The endoplasmic reticulum (ER) is the major site in the cell for protein folding and trafficking and is central to many cellular functions. Failure of the ER's adaptive capacity results in activation ...of the unfolded protein response (UPR), which intersects with many different inflammatory and stress signaling pathways. These pathways are also critical in chronic metabolic diseases such as obesity, insulin resistance, and type 2 diabetes. The ER and related signaling networks are emerging as a potential site for the intersection of inflammation and metabolic disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A number of chronic metabolic pathologies, including obesity, diabetes, cardiovascular disease, asthma, and cancer, cluster together to present the greatest threat to human health. As research in ...this field has advanced, it has become clear that unresolved metabolic inflammation, organelle dysfunction, and other cellular and metabolic stresses underlie the development of these chronic metabolic diseases. However, the relationship between these systems and pathological mechanisms is poorly understood. Here we discuss the role of cellular Ca2+ homeostasis as a critical mechanism integrating the myriad of cellular and subcellular dysfunctional networks found in metabolic tissues such as liver and adipose tissue in the context of metabolic disease, particularly in obesity and diabetes.
Unresolved metabolic inflammation and organelle dysfunction underlie the development of obesity-associated chronic diseases such as type 2 diabetes and cardiovascular disease. This review provides a synthesis revealing cellular Ca2+ homeostasis as a framework for integrating cellular and subcellular dysfunctional networks in the context of metabolic diseases.
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Intracellular and extracellular interactions with proteins enables the functional and mechanistic diversity of lipids. Fatty acid-binding proteins (FABPs) were originally described as intracellular ...proteins that can affect lipid fluxes, metabolism and signalling within cells. As the functions of this protein family have been further elucidated, it has become evident that they are critical mediators of metabolism and inflammatory processes, both locally and systemically, and therefore are potential therapeutic targets for immunometabolic diseases. In particular, genetic deficiency and small molecule-mediated inhibition of FABP4 (also known as aP2) and FABP5 can potently improve glucose homeostasis and reduce atherosclerosis in mouse models. Further research has shown that in addition to their intracellular roles, some FABPs are found outside the cells, and FABP4 undergoes regulated, vesicular secretion. The circulating form of FABP4 has crucial hormonal functions in systemic metabolism. In this Review we discuss the roles and regulation of both intracellular and extracellular FABP actions, highlighting new insights that might direct drug discovery efforts and opportunities for management of chronic metabolic diseases.
Inflammatory mechanisms in obesity Gregor, Margaret F; Hotamisligil, Gökhan S
Annual review of immunology,
04/2011, Volume:
29
Journal Article
Peer reviewed
The modern rise in obesity and its strong association with insulin resistance and type 2 diabetes have elicited interest in the underlying mechanisms of these pathologies. The discovery that obesity ...itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity. Here, we summarize the unique features of this metabolic inflammatory state, termed metaflammation and defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy. We explore the effects of such inflammation in metabolic tissues including adipose, liver, muscle, pancreas, and brain and its contribution to insulin resistance and metabolic dysfunction. Another area in which many unknowns still exist is the origin or mechanism of initiation of inflammatory signaling in obesity. We discuss signals or triggers to the inflammatory response, including the possibility of endoplasmic reticulum stress as an important contributor to metaflammation. Finally, we examine anti-inflammatory therapies for their potential in the treatment of obesity-related insulin resistance and glucose intolerance.
Endoplasmic Reticulum Stress Is Reduced in Tissues of Obese Subjects After Weight Loss
Margaret F. Gregor 1 ,
Ling Yang 1 ,
Elisa Fabbrini 2 ,
B. Selma Mohammed 2 ,
J. Christopher Eagon 2 ,
Gökhan S. ...Hotamisligil 1 and
Samuel Klein 2
1 Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts
2 Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri
Corresponding author: Samuel Klein, sklein{at}wustl.edu , or Gökhan S. Hotamisligil, ghotamis{at}hsph.harvard.edu
Abstract
OBJECTIVE— Obesity is associated with insulin resistance and type 2 diabetes, although the mechanisms linking these pathologies remain
undetermined. Recent studies in rodent models revealed endoplasmic reticulum (ER) stress in adipose and liver tissues and
demonstrated that ER stress could cause insulin resistance. Therefore, we tested whether these stress pathways were also present
in obese human subjects and/or regulated by weight loss.
RESEARCH DESIGN AND METHODS— Eleven obese men and women (BMI 51.3 ± 3.0 kg/m 2 ) were studied before and 1 year after gastric bypass (GBP) surgery. We examined systemic insulin sensitivity using hyperinsulinemic-euglycemic
clamp studies before and after surgery and collected subcutaneous adipose and liver tissues to examine ER stress markers.
RESULTS— Subjects lost 39 ± 9% body wt at 1 year after GBP surgery ( P < 0.001), which was associated with a marked improvement in hepatic, skeletal muscle, and adipose tissue insulin sensitivity.
Markers of ER stress in adipose tissue significantly decreased with weight loss. Specifically, glucose-regulated protein 78
(Grp78) and spliced X-box binding protein-1 (sXBP-1) mRNA levels were reduced, as were phosphorylated elongation initiation
factor 2α (eIF2α) and stress kinase c-Jun NH 2 -terminal kinase 1 (JNK1) (all P values <0.05). Liver sections from a subset of subjects showed intense staining for Grp78 and phosphorylated eIF2α before
surgery, which was reduced in post-GBP sections.
CONCLUSIONS— This study presents important evidence that ER stress pathways are present in selected tissues of obese humans and that these
signals are regulated by marked weight loss and metabolic improvement. Hence, this suggests the possibility of a relationship
between obesity-related ER stress and metabolic dysfunction in obese humans.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 9 December 2008.
M.F.G. and L.Y. contributed equally to this work.
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. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
See accompanying commentary, p. 518 .
Accepted November 24, 2008.
Received September 3, 2008.
DIABETES
The endoplasmic reticulum (ER) is a critical site of protein, lipid, and glucose metabolism, lipoprotein secretion, and calcium homeostasis. Many of the sensing, metabolizing, and signaling ...mechanisms for these pathways exist within or on the ER membrane domain. Here, we review the cellular functions of ER, how perturbation of ER homeostasis contributes to metabolic dysregulation and potential causative mechanisms of ER stress in obesity, with a particular focus on lipids, metabolic adaptations of ER, and the maintenance of its membrane homeostasis. We also suggest a conceptual framework of metabolic roundabout to integrate key mechanisms of insulin resistance and metabolic diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Obesity is a major problem worldwide that increases risk for a wide range of diseases, including diabetes and heart disease. As such, it is increasingly important to understand how excess adiposity ...can perturb normal metabolic functions. It is now clear that this disruption involves not only pathways controlling lipid and glucose homeostasis but also integration of metabolic and immune response pathways. Under conditions of nutritional excess, this integration can result in a metabolically driven, low-grade, chronic inflammatory state, referred to as “metaflammation,” that targets metabolically critical organs and tissues to adversely affect systemic homeostasis. Endoplasmic reticulum dysfunction is another important feature of chronic metabolic disease that is also linked to both metabolic and immune regulation. A thorough understanding of how these pathways intersect to maintain metabolic homeostasis, as well as how this integration is altered under conditions of nutrient excess, is important to fully understand, and subsequently treat, chronic metabolic diseases.
Proper function of the endoplasmic reticulum (ER) and mitochondria is crucial for cellular homeostasis, and dysfunction at either site has been linked to pathophysiological states, including ...metabolic diseases. Although the ER and mitochondria play distinct cellular roles, these organelles also form physical interactions with each other at sites defined as mitochondria-associated ER membranes (MAMs), which are essential for calcium, lipid and metabolite exchange. Here we show that in the liver, obesity leads to a marked reorganization of MAMs resulting in mitochondrial calcium overload, compromised mitochondrial oxidative capacity and augmented oxidative stress. Experimental induction of ER-mitochondria interactions results in oxidative stress and impaired metabolic homeostasis, whereas downregulation of PACS-2 or IP3R1, proteins important for ER-mitochondria tethering or calcium transport, respectively, improves mitochondrial oxidative capacity and glucose metabolism in obese animals. These findings establish excessive ER-mitochondrial coupling as an essential component of organelle dysfunction in obesity that may contribute to the development of metabolic pathologies such as insulin resistance and diabetes.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Metabolic and immune systems are the most fundamental requirements for survival, and many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily ...highly conserved. Consequently, metabolic and immune pathways are also highly integrated and interdependent. In the past decade, it became apparent that this interface plays a critical role in the pathogenesis of chronic metabolic diseases, particularly obesity and type 2 diabetes. Importantly, the inflammatory component in obesity and diabetes is now firmly established with the discovery of causal links between inflammatory mediators, such as tumor necrosis factor (TNF)-alpha and insulin receptor signaling and the elucidation of the underlying molecular mechanisms, such as c-Jun NH2-terminal kinase (JNK)- and inhibitor of nuclear factor-kappaB kinase-mediated transcriptional and posttranslational modifications that inhibit insulin action. More recently, obesity-induced endoplasmic reticulum stress has been demonstrated to underlie the initiation of obesity-induced JNK activation, inflammatory responses, and generation of peripheral insulin resistance. This article will review the link between stress, inflammation, and metabolic disease, particularly type 2 diabetes, and discuss the mechanistic and therapeutic opportunities that emerge from this platform by focusing on JNK and endoplasmic reticulum stress responses.
Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily ...conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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