Browsing by Subject "Adipocytes"
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Item Adipocyte-derived factors: physiological role and diagnostic use(2008-08-29) Scherer, Philipp E.Item Adiponectin and Toll-Like Receptor 4: Important Adipocyte Modulators of Systemic Glucose and Lipid Metabolism(2015-04-06) Tao, Caroline; Liang, Guosheng; Scherer, Philipp; Elmquist, Joel; Horton, Jay D.As a global epidemic, the prevalence of obesity and its complications have increased rapidly over the past few decades. Obesity, characterized by excessive amount of body fat accumulation, is a strong predictor to various major health conditions such as type 2 diabetes and cardiovascular disease. Two hallmark features of an unhealthy hypertrophic adipose tissue are decreased adiponectin secretion and increased adipose tissue inflammation. Released almost exclusively from adipocytes, adiponectin exerts potent insulin sensitizing effects on peripheral tissues. Using a series of inducible mouse models, we identified an adipocyte-specific regulatory mechanism for adiponectin expression and release. In addition to the role in maintaining glucose homeostasis, adiponectin is also found to exert anti-fibrotic, anti-inflammatory and anti-apoptotic properties in numerous other cell types. In the obese state, decreased adiponectin secretion contributes to increased adipose tissue inflammation. Toll-like receptor 4 is an important mediator of inflammatory response found abundantly on the cell surface of adipocytes. In this study, using an adipocyte- specific deletion, we demonstrated a dichotomous effect of Toll-like receptor 4 on adipose tissue functionality. Toll-like receptor 4 is essential for proper adipose tissue remodeling to promote healthy expansion during long term high-fat diet exposure. In contrast, toll-like receptor 4 can also be a mediator of insulin resistance during an acute challenge with saturated fatty acids. In summary, my studies highlight a tight in vivo regulation of adiponectin secretion and demonstrate the role of adipocyte toll-like receptor 4 in modulating systemic glucose homeostasis during the development of obesity.Item Adipose tissue in health and disease: why should we care?(2019-01-25) Scherer, Philipp E.Item Genetic Analysis of Adipose Lineage and Development(2008-05-13) Tang, Wei; Graff, Jonathan M.Adipose tissues protect t against traumatic and thermal insults, and regulate lifespan, reproduction and metabolism. The importance of forming the appropriate number of adipocytes is highlighted by the significant metabolic disturbances that accompany too few (lipodystrophy) or too many (obesity) adipocytes. Most of our current understanding about adipocyte formation come from in vitro culture studies. Little is known about adipose development in vivo because of the lack of genetic tools. To this end, I generated a few knock-in mice that offer both spatial and temporal controls to manipulate gene expression in adipose tissues. Here I demonstrate the application of one of the tools, PPARgamma tTA, in exploring some important aspects of adipose development, such as the adipose depot specification, the identity of adipocyte progenitor cells and their anatomical niche. Adipose tissues form throughout the body in various places in a stereotypical pattern, with each adipose depot displaying distinctive properties. As the first step to understand depot specificity, I used the PPARgamma tTA mice for lineage tracing on adipose tissues, and found that each adipose depot is specified at very distinctive developmental stages, suggesting that different adipose depots are derived from distinct origins. With new genetic tools, I also marked and isolated adipogenic progenitors. I found that the majority of adipocytes descend from a pool of PPARgamma -expressing proliferateing progenitors already commited early in post-natal life, prior to the development of most adipocytes. These progenitors are morphologically and moleculary distinct from adipocytes, have high potential to undergo adipogenesis both in vitro and in vivo after transplantation. Interestingly, some progenitors reside in the mural cell compartment of blood vessels that supply adipose depots and not in vessels of other tissues. The identification of the adipocyte progenitor and localization to the blood vessel wall indicate the presence of a vascular niche in adipose development and provide a basis to examine the interplay between adipogenesis and angiogenesis that could be exploited as a new avenue for obesity and diabetes therapies.Item Identification of ITGBL1: A Novel Regulator of Adipogenesis(2016-01-19) Spurgin, Stephen B.; Vishvanath, Lavanya; MacPherson, Karen A.; Hepler, Chelsea; Shao, Mengle; Gupta Rana K.Obesity is a global epidemic that increases the risk for chronic metabolic disease. Pathological expansion of white adipose tissue (WAT) leads to insulin resistance and cardiovascular disease. To date, the mechanisms driving the formation of new adipocytes in obesity remain unclear. We have identified a perivascular (mural) cell population that gives rise to new adipocytes in obese animals. These cells are defined by the expression of Zfp423, a transcription factor that drives the cell differentiation program. Using Zfp423-GFP reporter mice, we have isolated these adipocyte precursors and obtained global gene expression profiles. The most differentially regulated protein was ITGBL1, which was highly expressed in the Zfp423+ mural cells. Given its high expression in these primed early preadipocytes, we investigated the role of ITGBL1 in preadipocyte differentiation in vitro. Here, we show that shRNA or CRISPR-mediated inactivation of ITGBL1 expression increases the propensity of mesenchymal stem cells to undergo adipocyte differentiation. These data suggest that this previously uncharacterized protein serves as an inhibitor or "brake" on the adipocyte differentiation program in preadipocytes. Multiple analyses using available structures of homologous proteins show that Itgbl1 has high structural similarity to DLL1, a known Notch ligand. We show that inactivation of ITGBL1 expression decreases expression of key Notch target genes throughout adipogenesis, thus suggesting a role for ITGBL1 in the activation of Notch signaling (known to inhibit adipogenesis in mesenchymal stem cells in vitro). Ongoing efforts are focused on elucidating ITGBL1's mechanism of action and potential as a novel Notch ligand, as well as its physiological significance in vivo. These studies will lead to a better understanding of how adipose tissue expands in obesity, and how we might promote healthy adipose expansion, preventing insulin resistance and the onset of metabolic syndrome.Item Inadequacy of fat cells: mechanisms and management of America's major health problem(2007-03-16) Unger, Roger H.Item Lipotoxic disorders: America's impending clinical crisis(1999-09-30) Unger, Roger H.Item The Maladaptive Response of Adipose Tissue to High Fat Diet Feeding(2018-04-05) Morley, Thomas S.; Gupta, Rana K.; Scherer, Philipp; Brekken, Rolf A.; Kittler, Ralf; Kim, JamesThe ability of organisms, from yeast to humans, to safely store energy as dense hydrophobic carbon chains secured away in lipid droplets represents an incredible evolutionary advantage. The further use of adipocytes as a professional lipid storage cells emphasizes the importance and benefit of safe long term energy storage. As lipids are capable of acting intracellularly as both signaling molecules and detergents, there proper storage and sequestration is of pivotal importance if they are to be used for the maintenance of energy homeostasis. With the safe storage of energy dense lipids and their later partitioning to other metabolically active tissues, the production of ATP can continue to occur in multiple organs during periods of food deprivation. With this in mind, many early investigators saw the importance of adipose tissue, though its true importance was not recognized till relatively recently.Item Metabolic Regulation of Transcription Through Compartmentalized NAD+ Biosynthesis(2017-11-21) Ryu, Keun Woo; DeBerardinis, Ralph J.; Kraus, W. Lee; Elmquist, Joel; Mangelsdorf, David J.Extracellular signaling and nutrient availability are major factors for the cell fate decision. Responds to extracellular information requires metabolic alterations and differential gene expression. Recently emerging concept of metabolic regulation of transcription reveals that fluctuation of metabolite levels could modulate the activities of enzymes involved in gene regulation, which require substrates or cofactors that are intermediates of cell metabolism. However, how cells integrate extracellular signals (e.g. hormones) and cellular metabolic status to coordinate transcriptional outcome is poorly understood. Nicotinamide adenine dinucleotide (NAD+) is an essential small molecule co-factor in metabolic redox reactions as well as a substrate for many NAD+-dependent enzymes, such as poly(ADP-ribose) polymerases (PARPs; e.g., PARP-1) or sirtuins (SIRTs; e.g., SIRT-1), which many of them are known to play an important role in gene regulation. In mammalian cells, NAD+ is synthesized from nicotinamide mononucleotide (NMN) and ATP, by the family of enzymes known as nicotinamide mononucleotide adenylyl transferases (NMNATs). NMNATs exhibit unique subcellular localizations: NMNAT-1 in the nucleus NMNAT-2 in the cytosol and Golgi, and NMNAT-3 in the mitochondria, suggesting the compartmentalized regulation of NAD+ biosynthesis within the cell. However, the biological role of this compartmentalized NAD+ synthesis is largely unknown. Interestingly, NAD+ synthesizing enzymes localize at the subcellular compartment where the transcription (nucleus) or the cellular metabolism (cytoplasm and mitochondria) occurs. Using adipogenesis as a model, we found that compartmentalized NAD+ synthesis acts to integrate cellular glucose metabolism and the adipogenic transcription program during adipocyte differentiation. Nuclear NAD+ is depleted by the induction of cytoplasmic NMNAT-2, whose levels rapidly increase concomitantly with glucose metabolism during differentiation. Competition between nuclear NMNAT-1 and cytoplasmic NMNAT-2 for the common substrate, nicotinamide mononucleotide (NMN), leads to a precipitous reduction in nuclear NAD+ synthesis by NMNAT-1. This inhibits the catalytic activity of poly(ADP-ribose) polymerase 1 (PARP-1), an NAD+-dependent nuclear enzyme that ADP-ribosylates and inhibits the adipogenic transcription factor, C/EBPβ. Subsequent reversal of PARP-1-mediated repression and enhanced binding of C/EBPβ to adipogenic target genes drives differentiation. Thus, compartmentalized NAD+ synthesis functions as an integrator of cellular metabolism and signal-dependent transcriptional programs.Item Regulation of Metabolic Processes by Micrornas and Class I Histone Deacetylases(2013-01-17) Carrer, Michele; Olson, Eric N.Obesity is a medical condition resulting from accumulation of excess body fat that affects more than 30% of the adult population in the U.S. Obesity-related pathological conditions include heart disease, stroke, type 2 diabetes and certain types of cancer. Despite the high incidence and the elevated social costs, the molecular basis of obesity and associated metabolic syndrome are still poorly understood. Yet, the need for novel therapeutic approaches for the treatment and prevention of obesity remains. In humans and animal model of disease, hallmarks of obesity include dysregulation of genes involved in mitochondrial function, lipid uptake and lipid storage. The dynamic and modifiable regulation of transcriptional pathways that control mitochondrial function and adipogenesis, as well as additional aspects of mammalian metabolism, will provide new approaches for pharmacological intervention in obesity. Thus, the modulation of epigenetic histone modifications and microRNA functions represents a potentially powerful approach for the treatment of metabolic disorders. We show that the Ppargc1b gene, which encodes the PGC-1β protein, also co-transcribes two microRNAs, miR-378 and miR-378*. Mice lacking miR-378/378* are resistant to high fat diet-induced obesity and display enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Taken together, our findings reveal that miR-378 and miR-378* function as integral components of the regulatory circuit formed by PGC-1beta and nuclear hormone receptors to control the overall oxidative capacity and energy homeostasis of insulin-target tissues. MiR-378/378* mutant mice do not display overt phenotypes under normal laboratory conditions, whereas their phenotypes become apparent under conditions of stress, in this case in response to excessive caloric intake. Thus, pharmacological modulation of miR-378/378* function might represent an effective approach in the treatment of obesity. In obese humans and mice, the unused caloric energy resulting from excessive net caloric intake is converted to triglycerides and stored in adipocytes for further usage. Lipid accumulation within adipocytes is under the control of a cascade of transcription factors that interact with histone acetyltransferases and deacetylases. We show that histone deacetylase inhibitors efficiently block adipocyte differentiation in vitro. Furthermore, through a loss-of-function approach, we provide evidence that histone deacetylases 1 and 2 play redundant and requisite roles in adipogenesis. In conclusion, we unveiled previously unrecognized roles for miR-378/378* in the control of mitochondrial metabolism and energy homeostasis, and for histone deacetylases in the control of adipocyte differentiation.Item The Response of White Adipose Progenitor Cells to Physiological and Genetic Changes(2013-02-21) Zeve, Daniel; Johnson, Jane E.; Mangelsdorf, David J.; Olson, Eric N.; Graff, Jonathan M.We are in the midst of a dire, unprecedented and global epidemic of obesity and secondary sequelae, most prominently diabetes and hyperlipidemia. Underlying this epidemic are adipocytes and their inherent, dynamic ability to expand and renew. These abilities highlight a newly defined cell population within adipose tissue, the white adipose progenitor cell. These cells have the basic abilities that define a stem/progenitor cell, including the ability to proliferate and differentiate into mature adipocytes, opening up new studies into their involvement in both adipose development and growth. More specifically, interest lies in which physiological and genetic conditions can repress the adipogenic function of these cells, as these findings could lead to possible therapies for obesity and other metabolic diseases. We began our studies by examining the proliferative and adipogenic effect of both high fat diet and exercise on adipose progenitor cells. We found that while high fat diet increased adipose progenitor function, exercise dramatically reduced proliferation of the adipocyte progenitor in addition to diminishing new adipocyte formation during the exercise protocol. One physiological outcome of endurance exercise is the remodeling of skeletal muscle to more of a slow, oxidative fiber type composition. Thus, we hypothesized that type I skeletal muscle may also regulate the adipocyte progenitor. To directly test this hypothesis we analyzed the adipose progenitor cell in two, independent mouse lines that exhibit an increase of Type I fibers. These mice revealed that slow muscle fibers also reduce the activity of the adipocyte progenitor on normal chow and decrease adiposity while on high fat diet. Surprisingly, this effect may be due to non-nutritional factors, as the slow fiber mice exhibit no overt metabolic alterations on normal chow and conditioned media from muscle cell lines reduced pre-adipocyte function. These data suggest Type I fibers directly regulate the adipocyte progenitor cell, which may contribute to the reduced adiposity seen after exercise as well as the reduced adiposity of slow fiber mice in response to high fat diet. We next wanted to examine the genetics that control adipogenesis within the adipose progenitor cells. To do this, we activated Wnt signaling in either adipose progenitor cells or mature adipocytes. Wnt signaling is known to play a role in proliferation and differentiation in multiple stem cell lineages, including intestinal, bone and hematopoietic lineages, and thus we hypothesized that it may also play a role in in vivo adipogenesis and metabolism. Altering canonical Wnt signaling in mature fat tissues in mice had no discernable metabolic effects. In contrast, altering Wnt signaling in fat progenitors led to a depot-specific fate change and a paradoxical murine lipodystrophic syndrome that lacked the expected diabetes and ectopic fatty acid accumulation. Rather, muscle displayed increased glucose uptake and an insulin-independent increase in cell surface glucose transporters along with activation of AMPK and p38 MAPK. Muscle Wnt signaling was unaffected, indicating that these changes resulted from signals derived non-autonomously, which we found to be present in the serum of mutant mice. Thus, this model distinctively dissociates lipodystrophy from dysfunctional metabolism and uncovers a unique and potentially therapeutic method to lower blood glucose and improve metabolism.Item [Southwestern News](2005-12-01) Morales, KatherineItem [UT Southwestern Medical Center News](2008-09-18) McKenzie, AlineItem [UT Southwestern Medical Center News](2013-02-06) Lyda, AlexItem [UT Southwestern Medical Center News](2010-05-18) Shear, Kristen Holland