Association between low SIRT1 expression in visceral and subcutaneous adipose tissues and metabolic abnormalities in women with obesity and type 2 diabetes

https://doi.org/10.1016/j.diabres.2013.07.002Get rights and content

Abstract

Aims

To assess the importance of adipose tissue sirtuin 1 (SIRT1) in the regulation of whole-body metabolism in humans with obesity and type 2 diabetes.

Methods

In total, 19 non-diabetic obese women, 19 type 2 diabetic women undergoing gastric bypass surgery, and 27 normal-weight women undergoing gynecological surgery (total 65 women) were enrolled. Their anthropometric variables, abdominal fat distribution and metabolic parameters, serum adiponectin concentrations, and SIRT1 mRNA and protein and adiponectin mRNA expressions in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured.

Results

SIRT1 mRNA levels in VAT and SAT were similar and these levels were suppressed in obese and type 2 diabetic women compared to normal-weight subjects. These decreases in SIRT1 expression were observed in both adipocytes and non-fat cells. There was a strong association between adipose tissue SIRT1 mRNA and protein levels. Adipose SIRT1 expression correlated inversely with HOMA-IR and other insulin resistance-related parameters. Adipose SIRT1 and adiponectin mRNA expression correlated very strongly and positively. SIRT1 mRNA level in VAT correlated inversely with visceral obesity whereas its expression in SAT correlated negatively with body mass index.

Conclusions

Adipose tissue SIRT1 may play a key role in the regulation of whole body metabolic homeostasis in humans. Downregulation of SIRT1 in VAT may contribute to the metabolic abnormalities that are associated with visceral obesity.

Introduction

The yeast protein silent information regulator 2 (SIR2) is an NAD+-dependent protein deacetylase that is linked to the extension of lifespan that occurs in calorie restriction [1]. SIRT1, the mammalian protein with the highest homology to SIR2, is also associated with increased longevity in rodents on restricted calorie diets [2]. Calorie restriction also produces metabolic profiles that are associated with improvements in obesity-related diseases such as insulin resistance and type 2 diabetes; it has been claimed that the beneficial cellular effects of calorie restriction are largely mediated by the induction of SIRT1 [3]. Moreover, the dependence of SIRT1 activity on NAD+ levels means that it may serve as a sensor of changes in the nutritional status of cells and thereby mediate the regulation of metabolic processes [4]. Thus, it appears that SIRT1 may regulate the metabolic pathways that are modulated in calorie restriction and in obesity that is mainly caused by long-term calorie overload.

Adipose tissue serves as a storage site for lipids but also as an endocrine organ that secretes biologically active molecules that participate in whole-body energy metabolism and inflammation. Thus, by dysregulating these functions, adipose tissue itself is involved in the development of obesity-related disorders [5]. In adipose tissues, SIRT1 suppresses adipocyte differentiation and lipid accumulation by repressing peroxisome proliferator-activated receptor-γ [6]. SIRT1 is also a major regulator of the transcription and secretion of adiponectin, an adipokine that appears to be an important mediator of insulin sensitivity [7], [8]. In addition, SIRT1 suppresses adipose tissue inflammation by repressing nuclear factor (NF)-κB signaling [9], [10], [11], [12]. Conversely, adipocyte SIRT1 expression is suppressed in high-fat diet fed and genetically obese rodents [8]. Thus, impaired SIRT1 expression and activity in adipose tissues has been implicated in the development of obesity-related diseases [13], [14], [15].

Although SIRT1 has been extensively studied in cultured cells and experimental animals, there are only a few studies that have examined the expression and functions of SIRT1 in human adipose tissue. One of these showed that fasting in humans increases SIRT1 mRNA expression in subcutaneous adipose tissue (SAT) [16]. Conversely, SIRT1 mRNA expression in SAT is suppressed in obese subjects [9], [16]. In addition, SIRT1 mRNA levels correlate inversely with macrophage content in SAT of lean and obese human subjects [9]. Recently, SAT SIRT1 mRNA levels were found to associate significantly with energy expenditure and insulin sensitivity during hyperinsulinemic euglycemic clamps [17].

In the present study, the contribution of impaired SIRT1 expression in adipose tissues to the metabolic derangements associated with human obesity was assessed by addressing the following questions: (1) is SIRT1 expression in visceral adipose tissue (VAT) and SAT suppressed in obesity and type 2 diabetes; (2) if so, do SIRT1 mRNA levels associate with other metabolic parameters or abdominal fat distribution; and (3) do SIRT1 mRNA levels in human adipose tissues correlate with adiponectin mRNA levels in the same tissues? To answer these questions, paired VAT and SAT samples were obtained from obese, type 2 diabetic, and normal women undergoing abdominal surgery.

Section snippets

Study subjects

The study cohort consisted of 19 non-diabetic obese women (BMI  30), 19 women with type 2 diabetes, and 27 normal-weight (BMI  25) women. All obese and diabetic subjects were patients who underwent laparoscopic Roux-en-Y gastric bypass at the Obesity Center of the Inha University Hospital (Incheon, Korea) between July, 2010 and March, 2011. Four days before surgery, these patients were admitted and underwent routine physical examinations, systematic fasting biological analyses, and abdominal

Characteristics of the subjects

The clinical characteristics of the obesity, diabetes, and normal-weight control groups are described in Table 1 and their metabolic characteristics are summarized in Table 2. The obesity group (32.5 ± 1.98 yr) was significantly younger than the control group (39.7 ± 2.11 yr; p < 0.05) and the diabetes group (45.6 ± 1.90 yr; p < 0.01). Compared to the control group, the obesity group had significantly higher systolic and diastolic BP, HOMA-IR, and fasting plasma insulin and triglyceride concentrations,

Discussion

There is increasing evidence that SIRT1 plays an important role in the regulation of energy metabolism and glucose homeostasis [3]. This, together with the observation that adipose tissue itself participates in the pathogenesis of obesity-related disorders [5], has focused attention on the role that impaired SIRT1 expression in adipose tissues may play in the development of obesity-related diseases. While there are increasing studies on SIRT1 in cultured cell lines and experimental animals,

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0011591, 2011-0017028).

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