Elsevier

Journal of Hepatology

Volume 59, Issue 6, December 2013, Pages 1315-1322
Journal of Hepatology

Research Article
Adipose tissue and liver expression of SIRT1, 3, and 6 increase after extensive weight loss in morbid obesity

https://doi.org/10.1016/j.jhep.2013.07.027Get rights and content

Background & Aims

Severe obesity is associated with a state of chronic inflammation. Sirtuins (SIRT) are a family of conserved enzymes which are able to affect many metabolic and inflammatory pathways thereby potentially improving health and increasing lifespan.

Methods

We investigated the effect of weight loss on subcutaneous adipose tissue and liver mRNA and immunohistochemical expression of SIRT1, SIRT3, and SIRT6. Twenty-nine severely obese patients undergoing laparoscopic adjustable gastric banding (LAGB) were studied. Tissue samples were collected before and 6 months after LAGB surgery. Tissue mRNA expression levels of SIRT1, SIRT3, and SIRT6 were correlated with clinical, biochemical, and histological parameters. In vitro, we studied sirtuin expression in native and stimulated monocytes, adipocytes, and hepatocytes.

Results

SIRT1, SIRT3, and SIRT6 mRNA expression was higher in the subcutaneous adipose tissue than in the liver. Weight loss resulted in a significant induction of SIRT1, SIRT3, and SIRT6 expression in the subcutaneous adipose tissue. In the liver, a significant increase after weight loss was observed, particularly for SIRT3 and SIRT6 mRNA expression; immunohistochemically, SIRT1 and SIRT3 expression was upregulated. Endotoxin and tumor necrosis factor-alpha suppressed SIRT1, SIRT3, and SIRT6 expression in human monocytes. The same stimuli suppressed total sirtuin deacetylase activity again, mainly in monocytes and less in adipocytes and hepatocytes.

Conclusions

The relative abundance of adipose tissue mRNA expression of certain sirtuins exceeds its expression in the liver. Extensive weight loss increases sirtuin expression significantly both in adipose tissue and liver, probably as a consequence of reduced inflammation.

Introduction

Obesity is a worldwide pandemic disease affecting mortality. In recent years, our knowledge of mechanisms linking weight gain, obesity, and insulin resistance has expanded tremendously. On the other hand, many factors remain to be defined such as why only two thirds of the obese population develop obesity-related complications and one third remains “metabolically normal”. Data from several studies have suggested that metabolic dysfunction in obesity is associated with adipose tissue inflammation [1]. Since the first description of increased tumour necrosis factor-alpha (TNF-α) expression in the adipose tissue from obese people [2], data from numerous studies have revealed increased expression of various inflammatory and immune mediators. Adipose tissue, which is infiltrated by monocytes/macrophages and other inflammatory cells in morbid obesity [3], [4], [5], secretes numerous soluble mediators including adipocytokines, many classical cytokines such as TNF-α, interleukin (IL)-6, and IL-1 family members [6], [7], [8].

Sirtuins are a family of highly-conserved enzymes which have been discovered a decade ago. Sirtuins have been shown to affect different metabolic pathways thereby increasing life span and improving health in yeast, nematodes, and flies [9]. Moreover, sirtuins have been implicated in the regulation of inflammatory responses, such as TNF-α expression, in a NAD-dependent manner [10]. The role of the seven mammalian sirtuins, SIRT1 to SIRT7, in regulating lifespan, however, remains unclear and under discussion. For example, recent experiments in Caenorhabditis elegans and Drosophila melanogaster raised doubts on the role of SIRT2 on lifespan extension after calorie restriction [11], [12], [13]. Discussion has been reopened as a recent report observed for the first time that overexpression of a specific sirtuin can extend lifespan in mammals. In the report, male but not female mice overexpressing SIRT6 had a significantly longer lifespan than wild type mice [14], placing sirtuins again at the front line of ageing research.

Sirtuins have been demonstrated to regulate several metabolic and inflammatory pathways [9]. As the effects of weight loss on tissue expression of sirtuins after weight loss have not been investigated, we studied the expression of SIRT1, SIRT3, and SIRT6 in adipose and liver tissue in subjects undergoing bariatric surgery before and 6 months after surgery. In vitro, we studied the effect of pro-inflammatory stimuli on SIRT1, SIRT3, and SIRT6 mRNA and protein expression as well as nuclear sirtuin deacetylase activity.

Section snippets

Selection of patients

A total of 29 (7 male, 22 female) severely obese patients (BMI >40 kg/m2 or BMI >35 kg/m2 with significant co-morbidity) were enrolled in the study. All patients underwent minute clinical evaluation in our outpatient clinics for metabolic diseases and had a minimum 5-year history of unsuccessful attempts on dietary weight reduction. Type 2 diabetes mellitus, as defined by a fasting glucose of >126 mg/dl, was diagnosed in 3 patients (10.4%) before, and none of the patients after weight loss.

Changes in anthropomorphic, biochemical, and metabolic parameters

Twenty-two female (75.8%) and 7 male (24.2%) patients were included in this study. Gender-specific analyses did not result in significant differences between male and female subjects (data not shown). Placement of a laparoscopic gastric band was associated with an unmistakable weight loss after 6 months, ranging from 9.8 to 50.5 kg corresponding to a mean weight loss of 21.5 ± 9.8 kg. Accordingly, the mean BMI dropped from 43.2 ± 3.7 to 35.9 ± 4.7. Five-year longitudinal LAGB-induced weight loss data

Discussion

Sirtuins are highly conserved NAD+-dependent deacetylases that regulate lipid and glucose metabolism in the liver and have been shown to affect lifespan in several model organisms including mice. Although such effects are currently not entirely explained, sirtuins, especially SIRT6, regulate the activity of insulin and IGF-1, and interfere with inflammation, DNA repair, and cancer development [22]. We now demonstrate that (i) subcutaneous adipose tissue expresses significant quantities of

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Acknowledgements

We are indebted to the nursing staff at the Departments of Medicine and Surgery, Medical University Innsbruck. This work has been supported by the Christian Doppler Research Society.

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    These authors contributed equally to this work.

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