Alterations of Pancreatic Islet Structure, Metabolism and Gene Expression in Diet-Induced Obese C57BL/6J Mice

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From: PLoS ONE(Vol. 9, Issue 2)
Publisher: Public Library of Science
Document Type: Article
Length: 6,413 words
Lexile Measure: 1560L

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Author(s): Regan Roat 1, Vandana Rao 1, Nicolai M. Doliba 2, Franz M. Matschinsky 2, John W. Tobias 3, Eden Garcia 4, Rexford S. Ahima 1, Yumi Imai 1,4,*


Insulin resistance commonly seen in obesity is considered a risk factor for the development of type 2 diabetes (T2D) [1]. However, the failure of pancreatic islet insulin secretion to compensate for insulin resistance is the critical pathology that ultimately leads to T2D [2]-[4]. The critical role islets play in the pathogenesis of T2D is evidenced by gene wide association studies (GWAS) that have identified susceptibility loci for T2D more frequently associated with islet functions than insulin sensitivity [5]. Moreover, the progressive worsening of T2D in humans is thought to result from a gradual loss of functional [beta] cell mass [3]. Thus, there is strong interest in dissecting the molecular pathways that lead to the decline in mass and function of [beta] cells in T2D, especially as the disease remains a serious public health challenge with limited numbers of effective therapies to reverse the pathology [6].

Various animal models of obesity and diabetes have been used to identify mechanisms responsible for the development of T2D, and to test the efficacy of therapeutic interventions [7]. C57BL/6J (BL6J) mouse on high fat diet (HF) has been one of the most commonly employed models due to its wide availability, and the ease of genetic manipulation [8]. In addition, the development of obesity in BL6J results from diet and multiple genetic susceptibility loci in BL6J, and thus mimics human obesity [9]. Of note, BL6J from the Jackson laboratories, widely used especially in the US, carries a naturally occurring deletion of functional nicotinamide nucleotide transhydrogenase (NNT) protein [10]. NNT, an antioxidant defense gene, catalyzes the production of NADPH that facilitates detoxification of reactive oxygen species (ROS) through the regeneration of reduced glutathione, and knockdown of NNT increases ROS. NNT mutation in BL6J is reported to reduce insulin secretion compared with BL6 without NNT mutation [10]. However, despite their wide use, the analyses that focus on functional, morphological, and gene expression changes in islets of this model with NNT mutation upon HF challenge are relatively limited. Considering the critical role of islets in the development and progression of T2D in humans, we aimed to obtain comprehensive metabolic and gene expression data in islets associated with diet-induced obesity in this T2D mouse model with NNT mutation. We have identified wide arrays of structural, secretory, metabolic, and gene expression alterations in islets from HF fed BL6J that implicate both adaptation and decompensation to insulin resistance.

Materials and Methods

Animal studies

Experiments were performed in accordance with the Institutional Animal Care and Use Committee guidelines with its approvals. 4 week-old male BL6J mice (Jackson Laboratories) were housed n = 5/cage in 12 hour light: dark cycle, at ambient temperature of 22°C, and allowed free access to food and water. Groups of mice were fed normal rodent chow (NC) (4 kcal% fat; 5001 from Lab Diet), or high fat diet (HF)...

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Gale Document Number: GALE|A478827712