Touchstone Diabetes Center

Medicine, United States

Touchstone Diabetes Center

Medicine, United States
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Chen Z.,Center for Genetics of Host Defense | Holland W.,Touchstone Diabetes Center | Zhan X.,Center for Genetics of Host Defense | Zhan X.,CJ CheilJedang Inc. | And 7 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Sterile alpha motif domain containing protein 4 (Samd4) is an RNA binding protein that mediates translational repression. We identified a Samd4 missense mutation, designated supermodel, that caused leanness and kyphosis associated with myopathy and adipocyte defects in C57BL/6J mice. The supermodel mutation protected homozygous mice from high fat diet-induced obesity, likely by promoting enhanced energy expenditure through uncoupled mitochondrial respiration. Glucose tolerance was impaired due to diminished insulin release in homozygous mutant mice. The defects of metabolism in supermodel mice may be explained by dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling, evidenced by hypophosphorylation of 4E-BP1 and S6 in muscle and adipose tissues of homozygous mice. Samd4 may interface with mTORC1 signaling through an interaction with 14-3-3 proteins and with Akt, which phosphorylates Samd4 in vitro.

Nguyen H.,Histology and Immunohistochemistry | John G.B.,UT Southwestern Medical School | Scherer P.E.,Touchstone Diabetes Center
Aesthetic Surgery Journal | Year: 2014

Background: Light and electron microscopy have not identified a distinct anatomical structure associated with either skin wrinkles or creases, and a histological difference between wrinkled and adjacent skin has not been identified. Objectives: The authors investigate whether facial wrinkles are related to underlying lymphatic vessels and perilymphatic fat. Methods: Lymphatic vessels with a specialized tube of perilymphatic fat were identified beneath palmar creases. Sections of skin, adipose tissue, and muscle were harvested from each of 13 cadavers. Three sites were investigated: the transverse forehead crease, lateral orbicularis oculi wrinkle (crows feet), and the nasojugal crease. The tissue was paraffin embedded and processed. Two-step indirect immunohistochemistry was performed, and images were examined using laser confocal microscopy. Measurements were taken with software. Results: Every wrinkle examined was found above and within 1 mm of a major lymphatic vessel and its surrounding tube of adipose tissue. The results satisfied our null hypothesis and were statistically significant. Lymphatic vessels were identified by positive immunofluorescence as well as histological criteria. These findings have been further validated by fluorochrome tracer studies. Conclusions: An anatomical basis for wrinkles was identified among the specimens studied. Lymphatic vessels, along with the surrounding distinct perilymphatic fat, traveled directly beneath wrinkles and creases. Lymphatic dysregulation leads to inflammation, scarring, and fibrosis, but inadvertent injection of these vessels can be avoided with anatomical knowledge. © 2013 The American Society for Aesthetic Plastic Surgery, Inc.

Gaich G.,Lilly Research Laboratories | Chien J.Y.,Lilly Research Laboratories | Fu H.,Lilly Research Laboratories | Glass L.C.,Lilly Research Laboratories | And 6 more authors.
Cell Metabolism | Year: 2013

Summary Fibroblast growth factor 21 (FGF21) is a recently discovered metabolic regulator. Exogenous FGF21 produces beneficial metabolic effects in animal models; however, the translation of these observations to humans has not been tested. Here, we studied the effects of LY2405319 (LY), a variant of FGF21, in a randomized, placebo-controlled, double-blind proof-of-concept trial in patients with obesity and type 2 diabetes. Patients received placebo or 3, 10, or 20 mg of LY daily for 28 days. LY treatment produced significant improvements in dyslipidemia, including decreases in low-density lipoprotein cholesterol and triglycerides and increases in high-density lipoprotein cholesterol and a shift to a potentially less atherogenic apolipoprotein concentration profile. Favorable effects on body weight, fasting insulin, and adiponectin were also detected. However, only a trend toward glucose lowering was observed. These results indicate that FGF21 is bioactive in humans and suggest that FGF21-based therapies may be effective for the treatment of selected metabolic disorders. © 2013 Elsevier Inc.

Wernstedt Asterholm I.,Touchstone Diabetes Center | Wernstedt Asterholm I.,Gothenburg University | Tao C.,Touchstone Diabetes Center | Morley T.S.,Touchstone Diabetes Center | And 5 more authors.
Cell Metabolism | Year: 2014

Chronic inflammation constitutes an important link between obesity and its pathophysiological sequelae. In contrast to the belief that inflammatory signals exert a fundamentally negative impact on metabolism, we show that proinflammatory signaling in the adipocyte is in fact required for proper adipose tissue remodeling and expansion. Three mouse models with an adipose tissue-specific reduction in proinflammatory potential were generated that display a reduced capacity for adipogenesis in vivo, while the differentiation potential is unaltered in vitro. Upon high-fat-diet exposure, the expansion of visceral adipose tissue is prominently affected. This is associated with decreased intestinal barrier function, increased hepatic steatosis, and metabolic dysfunction. An impaired local proinflammatory response in the adipocyte leads to increased ectopic lipid accumulation, glucose intolerance, and systemic inflammation. Adipose tissue inflammation is therefore an adaptive response that enables safe storage of excess nutrients and contributes to a visceral depot barrier that effectively filters gut-derived endotoxin. © 2014 Elsevier Inc.

Sun K.,Touchstone Diabetes Center | Scherer P.E.,Touchstone Diabetes Center | Scherer P.E.,University of Texas Southwestern Medical Center
Cell Research | Year: 2012

Adipose tissue remodeling is a dynamic process during nutritional fluctuation that plays critical roles in metabolic homeostasis and insulin sensitivity. The process is highly regulated by many factors, including adipokines and cytokines that are locally released within fat pads. In a recent study published in Nature, Jonker and colleagues identified FGF1 as an important mediator that is selectively induced in fat cells by high-fat diet feeding and established the PPARγ-FGF1 axis as a critical pathway that regulates adipose tissue remodeling and ultimately systemic metabolic homeostasis. © 2012 IBCB, SIBS, CAS All rights reserved.

Gupta R.K.,Touchstone Diabetes Center
Current Biology | Year: 2014

In the United States alone, one-third of adults and nearly one-quarter of children are clinically obese. This growing epidemic is of serious concern as obesity confers a significant risk to developing numerous chronic conditions, including cancer, diabetes, and heart disease. The alarming incidence of obesity and the rising costs of treating the associated diseases has increased the urgency of acquiring a deeper understanding of all aspects of adipocyte (fat cell) biology, including how these cells form, how they are regulated, and how increased adiposity leads to disease. Since the turn of the new century we have witnessed great progress in understanding the complexities of adipocyte function and their developmental origin. As a result, our view of adipocytes has now changed dramatically. Here, I provide a brief primer on some of the hot topics that have emerged in this field of research, which now includes aspects of endocrinology, cardiology, cancer biology, and stem cell and developmental biology. I also highlight some of the unique opportunities for therapeutic targeting of adipose tissue in metabolic disease. © 2014 Elsevier Ltd. All rights reserved..

Stern J.H.,Touchstone Diabetes Center | Scherer P.E.,Touchstone Diabetes Center
Nature Reviews Gastroenterology and Hepatology | Year: 2015

In 2014, numerous noteworthy papers focusing on adipose tissue physiology were published. Many of these articles showed the promise of adipose-tissue-targeted approaches for therapeutic intervention in obesity and type 2 diabetes mellitus. Here, we highlight advances in the development and maintenance of brown and/or beige adipocytes and the metabolic implications of inflammation in adipose tissues. © 2015 Macmillan Publishers Limited.

Lamb T.M.,Texas A&M University | Finch K.E.,Texas A&M University | Finch K.E.,Touchstone Diabetes Center | Bell-Pedersen D.,Texas A&M University
Fungal Genetics and Biology | Year: 2012

The OS-pathway mitogen-activated protein kinase (MAPK) cascade of Neurospora crassa is responsible for adaptation to osmotic stress. Activation of the MAPK, OS-2, leads to the transcriptional induction of many genes involved in the osmotic stress response. We previously demonstrated that there is a circadian rhythm in the phosphorylation of OS-2 under constant non-stress inducing conditions. Additionally, several osmotic stress-induced genes are known to be regulated by the circadian clock. Therefore, we investigated if rhythms in activation of OS-2 lead to circadian rhythms in other known stress responsive targets. Here we identify three more osmotic stress induced genes as rhythmic: cat-1, gcy-1, and gcy-3. These genes encode a catalase and two predicted glycerol dehydrogenases thought to be involved in the production of glycerol. Rhythms in these genes depend upon the oscillator component FRQ. To investigate how the circadian signal is propagated to these stress induced genes, we examined the role of the OS-responsive transcription factor, ASL-1, in mediating circadian gene expression. We find that while the asl-1 transcript is induced by several stresses including an osmotic shock, asl-1 mRNA accumulation is not rhythmic. However, we show that ASL-1 is required for generating normal circadian rhythms of some OS-pathway responsive transcripts (bli-3, ccg-1, cat-1, gcy-1 and gcy-3) in the absence of an osmotic stress. These data are consistent with the possibility that post-transcriptional regulation of ASL-1 by the rhythmically activated OS-2 MAPK could play a role in generating rhythms in downstream targets. © 2011 Elsevier Inc.

Wang Q.A.,Touchstone Diabetes Center | Scherer P.E.,Touchstone Diabetes Center | Scherer P.E.,University of Texas Southwestern Medical Center | Gupta R.K.,Touchstone Diabetes Center
Journal of Lipid Research | Year: 2014

Adipocyte differentiation and function have become areas of intense focus in the field of energy metabolism; however, understanding the role of specific genes inthe establishment and maintenance of fat cell function can be challenging and complex. In this review, we offer practical guidelines for the study of adipocyte development and function. We discuss improved cellular and genetic systems for the study of adipose biology and highlight recent insights gained from these new approaches. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

Rutkowski J.M.,Touchstone Diabetes Center | Scherer P.E.,Touchstone Diabetes Center | Scherer P.E.,Southwestern Medical Center
Methods in Enzymology | Year: 2014

Adiponectin is a circulating bioactive hormone secreted by adipocytes as oligomers ranging in size from 90 kDa trimers and 180 kDa hexamers to larger high molecular weight oligomers that may reach 18- or 36-mers in size. While total circulating adiponectin levels correlate well with metabolic health, it is the relative distribution of adiponectin complexes that is most clinically relevant to glucose sensitivity and inflammation. High molecular weight adiponectin best mirrors insulin sensitivity, while trimeric adiponectin dominates with insulin resistance and adipose tissue inflammation. Experimental animal and in vitro models have also linked the relative fraction of high molecular weight adiponectin to its positive effects. Quantitating adiponectin size distribution thus provides a window into metabolic health and can serve as a surrogate marker for adipose tissue fitness. Here, we present a detailed protocol for isolating and quantitating adiponectin complexes in serum or plasma that has been extensively utilized for both human clinical samples and numerous animal models under various experimental conditions. Examples are presented of different adiponectin distributions and tips are provided for optimization using available equipment. Comparison of this rigorous approach to other available methods is also discussed. In total, this summary is a blueprint for the expanded quantitation and study of adiponectin complexes. © 2014 Elsevier Inc.

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