Obesity Resistance and Enhanced Insulin Sensitivity in Ahnak-/- Mice Fed a High Fat Diet Are Related to Impaired Adipogenesis and Increased Energy Expenditure

Shin, Jae Hoon; Kim, Il Yong; Kim, Yo Na; Shin, Sujin; Roh, Kyung Jin; Lee, Seo Hyun; Sohn, Minji; Cho, Soo Young; Lee, Sang Hyuk; Ko, Chang-Yong; Kim, Han Sung; Choi, Cheol Soo; Bae, Yun Soo; Seong, Je Kyung

doi:10.1371/journal.pone.0139720

Cited by 24 publications

(32 citation statements)

References 52 publications

(52 reference statements)

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“…In our previous studies, we reported that Ahnak À/À mice exhibit enhanced insulin sensitivity, higher energy expenditure, upregulated lipolysis of white adipose tissues, and impaired adipocyte differentiation (8,16,17). Intriguingly, we found pneumocyte hyperplasia and lung tumor development in Ahnak À/À mice.…”

Section: Introductionmentioning

confidence: 54%

“…25). AHNAK mRNA expression is highest in normal lung tissue among human tissues (15), and Ahnak mRNA was abundantly expressed in mouse lung tissue (26), suggesting physiologically important roles of Ahnak in lung. Collectively, these findings suggest that downregulation of Ahnak gene expression is associated with lung tumorigenesis.…”

Section: Ahnak Protein Expression Is Downregulated In Human Lung Cancersmentioning

confidence: 96%

“…Ahnak is an exceptionally large protein (700 kDa) that was initially identified from human neuroblastomas and skin epithelial cells (5,6). Ahnak is known to be a scaffolding protein that regulates cytoskeletal structure formation, muscle regeneration, calcium homeostasis, and signaling (7,8). Structurally, Ahnak is divided into three distinct regions: the amino-terminal region of 500 amino acids, the large central region of about 4,388 amino acids composed of 36 repeat units, and the carboxyl-terminal region of 1,003 amino acids (9).…”

Section: Introductionmentioning

confidence: 99%

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AHNAK Loss in Mice Promotes Type II Pneumocyte Hyperplasia and Lung Tumor Development

Park

Kim

Choi

et al. 2018

Molecular Cancer Research

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AHNAK is known to be a tumor suppressor in breast cancer due to its ability to activate the TGFβ signaling pathway. However, the role of AHNAK in lung tumor development and progression remains unknown. Here, the Ahnak gene was disrupted to determine its effect on lung tumorigenesis and the mechanism by which it triggers lung tumor development was investigated. First, AHNAK protein expression was determined to be decreased in human lung adenocarcinomas compared with matched nonneoplastic lung tissues. Then, Ahnak mice were used to investigate the role of AHNAK in pulmonary tumorigenesis. Ahnak mice showed increased lung volume and thicker alveolar walls with type II pneumocyte hyperplasia. Most importantly, approximately 20% of aged Ahnak mice developed lung tumors, and Ahnak mice were more susceptible to urethane-induced pulmonary carcinogenesis than wild-type mice. Mechanistically, Ahnak deficiency promotes the cell growth of lung epithelial cells by suppressing the TGFβ signaling pathway. In addition, increased numbers of M2-like alveolar macrophages (AM) were observed in Ahnak lungs, and the depletion of AMs in Ahnak lungs alleviated lung hyperplastic lesions, suggesting that M2-like AMs promoted the progression of lung hyperplastic lesions in Ahnak-null mice. Collectively, AHNAK suppresses type II pneumocyte proliferation and inhibits tumor-promoting M2 alternative activation of macrophages in mouse lung tissue. These results suggest that AHNAK functions as a novel tumor suppressor in lung cancer. The tumor suppressor function of AHNAK, in murine lungs, occurs by suppressing alveolar epithelial cell proliferation and modulating lung microenvironment. .

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Section: Introductionmentioning

confidence: 54%

Section: Ahnak Protein Expression Is Downregulated In Human Lung Cancersmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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AHNAK Loss in Mice Promotes Type II Pneumocyte Hyperplasia and Lung Tumor Development

Park

Kim

Choi

et al. 2018

Molecular Cancer Research

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“…In contrast to HDAC9, the peptidyl prolyl cis/trans isomerase Pin‐1 is upregulated during obesity (Nakatsu et al, ) and was shown through KO studies to be indispensable for adipogenesis in ASCs, which is consistent with observations that both genetic and chemical inhibition of Pin1 protected mice against diet‐induced obesity (A. Suzuki, Saeki, Ikuji, Uchida, & Uchida, ). Similar to Pin1, expression of the scaffolding protein Ahnak, which facilitates the Smad‐1 signaling required to induce PPARγ2 expression during adipogenesis, is also elevated in obesity and is upregulated during adipogenesis (J. Li, Yu, Pan, & Unger, ; J. H. Shin et al, ). Ahnak KO mice exhibited decreased fat mass and smaller adipocytes within adipose tissue, which correlated with the reduced adipogenesis observed in cultured ASCs harvested from these animals (J. H. Shin et al, , S. Shin, Seong, & Bae, ).…”

Section: Overview Of Recently Published Work In Ascsmentioning

confidence: 99%

“…Similar to Pin1, expression of the scaffolding protein Ahnak, which facilitates the Smad‐1 signaling required to induce PPARγ2 expression during adipogenesis, is also elevated in obesity and is upregulated during adipogenesis (J. Li, Yu, Pan, & Unger, ; J. H. Shin et al, ). Ahnak KO mice exhibited decreased fat mass and smaller adipocytes within adipose tissue, which correlated with the reduced adipogenesis observed in cultured ASCs harvested from these animals (J. H. Shin et al, , S. Shin, Seong, & Bae, ).…”

Section: Overview Of Recently Published Work In Ascsmentioning

confidence: 99%

Adipocyte biology: It is time to upgrade to a new model

Gijsen

2018

Journal Cellular Physiology

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Globally, the obesity pandemic is profoundly affecting quality of life and economic productivity, but efforts to address this, especially on a pharmacological level, have generally proven unsuccessful to date, serving as a stark demonstration that our understanding of adipocyte biology and pathophysiology is incomplete. To deliver better insight into adipocyte function and obesity, we need improved adipocyte models with a high degree of fidelity in representing the in vivo state and with a diverse range of experimental applications. Adipocyte cell lines, especially 3T3-L1 cells, have been used extensively over many years, but these are limited in terms of relevance and versatility. In this review, I propose that primary adipose-derived stromal/stem cells (ASCs) present a superior model with which to study adipocyte biology ex vivo. In particular, ASCs afford us the opportunity to study adipocytes from different, functionally distinct, adipose depots and to investigate, by means of in vivo/ex vivo studies, the effects of many different physiological and pathophysiological factors, such as age, body weight, hormonal status, diet and nutraceuticals, as well as disease and pharmacological treatments, on the biology of adipocytes and their precursors. This study will give an overview of the characteristics of ASCs and published studies utilizing ASCs, to highlight the areas where our knowledge is lacking. More comprehensive studies in primary ASCs will contribute to an improved understanding of adipose tissue, in healthy and dysfunctional states, which will enhance our efforts to more successfully manage and treat obesity.

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De novo lipogenesis and desaturation of fatty acids during adipogenesis in bovine adipose-derived mesenchymal stem cells

Yue

Zhang

et al. 2017

In Vitro Cell.Dev.Biol.-Animal

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Adipose-derived mesenchymal stem cells (ADSCs) are useful cell model to study adipogenesis and energy metabolism. However, the biological characteristics of bovine ADSCs (bADSCs) remain unclear. This study aimed to isolate and identify bADSCs and further investigate fatty acid (FA)-related gene expression and composition of FAs during adipogenesis. The growth curve showed the bADSCs of P5 cells had rapid proliferation superior to P10-P50. The colony formation assay showed colony number of P5 cells was higher than that of P50 cells (51.67 ± 3.06 vs 35.67 ± 6.43, P < 0.05). The immunofluorescence showed that bADSCs were positive for CD13, CD44, CD49d, CD90, CD105, and Vimentin while negative for CD34. The multipotential towards adipocyte, osteocyte, and chondrocyte was confirmed by specific histological staining and lineage gene expression. During adipogenic induction, the genes related to lipogenesis and lipolysis were assessed by real-time PCR and the FA composition was detected by GC-MS. Expression of lipogenesis-related genes showed coordinated regulation as peaking on day 7 and declining until induction ended, including PPARγ, SREBP1, ACC1, FAS, ELOVL6, SCD1, and FABP4. FA deposition-related genes (DGAT1 and ACAT1) increased until day 14. Lipolysis genes (CPT-1A, VLCAD, and ACO) showed a variant expression pattern. The profile of FAs showed that proportion of the FAs (C4-C15, ≥ C22) increased, but proportion of long-chain fatty acids (C16-C20) reduced after induction. And saturated FAs (SFA) decreased while monounsaturated FAs (MUFA) and polyunsaturated FAs (PUFA) increased during adipogenesis. These data suggest that bADSCs possess the characteristics of mesenchymal stem cells and have active de novo lipogenesis (DNL) and desaturation of FAs during adipogenesis.

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Obesity Resistance and Enhanced Insulin Sensitivity in Ahnak-/- Mice Fed a High Fat Diet Are Related to Impaired Adipogenesis and Increased Energy Expenditure

Cited by 24 publications

References 52 publications

AHNAK Loss in Mice Promotes Type II Pneumocyte Hyperplasia and Lung Tumor Development

AHNAK Loss in Mice Promotes Type II Pneumocyte Hyperplasia and Lung Tumor Development

Adipocyte biology: It is time to upgrade to a new model

De novo lipogenesis and desaturation of fatty acids during adipogenesis in bovine adipose-derived mesenchymal stem cells

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