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Journal ArticleDOI

Nutrient sensing and inflammation in metabolic diseases.

01 Dec 2008-Nature Reviews Immunology (NIH Public Access)-Vol. 8, Iss: 12, pp 923-934
TL;DR: This Review provides an overview of several important networks that sense and manage nutrients and discusses how they integrate with immune and inflammatory pathways to influence the physiological and pathological metabolic states in the body.
Abstract: The proper functioning of the pathways that are involved in the sensing and management of nutrients is central to metabolic homeostasis and is therefore among the most fundamental requirements for survival. Metabolic systems are integrated with pathogen-sensing and immune responses, and these pathways are evolutionarily conserved. This close functional and molecular integration of the immune and metabolic systems is emerging as a crucial homeostatic mechanism, the dysfunction of which underlies many chronic metabolic diseases, including type 2 diabetes and atherosclerosis. In this Review we provide an overview of several important networks that sense and manage nutrients and discuss how they integrate with immune and inflammatory pathways to influence the physiological and pathological metabolic states in the body.

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Citations
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Journal ArticleDOI
TL;DR: Preliminary results from clinical trials with salicylates and interleukin-1 antagonists support the notion that inflammation participates in the pathogenesis of type 2 diabetes and have opened the door for immunomodulatory strategies for the treatment of T2D that simultaneously lower blood glucose levels and potentially reduce the severity and prevalence of the associated complications of this disease.
Abstract: Components of the immune system are altered in obesity and type 2 diabetes (T2D), with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the vasculature and circulating leukocytes. These immunological changes include altered levels of specific cytokines and chemokines, changes in the number and activation state of various leukocyte populations and increased apoptosis and tissue fibrosis. Together, these changes suggest that inflammation participates in the pathogenesis of T2D. Preliminary results from clinical trials with salicylates and interleukin-1 antagonists support this notion and have opened the door for immunomodulatory strategies for the treatment of T2D that simultaneously lower blood glucose levels and potentially reduce the severity and prevalence of the associated complications of this disease.

2,845 citations

Journal ArticleDOI
TL;DR: It is established that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity, and that the NlrP3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.
Abstract: Obesity is generally considered an inflammatory state. Vishwa Dixit and his colleagues have now shown that excess dietary lipids leads to the activation of the Nlrp3 inflammasome, a sensor of the innate immune system, and that its genetic deficiency results in decreased inflammation and improved insulin sensitivity. These results suggest a possible new therapeutic avenue to treat the effects of obesity.

2,000 citations

Journal ArticleDOI
TL;DR: Endoplasmic reticulum stress and related signaling networks, (adipo)cytokines, and innate immunity are emerging as central pathways that regulate key features of NASH.

1,882 citations


Cites background from "Nutrient sensing and inflammation i..."

  • ...Because a highfat diet is needed in almost all experimental models to induce pathology, it is evident that dietary factors and nutrient sensing are cornerstones of these diseases.(113) Whereas genetic factors overall may play a minor role in the current epidemic of obesity, certain genetic factors might well offer explanations for a more progressive disease course in NAFLD....

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Journal ArticleDOI
09 Apr 2010-Science
TL;DR: Results support the emerging view that the gut microbiota contributes to metabolic disease and suggest that malfunction of the innate immune system may promote the development of metabolic syndrome.
Abstract: Metabolic syndrome is a group of obesity-related metabolic abnormalities that increase an individual's risk of developing type 2 diabetes and cardiovascular disease. Here, we show that mice genetically deficient in Toll-like receptor 5 (TLR5), a component of the innate immune system that is expressed in the gut mucosa and that helps defend against infection, exhibit hyperphagia and develop hallmark features of metabolic syndrome, including hyperlipidemia, hypertension, insulin resistance, and increased adiposity. These metabolic changes correlated with changes in the composition of the gut microbiota, and transfer of the gut microbiota from TLR5-deficient mice to wild-type germ-free mice conferred many features of metabolic syndrome to the recipients. Food restriction prevented obesity, but not insulin resistance, in the TLR5-deficient mice. These results support the emerging view that the gut microbiota contributes to metabolic disease and suggest that malfunction of the innate immune system may promote the development of metabolic syndrome.

1,804 citations

Journal ArticleDOI
TL;DR: It is now widely appreciated that chronic low-grade inflammation plays a key role in the initiation, propagation, and development of metabolic diseases, and numerous recent studies have implicated the transcription factor NF-κB in the development of such diseases, thereby further establishing inflammation as a critical factor in their etiology.

1,518 citations

References
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Journal ArticleDOI
21 Dec 2006-Nature
TL;DR: It is demonstrated through metagenomic and biochemical analyses that changes in the relative abundance of the Bacteroidetes and Firmicutes affect the metabolic potential of the mouse gut microbiota and indicates that the obese microbiome has an increased capacity to harvest energy from the diet.
Abstract: The worldwide obesity epidemic is stimulating efforts to identify host and environmental factors that affect energy balance. Comparisons of the distal gut microbiota of genetically obese mice and their lean littermates, as well as those of obese and lean human volunteers have revealed that obesity is associated with changes in the relative abundance of the two dominant bacterial divisions, the Bacteroidetes and the Firmicutes. Here we demonstrate through metagenomic and biochemical analyses that these changes affect the metabolic potential of the mouse gut microbiota. Our results indicate that the obese microbiome has an increased capacity to harvest energy from the diet. Furthermore, this trait is transmissible: colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota'. These results identify the gut microbiota as an additional contributing factor to the pathophysiology of obesity.

10,126 citations

Journal ArticleDOI
14 Dec 2006-Nature
TL;DR: Dysfunction of the immune response and metabolic regulation 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.
Abstract: 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.

7,536 citations


"Nutrient sensing and inflammation i..." refers background in this paper

  • ...jpg" NDATA ITEM> ]> The integration of metabolism and immunity (or of nutrient- and pathogen-sensing pathways) can be traced back to an evolutionary need for survival, which resulted in the co-development of the organ systems and signalling pathways that mediate these two processe...

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Journal ArticleDOI
01 Jan 1993-Science
TL;DR: A role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity is indicated.
Abstract: Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

7,347 citations

Journal ArticleDOI
TL;DR: It is proposed that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue, and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance.
Abstract: Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance However, the underlying molecular pathways are largely unknown In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO) The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue

6,165 citations

Journal ArticleDOI
TL;DR: Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids.
Abstract: The endoplasmic reticulum (ER) responds to the accumulation of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways - cumulatively called the unfolded protein response (UPR). Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids. The arms of the UPR are integrated to provide a response that remodels the secretory apparatus and aligns cellular physiology to the demands imposed by ER stress.

5,701 citations


"Nutrient sensing and inflammation i..." refers background in this paper

  • ...This programme includes the upregulation of ER-resident chaperone proteins , which promote protein folding, and the production of components of the protein-degradation apparatus that assist in the re-establishment of ER homeostasi...

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