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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Inflammation and metabolic disorders

For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phag...

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The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients. This should have been an important clue to link inflammation to the pathogenesis of type 2 diabetes (T2D), but the antihyperglycemic and antiinflammatory effects of salicylates were not connected to the pathogenesis of insulin resistance until recently. Together with the discovery of an important role for tissue macrophages, these new findings are helping to reshape thinking about how obesity increases the risk for developing T2D and the metabolic syndrome. The evolving concept of insulin resistance and T2D as having immunological components and an improving picture of how inflammation modulates metabolism provide new opportunities for using antiinflammatory strategies to correct the metabolic consequences of excess adiposity.

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Inflammation and insulin resistance

Oxidative Stress, Inflammation, and Cancer: How Are They Linked?

OBJECTIVE— Diabetes and obesity are characterized by a low-grade inflammation whose molecular origin is unknown. We previously determined, first, that metabolic endotoxemia controls the inflammatory tone, body weight gain, and diabetes, and second, that high-fat feeding modulates gut microbiota and the plasma concentration of lipopolysaccharide (LPS), i.e., metabolic endotoxemia. Therefore, it remained to demonstrate whether changes in gut microbiota control the occurrence of metabolic diseases. RESEARCH DESIGN AND METHODS— We changed gut microbiota by means of antibiotic treatment to demonstrate, first, that changes in gut microbiota could be responsible for the control of metabolic endotoxemia, the low-grade inflammation, obesity, and type 2 diabetes and, second, to provide some mechanisms responsible for such effect. RESULTS— We found that changes of gut microbiota induced by an antibiotic treatment reduced metabolic endotoxemia and the cecal content of LPS in both high-fat–fed and ob/ob mice. This effect was correlated with reduced glucose intolerance, body weight gain, fat mass development, lower inflammation, oxidative stress, and macrophage infiltration marker mRNA expression in visceral adipose tissue. Importantly, high-fat feeding strongly increased intestinal permeability and reduced the expression of genes coding for proteins of the tight junctions. Furthermore, the absence of CD14 in ob/ob CD14 − / − mutant mice mimicked the metabolic and inflammatory effects of antibiotics. CONCLUSIONS— This new finding demonstrates that changes in gut microbiota controls metabolic endotoxemia, inflammation, and associated disorders by a mechanism that could increase intestinal permeability. It would thus be useful to develop strategies for changing gut microbiota to control, intestinal permeability, metabolic endotoxemia, and associated disorders.

/pdf/changes-in-gut-microbiota-control-metabolic-endotoxemia-4yudz59erv.pdf

Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice

Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation, and oxidative stress caused dysregulated production of adipocytokines (fat-derived hormones), including adiponectin, plasminogen activator inhibitor-1, IL-6, and monocyte chemotactic protein-1. Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis. Collectively, our results suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.

/pdf/increased-oxidative-stress-in-obesity-and-its-impact-on-2ocfpcn6dr.pdf

Increased oxidative stress in obesity and its impact on metabolic syndrome

This invention relates to new indole derivatives of formula (I), wherein R1 is hydrogen, halogen, nitro, carboxy, protected carboxy, acyl, etc., R2 is hydrogen, halogen, lower alkenyl, acyl, etc., R3 is lower alkenyl or lower alkyl, both of which are optionally substituted with aryl optionally substituted with one or more substituent(s) selected from the group consisting of halogen, aryl, lower alkoxy, etc., and R4 is carboxy, protected carboxy, acyl, etc., in addition to their significances above, R?1 and R2?, together with the carbon atoms to which they are attached, represent a 4- to 7-membered carboxylic ring optionally substituted with oxo, or its pharmaceutically acceptable salt, which is useful as a medicament; and to new use of cyclic nucleotide-PDE inhibitors.

INDOLE DERIVATIVES AS cGMP-PDE INHIBITORS

Remedies for bone diseases comprising, as active ingredient, droloxifene or a salt thereof.

Remedies for bone diseases

The pharmacological characterization of FK 739, a new angiotensin II-receptor antagonist.

A polymer or its salt which is obtainable by polymerization of a monomer of the formula (I) or its salt in the presence of a radical initiator, or by polymerization of a monomer of the formula (I) or its salt with a monomer of the formula (II) or its salt in a molar ratio of (I): (II) being 1:0.1 to 1:25 in the presence of a radical initiatorwherein R1 and R3 are each hydrogen atom or lower alkyl group, R2 and R4 are each acyl group,aliphatic silyl group,amino lower alkyl group which may have one or more suitable substituent(s),heterocyclic group which may have one or more suitable substituent(s) orcarboxy group esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/or lower alkenoyl.

Yoshimitsu Nakajima

Papers

Increased oxidative stress in obesity and its impact on metabolic syndrome

INDOLE DERIVATIVES AS cGMP-PDE INHIBITORS

Remedies for bone diseases

The pharmacological characterization of FK 739, a new angiotensin II-receptor antagonist.

Polymer and its use for the treatment and/or prevention of hyperphosphoremia