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      The Multifaceted Roles of Adipose Tissue—Therapeutic Targets for Diabetes and Beyond: The 2015 Banting Lecture

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      Diabetes
      American Diabetes Association

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          Abstract

          The Banting Medal for Scientific Achievement is the highest scientific award of the American Diabetes Association (ADA). Given in memory of Sir Frederick Banting, one of the key investigators in the discovery of insulin, the Banting Medal is awarded annually for scientific excellence, recognizing significant long-term contributions to the understanding, treatment, or prevention of diabetes. Philipp E. Scherer, PhD, of the Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX, received the prestigious award at the ADA's 75th Scientific Sessions, 5–9 June 2015, in Boston, MA. He presented the Banting Lecture, “The Multifaceted Roles of Adipose Tissue—Therapeutic Targets for Diabetes and Beyond,” on Sunday, 7 June 2015.

          A number of different cell types contribute to the cellular architecture of adipose tissue. Although the adipocyte is functionally making important contributions to systemic metabolic homeostatis, several additional cell types contribute a supportive role to bestow maximal flexibility on the tissue with respect to many biosynthetic and catabolic processes, depending on the metabolic state. These cells include vascular endothelial cells, a host of immune cells, and adipocyte precursor cells and fibroblasts. Combined, these cell types give rise to a tissue with remarkable flexibility with respect to expansion and contraction, while optimizing the ability of the tissue to act as an endocrine organ through the release of many protein factors, critically influencing systemic lipid homeostasis and biochemically contributing many metabolites. Using an example from each of these categories—adiponectin as a key adipokine, sphingolipids as critical mediators of insulin sensitivity, and uridine as an important metabolite contributed by the adipocyte to the systemic pool—I will discuss the emerging genesis of the adipocyte over the past 20 years from metabolic bystander to key driver of metabolic flexibility.

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          Most cited references51

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          Obesity-associated improvements in metabolic profile through expansion of adipose tissue.

          Excess caloric intake can lead to insulin resistance. The underlying reasons are complex but likely related to ectopic lipid deposition in nonadipose tissue. We hypothesized that the inability to appropriately expand subcutaneous adipose tissue may be an underlying reason for insulin resistance and beta cell failure. Mice lacking leptin while overexpressing adiponectin showed normalized glucose and insulin levels and dramatically improved glucose as well as positively affected serum triglyceride levels. Therefore, modestly increasing the levels of circulating full-length adiponectin completely rescued the diabetic phenotype in ob/ob mice. They displayed increased expression of PPARgamma target genes and a reduction in macrophage infiltration in adipose tissue and systemic inflammation. As a result, the transgenic mice were morbidly obese, with significantly higher levels of adipose tissue than their ob/ob littermates, leading to an interesting dichotomy of increased fat mass associated with improvement in insulin sensitivity. Based on these data, we propose that adiponectin acts as a peripheral "starvation" signal promoting the storage of triglycerides preferentially in adipose tissue. As a consequence, reduced triglyceride levels in the liver and muscle convey improved systemic insulin sensitivity. These mice therefore represent what we believe is a novel model of morbid obesity associated with an improved metabolic profile.
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            Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI.

            Adipocytes are embedded in a unique extracellular matrix whose main function is to provide mechanical support, in addition to participating in a variety of signaling events. During adipose tissue expansion, the extracellular matrix requires remodeling to accommodate adipocyte growth. Here, we demonstrate a general upregulation of several extracellular matrix components in adipose tissue in the diabetic state, therefore implicating "adipose tissue fibrosis" as a hallmark of metabolically challenged adipocytes. Collagen VI is a highly enriched extracellular matrix component of adipose tissue. The absence of collagen VI results in the uninhibited expansion of individual adipocytes and is paradoxically associated with substantial improvements in whole-body energy homeostasis, both with high-fat diet exposure and in the ob/ob background. Collectively, our data suggest that weakening the extracellular scaffold of adipocytes enables their stress-free expansion during states of positive energy balance, which is consequently associated with an improved inflammatory profile. Therefore, the disproportionate accumulation of extracellular matrix components in adipose tissue may not be merely an epiphenomenon of metabolically challenging conditions but may also directly contribute to a failure to expand adipose tissue mass during states of excess caloric intake.
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              Fibrosis and adipose tissue dysfunction.

              Fibrosis is increasingly appreciated as a major player in adipose tissue dysfunction. In rapidly expanding adipose tissue, pervasive hypoxia leads to an induction of HIF1α that in turn leads to a potent profibrotic transcriptional program. The pathophysiological impact of adipose tissue fibrosis is likely to play an equally important role on systemic metabolic alterations as fibrotic conditions play in the liver, heart, and kidney. Here, we discuss recent advances in our understanding of the genesis, modulation, and systemic impact of excessive extracellular matrix (ECM) accumulation in adipose tissue of both rodents and humans and the ensuing impact on metabolic dysfunction. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Diabetes
                Diabetes
                diabetes
                diabetes
                Diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                June 2016
                18 May 2016
                : 65
                : 6
                : 1452-1461
                Affiliations
                Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX
                Author notes
                Corresponding author: Philipp E. Scherer, philipp.scherer@ 123456utsouthwestern.edu .
                Article
                0339
                10.2337/db16-0339
                4878420
                27222389
                7324d32c-f34b-477b-8111-198c49a8e73d
                © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
                History
                : 14 March 2016
                : 28 March 2016
                Page count
                Pages: 10
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases http://dx.doi.org/10.13039/100000062
                Award ID: P01-DK088761
                Award ID: R01-DK099110
                Award ID: R01-DK55758
                Categories
                Banting Lecture

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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