Adipose Tissue μ-Crystallin Is a Thyroid Hormone-Binding Protein Associated With Systemic Insulin Sensitivity

Background: Circulating thyroid hormones have been described to be intrinsically associated with insulin sensitivity in healthy subjects. μ-Crystallin is a nicotinamide adenine dinucleotide phosphate-dependent thyroid hormone-binding protein that has been shown to bind T3 in the cytoplasm. We aimed to study μ-Crystallin expression in adipose tissue and in muscle in association with insulin action and thyroid function. Methods: μ-Crystallin gene expression was studied in 81 visceral and 75 sc adipose tissue samples and in 26 muscle samples from a cohort of subjects with a wide spectrum of adiposity (cohort 1). μ-Crystallin was also evaluated in 30 morbidly obese subjects in whom insulin action was evaluated using euglycemic clamp (cohort 2) and in 22 sc adipose tissue samples obtained before and after bariatric surgery-induced weight loss (cohort 3). μ-Crystallin was also evaluated during differentiation of human adipocytes. μ-Crystallin was overexpressed in human sc adipocytes using lentiviruses. Results: μ-Crystallin gene expression was 2.6- to 3-fold higher in sc vs visceral adipose tissue in direct association with the expression of thyroid hormone receptor α 1 in cohort 1 and cohort 2. Visceral, but not sc, adipose tissue μ-Crystallin was positively associated with the serum T3/T4 ratio in cohort 1 and with insulin sensitivity in cohort 2. In fact, μ-Crystallin gene expression was significantly decreased in visceral adipose tissue (−43%) and in muscle (−26%) in subjects with impaired fasting glucose and type 2 diabetes. Weight loss did not result in significant sc adipose tissue μ-Crystallin changes. μ-Crystallin overexpression led to increased insulin-induced Ser473Akt phosphorylation in sc adipocytes. During differentiation of adipocytes, μ-Crystallin gene expression decreased in both visceral (P = .006) and sc (P = .003) adipocytes from obese subjects. Conclusion: Visceral, but not sc, adipose tissue μ-Crystallin is an adipose tissue factor linked to parameters of thyroid hormone action (T3/T4 ratio) and might mediate the interaction of thyroid function and insulin sensitivity.

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LMO3 reprograms visceral adipocyte metabolism during obesity

Journal of Molecular Medicine ◽

10.1007/s00109-021-02089-9 ◽

2021 ◽

Author(s):

Gabriel Wagner ◽

Anna Fenzl ◽

Josefine Lindroos-Christensen ◽

Elisa Einwallner ◽

Julia Husa ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Visceral Adipose Tissue ◽

Tissue Expansion ◽

Oxidative Capacity ◽

Glut4 Translocation ◽

Mitochondrial Oxidative Capacity ◽

Visceral Adipose

Abstract Obesity and body fat distribution are important risk factors for the development of type 2 diabetes and metabolic syndrome. Evidence has accumulated that this risk is related to intrinsic differences in behavior of adipocytes in different fat depots. We recently identified LIM domain only 3 (LMO3) in human mature visceral adipocytes; however, its function in these cells is currently unknown. The aim of this study was to determine the potential involvement of LMO3-dependent pathways in the modulation of key functions of mature adipocytes during obesity. Based on a recently engineered hybrid rAAV serotype Rec2 shown to efficiently transduce both brown adipose tissue (BAT) and white adipose tissue (WAT), we delivered YFP or Lmo3 to epididymal WAT (eWAT) of C57Bl6/J mice on a high-fat diet (HFD). The effects of eWAT transduction on metabolic parameters were evaluated 10 weeks later. To further define the role of LMO3 in insulin-stimulated glucose uptake, insulin signaling, adipocyte bioenergetics, as well as endocrine function, experiments were conducted in 3T3-L1 adipocytes and newly differentiated human primary mature adipocytes, engineered for transient gain or loss of LMO3 expression, respectively. AAV transduction of eWAT results in strong and stable Lmo3 expression specifically in the adipocyte fraction over a course of 10 weeks with HFD feeding. LMO3 expression in eWAT significantly improved insulin sensitivity and healthy visceral adipose tissue expansion in diet-induced obesity, paralleled by increased serum adiponectin. In vitro, LMO3 expression in 3T3-L1 adipocytes increased PPARγ transcriptional activity, insulin-stimulated GLUT4 translocation and glucose uptake, as well as mitochondrial oxidative capacity in addition to fatty acid oxidation. Mechanistically, LMO3 induced the PPARγ coregulator Ncoa1, which was required for LMO3 to enhance glucose uptake and mitochondrial oxidative gene expression. In human mature adipocytes, LMO3 overexpression promoted, while silencing of LMO3 suppressed mitochondrial oxidative capacity. LMO3 expression in visceral adipose tissue regulates multiple genes that preserve adipose tissue functionality during obesity, such as glucose metabolism, insulin sensitivity, mitochondrial function, and adiponectin secretion. Together with increased PPARγ activity and Ncoa1 expression, these gene expression changes promote insulin-induced GLUT4 translocation, glucose uptake in addition to increased mitochondrial oxidative capacity, limiting HFD-induced adipose dysfunction. These data add LMO3 as a novel regulator improving visceral adipose tissue function during obesity. Key messages LMO3 increases beneficial visceral adipose tissue expansion and insulin sensitivity in vivo. LMO3 increases glucose uptake and oxidative mitochondrial activity in adipocytes. LMO3 increases nuclear coactivator 1 (Ncoa1). LMO3-enhanced glucose uptake and mitochondrial gene expression requires Ncoa1.

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The mRNA of protein disulfide isomerase and its homologue the thyroid hormone binding protein is strongly expressed in adipose tissue

Molecular and Cellular Endocrinology ◽

10.1016/0303-7207(90)90123-p ◽

1990 ◽

Vol 73 (2-3) ◽

pp. 105-110 ◽

Cited By ~ 3

Author(s):

S. Klaus ◽

L. Casteilla ◽

E. Hentz ◽

C. Dani ◽

D. Ricquier

Keyword(s):

Adipose Tissue ◽

Thyroid Hormone ◽

Protein Disulfide Isomerase ◽

Binding Protein ◽

Hormone Binding ◽

Disulfide Isomerase ◽

Hormone Binding Protein ◽

Protein Disulfide

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Markers of Adipogenesis, but Not Inflammation, in Adipose Tissue Are Independently Related to Insulin Sensitivity

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-00597 ◽

2017 ◽

Vol 102 (8) ◽

pp. 3040-3049 ◽

Cited By ~ 13

Author(s):

Natalia Matulewicz ◽

Magdalena Stefanowicz ◽

Agnieszka Nikołajuk ◽

Monika Karczewska-Kupczewska

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Immune Cells ◽

Insulin Signaling ◽

Transcriptional Level ◽

Altered Expression ◽

Ecm Remodeling ◽

Expression Of Genes ◽

Obese Subjects

Abstract Context In obesity, adipose tissue (AT) undergoes dynamic remodeling, including an alternation in adipogenesis, AT-resident cell content, angiogenesis, and turnover of extracellular matrix (ECM) components. Studies of AT in humans have been carried out mostly in people with severe metabolic abnormalities, like type 2 diabetes or morbid obesity. Objective The purpose of this study was to investigate subcutaneous AT gene expression of markers of adipogenesis, ECM remodeling, and inflammation in young, healthy, overweight or obese subjects. Design The study group comprised 83 normal-weight, 48 overweight, and 19 obese subjects. Euglycemic hyperinsulinemic clamp, biopsy of subcutaneous AT, and isolation of peripheral blood mononuclear cells (PBMCs) were performed. Gene expression was measured with real-time polymerase chain reaction. Results Overweight/obese subjects had lower AT expression of markers of adipogenesis, insulin signaling, and angiogenesis; higher expression of markers of ECM remodeling; altered expression of genes of the nuclear factor-κ-B (NFκB), but not c-Jun NH2-terminal kinase, pathway; and higher expression of macrophage markers but not markers of other immune cells. In multiple regression analysis, the expression of CEBPA, ADIPOQ, IRS1, IRS2, SLC2A4, and MMP9 was associated with insulin sensitivity independently of body mass index. No differences were found in inflammatory-gene PBMC expression. Conclusion Overweight/obesity is associated with altered expression of genes of adipogenesis, insulin signaling, ECM remodeling, and inflammation. NFκB seems to be the earliest inflammatory pathway altered at the transcriptional level in AT. Macrophages seem to be the first immune cells to infiltrate AT. Adipogenesis and ECM remodeling are the initial processes in AT that are independently associated with insulin sensitivity.

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Dynamic Strength Training Improves Insulin Sensitivity without Altering Plasma Levels and Gene Expression of Adipokines in Subcutaneous Adipose Tissue in Obese Men

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-0382 ◽

2006 ◽

Vol 91 (12) ◽

pp. 5107-5112 ◽

Cited By ~ 94

Author(s):

E. Klimcakova ◽

J. Polak ◽

C. Moro ◽

J. Hejnova ◽

M. Majercik ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Strength Training ◽

Plasma Levels ◽

Dynamic Strength ◽

Whole Body ◽

Obese Subjects ◽

Dynamic Strength Training

Abstract Context: Obesity is characterized by a low-grade inflammatory state, which could play a role in insulin resistance. Dynamic strength training improves insulin sensitivity. Objective: The objective of this study was to investigate, in obese subjects, whether the insulin sensitizing effect of dynamic strength training is associated with changes in plasma levels and gene expression of adipokines potentially involved in the development of insulin resistance. Design: Twelve obese male subjects were investigated before and at the end of 3 months of dynamic strength training. Insulin sensitivity was evaluated using euglycemic-hyperinsulinemic clamp. Blood samples and needle biopsy samples of sc abdominal adipose tissue were obtained. The plasma levels and adipose tissue mRNA levels of adiponectin, leptin, IL-1β, IL-6, and TNF-α were determined. Results: The training induced an increase in the whole-body glucose disposal rate by 24% (P = 0.04). The body weight was not altered during the training. Plasma levels of leptin decreased during the training (16.6 ± 6.3 vs. 13.1 ± 5.7 ng/ml) by 21% (P < 0.02), whereas no change in plasma levels of other adipokines and C-reactive protein was observed. Gene expression of the investigated adipokines was not changed in sc adipose tissue during the training. Conclusions: In obese subjects, the dynamic strength training resulted in an improvement of whole-body insulin sensitivity. The increase in insulin sensitivity was not associated with training-induced modifications of plasma levels or adipose tissue gene expression of adipokines supposedly involved in the development of insulin resistance.

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Plasma PTX3 protein levels inversely correlate with insulin secretion and obesity, whereas visceral adipose tissue PTX3 gene expression is increased in obesity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00163.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. E1254-E1261 ◽

Cited By ~ 39

Author(s):

O. Osorio-Conles ◽

M. Guitart ◽

M. R. Chacón ◽

E. Maymo-Masip ◽

J. M. Moreno-Navarrete ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Insulin Secretion ◽

Oral Glucose ◽

Mrna Levels ◽

Inverse Association ◽

Protein Levels ◽

Obese Subjects ◽

Glucose Stimulated Insulin Secretion ◽

Visceral Adipose

Plasma acutephase protein pentraxin 3 (PTX3) concentration is dysregulated in human obesity and metabolic syndrome. Here, we explore its relationship with insulin secretion and sensitivity, obesity markers, and adipose tissue PTX3 gene expression. Plasma PTX3 protein levels were analyzed in a cohort composed of 27 lean [body mass index (BMI) ≤25 kg/m2] and 48 overweight (BMI 25–30 kg/m2) men ( cohort 1). In this cohort, plasma PTX3 was negatively correlated with fasting triglyceride levels and insulin secretion after intravenous and oral glucose administration. Plasma PTX3 protein and PTX3 gene expression in visceral (VAT) and subcutaneous (SAT) whole adipose tissue and adipocyte and stromovascular fractions were analyzed in cohort 2, which was composed of 19 lean, 28 overweight, and 15 obese subjects (BMI >30 kg/m2). An inverse association with body weight and waist/hip ratio was observed in cohort 2. In VAT depots, PTX3 mRNA levels were higher in subjects with BMI >25 kg/m2than in lean subjects, positively correlated with IL-1β mRNA levels, and higher in the adipocyte than stromovascular fraction. Human preadipocyte SGBS cell line was used to study PTX3 production in response to factors that obesity entails. In SGBS adipocytes, PTX3 gene expression was enhanced by IL-1β and TNFα but not IL-6 or insulin. In conclusion, the negative correlation between PTX3 and glucose-stimulated insulin secretion suggests a role for PTX3 in metabolic control. PTX3 gene expression is upregulated in VAT depots in obesity, despite lower plasma PTX3 protein, and by some proinflammatory cytokines in cultured adipocytes.

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Adipose Y5R mRNA is higher in obese than non-obese humans and is correlated with obesity parameters

Experimental Biology and Medicine ◽

10.1177/1535370218774889 ◽

2018 ◽

Vol 243 (9) ◽

pp. 786-795 ◽

Cited By ~ 4

Author(s):

Saimai Chatree ◽

Chantacha Sitticharoon ◽

Pailin Maikaew ◽

Panapat Uawithya ◽

Supornpim Chearskul

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Visceral Adipose Tissue ◽

Visceral Fat ◽

Hip Circumference ◽

Adipose Tissues ◽

Obese Subjects ◽

Positive Correlations ◽

Visceral Adipose ◽

Y Receptors

Neuropeptide Y is mainly expressed in the central nervous system to regulate food intake via its receptors, Y receptors, and in various peripheral tissues including adipose tissue. The objectives of this study were to compare Y5R mRNA and adipocyte parameters consisting of area, width, height, and perimeter either between obese and non-obese subjects or between subcutaneous and visceral fat as well as to compare between NPY, Y1R, Y2R, and Y5R mRNA expressions in subcutaneous and visceral adipose tissues. In subcutaneous and visceral adipose tissues, Y5R was greater in obese than in non-obese humans (both P < 0.05). Y1R mRNA expression was highest followed by Y5R, Y2R, and NPY mRNA expressions, respectively, in subcutaneous and visceral adipose tissues. Visceral Y5R mRNA had positive correlations with body weight, body mass index, waist circumference, hip circumference (R ≍ 0.4), and visceral Y1R mRNA (R = 0.773), but had a negative correlation with the quantitative insulin sensitivity check index (R=−0.421) (all P < 0.05). Subcutaneous and visceral adipocyte parameters were positively correlated with body weight, waist circumference, hip circumference, and waist-to-hip ratio, with greater values of correlation coefficient shown in visceral (R ≍ 0.5–0.8) than in subcutaneous adipocytes (R ≍ 0.4–0.6, all P < 0.05). The parameters of visceral adipocytes had positive correlations with serum NPY levels (R ≍ 0.4, all P < 0.05). Y5R mRNA in visceral adipose tissue is related to increased obesity and reduced insulin sensitivity. The dominant Y receptors in subcutaneous and visceral adipose tissue might be the Y1R and Y5R. Visceral adipocytes show higher correlations with obesity parameters than subcutaneous adipocytes, suggestive of an increased risk of metabolic syndrome in visceral obesity. Y1R and Y5R in visceral adipose tissue might be targets of drug development in prevention or treatment of adiposity. Impact statement Obesity, defined as excess fat accumulation, has been increasingly diagnosed worldwide causing adverse health consequences. The novel findings of this study were that Y5R mRNA expression in both subcutaneous and visceral fat was higher in obese than non-obese subjects. Furthermore, Y5R only in visceral fat, not subcutaneous fat, was positively correlated with visceral Y1R and obesity parameters but it was negatively correlated with the QUICKI. Moreover, we found that Y1R expression was highest followed by Y5R and Y2R, respectively, in both subcutaneous and visceral fat. Our results suggested that Y5R in visceral fat was associated with increased obesity and decreased insulin sensitivity. Y1R and Y5R might be the dominant receptors that mediate the effect of NPY-induced fat accumulation in both subcutaneous and visceral adipose tissues. Y1R and Y5R in visceral adipose tissue might be targets of drug development in prevention or treatment of obesity.

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Visceral Adipose Tissue Is Associated with Circulating High Affinity Growth Hormone-Binding Protein

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.82.3.3836 ◽

1997 ◽

Vol 82 (3) ◽

pp. 760-764 ◽

Cited By ~ 16

Author(s):

Corné A. M. Roelen ◽

Hans P. F. Koppeschaar ◽

Wouter R. de Vries ◽

Yvonne E. M. Snel ◽

Manorath E. Doerga ◽

...

Keyword(s):

Growth Hormone ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Binding Protein ◽

Hormone Binding ◽

High Affinity ◽

Growth Hormone Binding Protein ◽

Hormone Binding Protein ◽

Visceral Adipose

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Changes in adipose tissue lipolysis gene expression and insulin sensitivity after weight loss

Endocrine Connections ◽

10.1530/ec-19-0507 ◽

2020 ◽

Vol 9 (2) ◽

pp. 90-100 ◽

Cited By ~ 1

Author(s):

Monika Karczewska-Kupczewska ◽

Agnieszka Nikołajuk ◽

Radosław Majewski ◽

Remigiusz Filarski ◽

Magdalena Stefanowicz ◽

...

Keyword(s):

Gene Expression ◽

Weight Loss ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Intervention Program ◽

Dietary Intervention ◽

Normal Weight ◽

Control Group ◽

Metabolic Complications ◽

Obese Subjects

Objective Insulin resistance is a major pathophysiological link between obesity and its metabolic complications. Weight loss (WL) is an effective tool to prevent obesity-related diseases; however, the mechanisms of an improvement in insulin sensitivity (IS) after weight-reducing interventions are not completely understood. The aim of the present study was to analyze the relationships between IS and adipose tissue (AT) expression of the genes involved in the regulation of lipolysis in obese subjects after WL. Methods Fifty-two obese subjects underwent weight-reducing dietary intervention program. The control group comprised 20 normal-weight subjects, examined at baseline only. Hyperinsulinemic-euglycemic clamp and s.c. AT biopsy with subsequent gene expression analysis were performed before and after the program. Results AT expression of genes encoding lipases (PNPLA2, LIPE and MGLL) and lipid-droplet proteins enhancing (ABHD5) and inhibiting lipolysis (PLIN1 and CIDEA) were decreased in obese individuals in comparison with normal-weight individuals. The group of 38 obese participants completed dietary intervention program and clamp studies, which resulted in a significant WL and an improvement in mean IS. However, in nine subjects from this group IS did not improve in response to WL. AT expression of PNPLA2, LIPE and PLIN1 increased only in the group without IS improvement. Conclusions Excessive lipolysis may prevent an improvement in IS during WL. The change in AT PNPLA2 and LIPE expression was a negative predictor of the change in IS after WL.

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