PPARγ signaling and metabolism: the good, the bad and the future
Maryam Ahmadian,Jae Myoung Suh,Nasun Hah,Christopher Liddle,Annette R. Atkins,Michael Downes,Ronald M. Evans +6 more
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TLDR
This review highlights key advances in understanding PPARγ signaling in energy homeostasis and metabolic disease and also provides new explanations for adverse events linked to TZD-based therapy.Abstract:
Thiazolidinediones (TZDs) are potent insulin sensitizers that act through the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) and are highly effective oral medications for type 2 diabetes. However, their unique benefits are shadowed by the risk for fluid retention, weight gain, bone loss and congestive heart failure. This raises the question as to whether it is possible to build a safer generation of PPARγ-specific drugs that evoke fewer side effects while preserving insulin-sensitizing potential. Recent studies that have supported the continuing physiologic and therapeutic relevance of the PPARγ pathway also provide opportunities to develop newer classes of molecules that reduce or eliminate adverse effects. This review highlights key advances in understanding PPARγ signaling in energy homeostasis and metabolic disease and also provides new explanations for adverse events linked to TZD-based therapy.read more
Citations
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Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal.
TL;DR: This review focuses on biochemical concepts of lipidPeroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting geneexpression and promoting cell death.
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What We Talk About When We Talk About Fat
TL;DR: New perspective is gained on the roles played by adipocyte in a variety of homeostatic processes and on the mechanisms used by adipocytes to communicate with other tissues and how these relationships are altered during metabolic disease and how they might be manipulated to restore metabolic health.
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Macrophages, Immunity, and Metabolic Disease
TL;DR: The pathophysiological link between macrophages, obesity, and insulin resistance is discussed, highlighting the dynamic immune cell regulation of adipose tissue inflammation and the new therapeutic targets that have emerged.
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Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review.
Limei Wang,Birgit Waltenberger,Eva-Maria Pferschy-Wenzig,Martina Blunder,Xin Liu,Clemens Malainer,Tina Blazevic,Stefan Schwaiger,Judith M. Rollinger,Elke H. Heiss,Daniela Schuster,Brigitte Kopp,Rudolf Bauer,Hermann Stuppner,Verena M. Dirsch,Atanas G. Atanasov +15 more
TL;DR: A significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources.
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Regulation of metabolism by the innate immune system
TL;DR: The roles of innate immune cells involved in secreting inflammatory factors in the obese state, including proinflammatory adipose tissue macrophages and natural killer cells are reviewed.
References
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Journal ArticleDOI
Muscle-specific Pparg deletion causes insulin resistance
Andrea L. Hevener,Weimin He,Yaacov Barak,Jamie Le,Gautam Bandyopadhyay,Peter Olson,Peter Olson,Jason J. Wilkes,Ronald M. Evans,Ronald M. Evans,Jerrold M. Olefsky +10 more
TL;DR: A crucial role for muscle PPAR-γ in the maintenance of skeletal muscle insulin action, the etiology of insulin resistance and the action of TZDs is revealed.
Journal ArticleDOI
PPAR-γ regulates osteoclastogenesis in mice
TL;DR: Examination of the underlying mechanisms suggested that PPAR-γ functions as a direct regulator of c-fos expression, an essential mediator of osteoclastogenesis, and its ligands have a previously unrecognized role in promoting osteoc Last differentiation and bone resorption.
Journal ArticleDOI
Differential activation of adipogenesis by multiple PPAR isoforms.
Regina P. Brun,Peter Tontonoz,Barry M. Forman,Ramsey Ellis,J Chen,Ronald M. Evans,Bruce M. Spiegelman +6 more
TL;DR: Data strongly suggest that PPARgamma is the predominant receptor regulating adipogenesis; however, they also suggest thatPPARalpha may play a role in differentiation of certain adipose depots in response to a different set of physiologic activators or in certain disease states.
Journal ArticleDOI
Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation
Jang Hyun Choi,Alexander S. Banks,Theodore M. Kamenecka,Scott A. Busby,Michael J. Chalmers,Naresh Kumar,Dana S. Kuruvilla,Youseung Shin,Yuanjun He,John B. Bruning,David Marciano,Michael D. Cameron,Dina Laznik,Michael J. Jurczak,Stephan C. Schürer,Dusica Vidovic,Gerald I. Shulman,Bruce M. Spiegelman,Patrick R. Griffin +18 more
TL;DR: Novel synthetic compounds are described that have a unique mode of binding to PPARγ, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice, and one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PParγ drugs.
Journal ArticleDOI
Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones
Andrea L. Hevener,Jerrold M. Olefsky,Donna Reichart,M. T. Audrey Nguyen,Gautarn Bandyopadyhay,Ho-Yin Leung,Matthew J. Watt,Christopher Benner,Mark A. Febbraio,Anh-Khoi Nguyen,Brian Folian,Shankar Subramaniam,Frank J. Gonzalez,Christopher K. Glass,Mercedes Ricote +14 more
TL;DR: Findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.
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