Obesity Is Associated With Low NAD<sup>+</sup>/SIRT Pathway Expression in Adipose Tissue of BMI-Discordant Monozygotic Twins

Jukarainen, Sakari; Heinonen, Sini; Rämö, Joel; Rinnankoski‐Tuikka, Rita; Rappou, Elisabeth; Tümmers, Mark; Muniandy, Maheswary; Hakkarainen, Antti; Lundbom, Jesper; Lundbom, Nina; Kaprio, Jaakko; Rissanen, Aila; Pirinen, Eija; Pietiläinen, Kirsi H.

doi:10.1210/jc.2015-3095

Cited by 125 publications

(150 citation statements)

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“…It is also possible that the alterations in circulating extracellular NAMPT (eNAMPT) affects neuronal metabolic signals associated with hypothalamus, and is involved in the pathogenesis of systemic metabolic complications observed in ANKO mice (Imai and Yoshino, 2013; Yoon et al, 2015). Given previous findings demonstrating that reduction in adipose NAMPT expression and NAD + content is associated with obesity and its metabolic complications in people and rodents (Ando et al, 2005; Jukarainen et al, 2015; Kovacikova et al, 2008; Mercader et al, 2008; Xu et al, 2012; Yoshino et al, 2011), our data strongly suggest that impaired NAMPT-mediated NAD + biosynthesis in adipose tissue plays a causative role in the pathophysiology of obesity-associated metabolic derangements, and thereby could be an important therapeutic target. Indeed, recent studies have shown that systemic administration of NAD + intermediates, such as NMN and NR, improves insulin resistance, dyslipidemia, NAFLD, and glucose intolerance, in obese mice (Canto et al, 2012; Canto et al, 2015; Gariani et al, 2015; Imai and Yoshino, 2013; Yoshino et al, 2011).…”

Section: Discussionsupporting

confidence: 76%

“…Aging, which is another major risk factor of metabolic complications, also impairs NAMPT-mediated NAD + biosynthesis in adipose tissue (Yoshino et al, 2011). Interestingly, data obtained from recent studies conducted in people demonstrate that the alterations in adipose NAMPT-mediated NAD + biosynthesis are associated with obesity and its metabolic complications (Jukarainen et al, 2015; Kovacikova et al, 2008; Varma et al, 2007; Xu et al, 2012). For example, adipose tissue NAMPT protein content or NAMPT gene expression is decreased in subjects who are insulin-resistant, compared to body mass index matched insulin-sensitive counterparts (Varma et al, 2007; Xu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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NAMPT-Mediated NAD + Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

et al. 2016

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SUMMARY Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD+ biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle, and adipose tissue dysfunction, manifested by increased plasma free fatty acids concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARγ (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARγ targets in adipose tissue. Remarkably, these deleterious alterations were normalized by administering rosiglitazone or a key NAD+ intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

NAMPT-Mediated NAD + Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

et al. 2016

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“…5B), thus confirming a critical role of MAPK activation in high-glucose induction of RTA expression. To investigate other mechanisms that might be involved in high-glucose induction of KSHV lytic replication, we examined the expression of SIRT1, which is a member of the class III HDACs and a key factor involved in the development of diabetes (34)(35)(36)(37)(38)(39)(40). In addition, several previous studies demonstrated the involvement of SIRT1 in the regulation of KSHV lytic gene expression through epigenetic remodeling (41)(42)(43).…”

Section: Methodsmentioning

confidence: 99%

High Glucose Induces Reactivation of Latent Kaposi's Sarcoma-Associated Herpesvirus

Zeng

Sha

et al. 2016

J Virol

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A high prevalence of Kaposi's sarcoma (KS) is seen in diabetic patients. It is unknown if the physiological conditions of diabetes contribute to KS development. We found elevated levels of viral lytic gene expression when Kaposi's sarcoma-associated herpesvirus (KSHV)-infected cells were cultured in high-glucose medium. To demonstrate the association between high glucose levels and KSHV replication, we xenografted telomerase-immortalized human umbilical vein endothelial cells that are infected with KSHV (TIVE-KSHV cells) into hyperglycemic and normal nude mice. The injected cells expressed significantly higher levels of KSHV lytic genes in hyperglycemic mice than in normal mice. We further demonstrated that high glucose levels induced the production of hydrogen peroxide (H 2 O 2 ), which downregulated silent information regulator 1 (SIRT1), a class III histone deacetylase (HDAC), resulting in the epigenetic transactivation of KSHV lytic genes. These results suggest that high blood glucose levels in diabetic patients contribute to the development of KS by promoting KSHV lytic replication and infection. IMPORTANCEMultiple epidemiological studies have reported a higher prevalence of classic KS in diabetic patients. By using both in vitro and in vivo models, we demonstrated an association between high glucose levels and KSHV lytic replication. High glucose levels induce oxidative stress and the production of H 2 O 2 , which mediates the reactivation of latent KSHV through multiple mechanisms. Our results provide the first experimental evidence and mechanistic support for the association of classic KS with diabetes. K aposi's sarcoma (KS) is a vascular neoplasia etiologically associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection (1). KSHV establishes a lifelong persistent latent infection following acute infection. Reactivation of the latent virus into productive lytic replication plays a pivotal role in the initiation and progression of KS, as viral load positively correlates with KS progression. Indeed, treatment of KS patients with antiherpesvirus drugs effectively leads to regression of KS tumors (2-6).Unlike iatrogenic or AIDS-associated KS, classic KS occurs predominantly in elderly men of Mediterranean or Jewish descent who have no apparent immune suppression (7). The exact cause of the development of classic KS remains undefined. Asthma, allergies in males, topical corticosteroid use, and infrequent bathing have been suggested to be risk factors for classic KS (8,9). Multiple studies have also documented a high prevalence of classic KS in patients with diabetes mellitus (10-13), a metabolic syndrome that manifests with elevated levels of blood glucose and episodic ketoacidosis, due to either a lack of insulin (type 1 diabetes) or cellular resistance to insulin (type 2 diabetes). High levels of KSHV DNA and seropositivity have been seen in diabetic patients (14-16). However, no study has ever determined if diabetes is the cause or an effect of KS and whether high glucose levels play ...

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“…PPARGC1A is a transcriptional coactivator that modulates the genes involved in energy metabolism, being a central regulator of mitochondria biogenesis [24][25][26][27]. SIRT1, which is another important mediator of mitochondrial biogenesis and energy expenditure in AT [27][28][29], is widely known as a negative regulator of cellular senescence [30,31]. In humans, increased AT SIRT1 mRNA levels and activity associates with mitochondrial function [28,29] and with reduced markers of cellular senescence [32,33].…”

Section: Discussionmentioning

confidence: 99%

“…SIRT1, which is another important mediator of mitochondrial biogenesis and energy expenditure in AT [27][28][29], is widely known as a negative regulator of cellular senescence [30,31]. In humans, increased AT SIRT1 mRNA levels and activity associates with mitochondrial function [28,29] and with reduced markers of cellular senescence [32,33]. Furthermore, DBC1 interacts and inhibits the activity of Sirt1 [34], a crucial component for the prevention of cellular senescence [35,36].…”

Section: Discussionmentioning

confidence: 99%

Adipose TSHB in Humans and Serum TSH in Hypothyroid Rats Inform About Cellular Senescence

Moreno-Navarrete

Liñares-Pose

Sabater

et al. 2018

Cell Physiol Biochem

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Background/Aims: Thyroid hormones have been recently linked to senescence and longevity. Given the recent description of TSHB mRNA in human adipose tissue (AT), we aimed to investigate the relationship between local AT TSH and adipose tissue senescence. Methods: TSHB mRNA (measured by real-time PCR) and markers of adipose tissue senescence [BAX, DBC1, TP53, TNF (real-time PCR), telomere length (Telo TAGGG Telomere Length Assay) and lipidomics (liquid chromatography mass spectrometry)] were analysed in subcutaneous (SAT) and visceral (VAT) AT from euthyroid subjects. The chronic effects of TSH were also investigated in AT from hypothyroid rats and after recombinant human TSH (rhTSH) administration in human adipocytes. Results: Both VAT and SAT TSHB gene expression negatively correlated with markers of AT cellular senescence (BAX, DBC1, TP53, TNF gene expression and specific glucosylceramides) and positively associated with telomere length. Supporting these observations, both rhTSH administration in human adipocytes and increased TSH in hypothyroid rats resulted in decreased markers of cellular senescence (Bax and Tp53 mRNA) in both gonadal and subcutaneous white adipose tissue. Conclusion: These data point to a possible role of TSH in AT cellular senescence.

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Obesity Is Associated With Low NAD⁺/SIRT Pathway Expression in Adipose Tissue of BMI-Discordant Monozygotic Twins

Abstract: Our data highlight a strong relationship of reduced NAD(+)/SIRT pathway expression with acquired obesity, inflammation, insulin resistance, and impaired mitochondrial protein homeostasis in SAT.

Cited by 125 publications

References 39 publications

NAMPT-Mediated NAD + Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

NAMPT-Mediated NAD + Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

High Glucose Induces Reactivation of Latent Kaposi's Sarcoma-Associated Herpesvirus

Adipose TSHB in Humans and Serum TSH in Hypothyroid Rats Inform About Cellular Senescence

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Obesity Is Associated With Low NAD+/SIRT Pathway Expression in Adipose Tissue of BMI-Discordant Monozygotic Twins

Abstract: Our data highlight a strong relationship of reduced NAD(+)/SIRT pathway expression with acquired obesity, inflammation, insulin resistance, and impaired mitochondrial protein homeostasis in SAT.

Cited by 125 publications

References 39 publications

NAMPT-Mediated NAD + Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

NAMPT-Mediated NAD + Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

High Glucose Induces Reactivation of Latent Kaposi's Sarcoma-Associated Herpesvirus

Adipose TSHB in Humans and Serum TSH in Hypothyroid Rats Inform About Cellular Senescence

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Obesity Is Associated With Low NAD⁺/SIRT Pathway Expression in Adipose Tissue of BMI-Discordant Monozygotic Twins