Role of Sirtuins in Adipose Tissue Development and Metabolism

Sirtuins (silent information regulators, sirts) via modification of histones, as well as transcription factors and co-regulators, control expression of other genes, particularly those involved in the organism response to stress. Detection of sirtuin expression in adipocytes initiated interest in their role in adipose tissue development and metabolism. This chapter presents how sirtuins control the critical steps of preadipocytes’ differentiation and proliferation, as well as the process of adipose tissue browning. Moreover, it shows in vitro and in vivo data proving that sirtuins are involved in the regulation of lipogenesis, lipolysis, and secretory activity of adipose tissue. Due to all these reasons, sirtuins may constitute potential targets in the treatment of obesity and related complications

Association of polymorphism in genes encoding κB inhibitors (IκB) with susceptibility to and phenotype of Graves' disease: a case-control study

<p>Abstract</p> <p>Background</p> <p>Genes related to the nuclear factor-κB (NF-κB), a key transcription factor involved in regulation of immune responses, are interesting candidates for association studies in autoimmune disorders. The aim of this study was to investigate an association of polymorphisms in two genes encoding NF-κB inhibitors: <it>IKBL </it>(encoding inhibitor of κB-like) and <it>NFKBIA </it>(encoding κB inhibitor α), withsusceptibility to and phenotype of Graves' disease (GD).</p> <p>Methods</p> <p>A population-based, case-control association study comprising 481 patients with GD and 455 healthy controls was performed. We analyzed 3 single nucleotide polymorphisms (SNPs) in <it>IKBL </it>[promoter region -62T/A substitution (rs2071592), intron 1 C/T substitution (rs2071591) and exon 4 T/C substitution (rs3130062)] and 3 SNPs in <it>NFKBIA </it>[G/A substitution in 3' untranslated region (rs696) and two promoter region polymorphisms -297C/T (rs2233409) and -826C/T (rs2233406)] by the PCR-restriction fragment length polymorphism (RFLP) method.</p> <p>Results</p> <p>The two SNPs in <it>IKBL </it>(rs2071592 and rs2071591) were in a strong linkage disequilibrium (D' = 0.835) and the AT haplotype was associated with susceptibility to GD (p < 10^-4, OR = 1.61 [95%CI:1.21-2.14]). Moreover subgroup analysis revealed a gen-gen interaction between the investigated <it>IKBL </it>haplotype and <it>HLA-DRB1</it>*03 allele (p < 10^-4). The investigated <it>NFKBIA </it>SNPs were not associated with susceptibility to GD. However, when correlated with phenotype, the -297T (rs2233409) and -826T (rs2233406) alleles were associated with the development of clinically evident ophthalmophaty (p = 0.004, p_c= 0.07, OR = 1.65 [95%CI: 1.18-2.38] and p = 0.002, p_c= 0.036, OR = 1.67 [95%CI: 1.20-2.36], respectively).</p> <p>Conclusion</p> <p>Our results suggest that SNPs in genes encoding NF-κB inhibitors may contribute to the development and clinical phenotype of GD.</p

Functional polymorphisms of the leptin and leptin receptor genes are associated with longevity and with the risk of myocardial infarction and of type 2 diabetes mellitus

Wstęp: Długowieczności często towarzyszy dobry stan zdrowia, opóźnione zachorowanie na „choroby związane z wiekiem”, których przebieg jest zwykle łagodny. Leptyna (LEP) znacząco wpływa na metabolizm oraz na inne funkcje organizmu. Aby sprawdzić, czy ekstremalna długowieczność i jej fenotyp są powiązane z odmianami genów leptyny i receptora leptyny (LEPR), przebadaliśmy częstość występowania polimorfizmów –2548 G/A i +19 G/A genu LEP oraz K109R, Q223R, i K656N genu LEPR u stulatków i w grupach kontrolnych.Materiał i metody: Częstość występowania polimorfizmów genów LEP i LEPR badano metodą analizy długości fragmentów restrykcyjnych u 128 stulatków, 414 młodych kontroli (Y), 226 pacjentów z zawałem serca (MI) i u 190 pacjentów z cukrzycą 2 typu (DM2).Wyniki: Genotyp GG polimorfizmu –2548 G/A genu LEP był znamiennie częstszy u stulatków niż w grupach Y, MI i DM2 (odpowiednio p = 0,048, p = 0,003 i p = 0,049). Genotyp AA polimorfizmu K109R genu LEPR był znamiennie rzadszy u stulatków niż w grupach Y, MI i DM2 (odpowiednio p = 0,026, p = 0,013 i p = 0,001).Wnioski: Sugerujemy, że szlak oddziaływań leptyny bierze udział w regulowaniu długości życia, być może poprzez modulowanie ryzyka zachorowania na MI i DM2. (Endokrynol Pol 2014; 65 (1): 11–16)Introduction: Longevity is commonly associated with good health and with delayed onset of age-related diseases with usually benign course. Leptin (LEP) significantly affects metabolism and numerous functions of the organism. To find out if extreme longevity and its phenotype are associated with genetic variants of leptin and leptin receptor (LEPR) genes, we analysed the frequencies of the –2548 G/A and +19 G/A LEP, as well as the K109R, Q223R, and K656N LEPR polymorphisms in centenarians and in control groups.Material and methods: The frequencies of the LEP and LEPR polymorphisms were tested by restriction fragment length polymorphism in 128 centenarians, 414 young controls (Y), 226 myocardial infarction (MI) patients, and 190 type 2 diabetes mellitus (DM2) patients.Results: The GG genotype of the –2548 G/A LEP polymorphism was significantly more common in centenarians than in the Y, MI and DM2 groups (p = 0.048, p = 0.003, p = 0.049, respectively). In addition, the AA genotype of the K109R LEPR polymorphism was significantly less frequent in centenarians than in the Y, MI, and DM2 groups (p = 0.026, p = 0.013, and p = 0.001, respectively).Conclusions: We suggest that the leptin pathway plays a role in the regulation of longevity, possibly by modulating the risk of development of MI and of DM2. (Endokrynol Pol 2014; 65 (1): 11–16

Total and high molecular weight adiponectin and level-modifying polymorphisms of ADIPOQ in centenarians

Wstęp: Adiponektyna odgrywa ochronną rolę w patogenezie otyłości, cukrzycy typu 2 i chorób układu krążenia. Polimorfizmy &#8211;11377C > G, &#8211;11391G > A, i &#8211;11426A > G promotora ADIPOQ wpływają na stężenie adiponektyny. Autorzy zbadali stężenie całkowitej i wysokocząsteczkowej adiponektyny u stulatków i powiązali je z parametrami biochemicznymi. Sprawdzili, czy modyfikujące stężenie adiponektyny polimorfizmy ADIPOQ korelują z długowiecznością. Materiał i metody: Stężenia całkowitej i wielkocząsteczkowej adiponektyny oznaczono metodą ELISA u 40 stulatków. Częstość występowania polimorfizmów ADIPOQ zbadano metodą analizy długości fragmentów restrykcyjnych u 148 stulatków, 414 młodych, zdrowych ochotników, 207 chorych po przebytym zawale serca i u 190 chorych z cukrzycą typu 2. Wyniki: Średnie stężenie całkowitej adiponektyny u stulatków wynosiło 13,19 &#177; 1,37 &#956;g/ml, a adiponektyny wielkocząsteczkowej 9,17 &#177; 1,15 &#956;g/ml. Stężenia te pozytywnie korelowały ze stężeniem HDL (odpowiednio r = 0,4696, p = 0,0025 i r = 0,3912, p = 0,015), a negatywnie z BMI (r = &#8211;0,3702, p = 0,034 i r = &#8211;0,3963, p = 0,025) i stężeniem triglicerydów (r = &#8211;0,346, p = 0,028 i r = &#8211;0,3227, p = 0,045). Bardzo rzadki genotyp AA polimorfizmu -11391G > A występował znamiennie częściej u stulatków niż u młodych kontroli (p = 0,026) i, w porównaniu z genotypem GG, był związany z 2,4-krotnie wyższym stężeniem całkowitej adiponektyny (26,53 &#177; 13,29 &#956;g/ml v. 10,97 &#177; 4,28 &#956;g/ml) i prawie 3-krotnie wyższym stężeniem adiponektyny wielkocząsteczkowej (20,65 &#177; 12,72 &#956;g/ml v. 7,36 &#177; 3,35 &#956;g/ml). Wnioski: Korelacja pomiędzy stężeniami całkowitej i wielkocząsteczkowej adiponektyny u stulatków a korzystnymi z punktu widzenia ryzyka sercowo-naczyniowego parametrami biochemicznymi może świadczyć o udziale adiponektyny w promowaniu długowieczności. (Endokrynol Pol 2012; 63 (6): 439&#8211;446)Introduction: Adiponectin demonstrates a protective role against the development of obesity, type 2 diabetes mellitus, and cardiovascular disease. The &#8211;11377C > G, &#8211;11391G > A, and &#8211;11426A > G promoter polymorphisms of ADIPOQ gene influence the level of circulating adiponectin. We examined the level of total and high molecular weight (HMW) adiponectin in centenarians and associated it with biochemical parameters. We checked if the expression and concentration-modifying polymorphisms of ADIPOQ are associated with extreme longevity. Material and methods: Total and HMW adiponectin were examined using ELISA in 40 female centenarians. The frequencies of the ADIPOQ polymorphisms were tested by restriction fragment length polymorphism in 148 centenarians, 414 young controls, in 207 myocardial infarction patients, and in 190 type 2 diabetes mellitus patients. Results: The mean concentration of total adiponectin in centenarians was 13.19 &#177; 1.37 mg/mL and of HMW adiponectin it was 9.17 &#177; 1.15 mg/mL. They were positively correlated with HDL (r = 0.4696, p = 0.0025 and r = 0.3912, p = 0.015, respectively), and negatively with BMI (r = &#8211;0.3702, p = 0.034 and r = &#8211;0.3963, p = 0.025) and triglycerides (r = &#8211;0.346, p = 0.028 and r = &#8211;0.3227, p = 0.045). A very rare AA genotype of the &#8211;11391G > A polymorphism was significantly more common in centenarians than in young controls (p = 0.026) and, while compared to the GG genotype, it was associated with a 2.4-fold higher mean concentration of total adiponectin (26.53 &#177; 13.29 mg/ mL v. 10.97 &#177; 4.28 mg/mL) and with an almost 3-fold higher mean HMW adiponectin (20.65 &#177; 12.72 mg/mL v. 7.36 &#177; 3.35 mg/mL). Conclusions: Serum adiponectin concentration in female centenarians is associated with biochemical parameters that are favourable for cardiovascular risk. We suggest that adiponectin might be of importance for extreme longevity. (Endokrynol Pol 2012; 63 (6): 439&#8211;446

Prevalence and socioeconomic predictors of diagnosed and undiagnosed diabetes in oldest-old and younger Caucasian seniors: results from the PolSenior study

Introduction: Type 2 diabetes is one of the most common diseases in the aging population; however, data concerning correlates of diabetes in age-advanced individuals are limited. The study aimed to identify the socioeconomic correlates of diabetes in representative groups of oldest-old (≥ 85 years) and younger (65 to 84 years) Polish Caucasian seniors. Material and methods: PolSenior is a multicentre, population-based study conducted in Poland. Fasting plasma glucose levels and data from detailed medical questionnaires were obtained from 2128 male and 1961 female study participants aged ≥ 65 years. Multivariate logistic regression was used to identify significant socioeconomic risk factors for diabetes and undiagnosed diabetes. Results: The overall prevalence of diabetes in the study group was 21.9% (24.0% in women vs. 19.9% in men, p = 0.002), with an estimated weighted prevalence for all older Poles of 23.1%. Nearly one-fifth of cases were previously undiagnosed. Diabetes was more common in the younger elderly (65–84 years) than in the oldest-old (≥ 85 years) (23.4% vs. 18.6%, p &lt; 0.001). The frequency of diabetes was higher in women than in men (24.0% vs. 19.9%, p &lt; 0.002); however, men remained undiagnosed more commonly than women (4.7% vs. 3.3%, p = 0.029). The frequency of diabetes was higher among urban than rural dwellers (23% vs. 20.4%, p = 0.048). It was also related to marital status in women (p = 0.036) and occupation in men (p = 0.015). Multivariate logistic regression analysis revealed that the independent risk factors for diabetes were body mass index (BMI) and marital status in women, while in men it was solely BMI. Undiagnosed diabetes was more frequent among rural than city dwellers (4.8% vs. 3.5%, p = 0.03). In multivariate logistic regression analysis, only BMI and place of residence remained significant risk factors for being undiagnosed. Conclusions: The prevalence of diabetes in the ≥ 65-year-old population exceeds 20% but is lower in the oldest-old than in the younger elderly and is modified by socioeconomic factors. Many elderly individuals remain undiagnosed and do not benefit from the currently available therapy

microRNAs in Human Adipose Tissue Physiology and Dysfunction

In recent years, there has been a large amount of evidence on the role of microRNA (miRNA) in regulating adipose tissue physiology. Indeed, miRNAs control critical steps in adipocyte differentiation, proliferation and browning, as well as lipolysis, lipogenesis and adipokine secretion. Overnutrition leads to a significant change in the adipocyte miRNOME, resulting in adipose tissue dysfunction. Moreover, via secreted mediators, dysfunctional adipocytes may impair the function of other organs and tissues. However, given their potential to control cell and whole-body energy expenditure, miRNAs also represent critical therapeutic targets for treating obesity and related metabolic complications. This review attempts to integrate present concepts on the role miRNAs play in adipose tissue physiology and obesity-related dysfunction and data from pre-clinical and clinical studies on the diagnostic or therapeutic potential of miRNA in obesity and its related complications

In Search of New Therapeutic Targets in Obesity Treatment: Sirtuins

Most of the available non-invasive medical therapies for obesity are non-efficient in a long-term evaluation; therefore there is a constant need for new methods of treatment. Research on calorie restriction has led to the discovery of sirtuins (silent information regulators, SIRTs), enzymes regulating different cellular pathways that may constitute potential targets in the treatment of obesity. This review paper presents the role of SIRTs in the regulation of glucose and lipid metabolism as well as in the differentiation of adipocytes. How disturbances of SIRTs’ expression and activity may lead to the development of obesity and related complications is discussed. A special emphasis is placed on polymorphisms in genes encoding SIRTs and their possible association with susceptibility to obesity and metabolic complications, as well as on data regarding altered expression of SIRTs in human obesity. Finally, the therapeutic potential of SIRTs-targeted strategies in the treatment of obesity and related disorders is discussed

Endocrine Disorders Accompanying Obesity - Effect or Cause?

Endocrine disorders including hypothyroidism and hypercortisolism are considered as causes of secondary obesity. However, several hormonal abnormalities can also be found in individuals with primary (simple) obesity. Part of them results from the adipose tissue dysfunction that, via secreted adipokines, modulates the function of endocrine organs and can be reversed with weight loss. However, part of them correspond to the real endocrine disorder and require appropriate treatment. Therefore in the management of obese patients, it is essential to distinguish between obesity-related abnormal results of hormonal tests and underlying endocrine disorder. This chapter presents pathophysiological concepts of obesity-related changes in the endocrine system and briefly reviews diagnostic algorithms helpful in distinguishing them from the co-existing endocrine disorders