechanism for this pathophysiological difference is largely unknown. To understand the molecular basis of this difference, we sequenced 10,437 expressed sequence tags (ESTs) from a human omental fat cDNA library and discovered a novel visceral fat depot-specific secretory protein, which we have named omentin. Omentin ESTs were more abundant than many known adipose genes, such as perilipin, adiponectin, and leptin in the cDNA library. Protein sequence analysis indicated that omentin mRNA encodes a peptide of 313 amino acids, containing a secretory signal sequence and a fibrinogen-related domain. Northern analysis demonstrated that omentin mRNA was predominantly expressed in visceral adipose tissue and was barely detectable in sc fat depots in humans and rhesus monkeys. Quantative real-time PCR showed that omentin mRNA was expressed in stromal vascular cells, but not fat cells, isolated from omental adipose tissue, with >150-fold less in sc cell fractions. Accordingly, omentin protein was secreted into the culture medium of omental, but not sc, fat explants. Omentin was detectable in human serum by Western blot analysis. Addition of recombinant omentin in vitro did not affect basal but enhanced insulin-stimulated glucose uptake in both sc (47%, n = 9, P = 0.003) and omental (∼30%, n = 3, P < 0.05) human adipocytes. Omentin increased Akt phosphorylation in the absence and presence of insulin. In conclusion, omentin is a new adipokine that is expressed in omental adipose tissue in humans and may regulate insulin action.

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