Advancing age and insulin resistance: role of plasma tumor necrosis factor-α

Paolisso, Giuseppe; Rizzo, Maria Rosaria; Mazziotti, Gherardo; Tagliamonte, Maria; Gambardella, A.; Rotondi, Mario; Carella, Carlo; Giugliano, Dario; Varricchio, M; D'Onofrio, F

doi:10.1152/ajpendo.1998.275.2.e294

Cited by 156 publications

(150 citation statements)

References 30 publications

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“…A ge-associated decrease in glucose tolerance has been noted since 1920 (1). This early finding was confirmed by a later observation that tissue responsiveness to insulin was diminished in elderly subjects (2,3).…”

mentioning

confidence: 76%

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Ren

Pae

et al. 2007

The Journal of Immunology

243

209

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The incidence of type 2 diabetes (T2D) increases with age. Low‐grade inflammation in AT is implicated in development of insulin resistance and T2D. We conducted a study to determine if inflammatory responses are upregulated with age in AT. Results show that visceral AT from old mice had significantly higher expression of mRNA levels of IL‐1β, IL‐6, TNF‐α, and COX‐2 than those of young mice (263, 208, 165, and 73%, higher respectively). In determining the relative contribution of different components of AT to these age‐related changes, we found that adipocytes (AD) from old mice produced significantly more (2 to 3 folds) IL‐6 and PGE2 than those from young mice while no significant age difference was observed in their production by stromal vascular cells. There was no significant effect of age on number of Mϕ/g AT and Mϕ of either age group produced significantly more IL‐6 when incubated in conditioned medium from old AD compared to that of young. Blocking NF‐κB activation reduced IL‐6 production while addition of ceramide or sphingomyelinase increased IL‐6 production in young AD to a level comparable to that of old AD. Inhibiting de novo ceramide synthesis reduced IL‐6 production by AD. NF‐κB regulates expression of inflammatory products including COX‐2 and IL‐6. Ceramide was shown to increase COX‐2 expression in aged Mϕ through NF‐κB activation. Thus, these data suggest a potential role for ceramide and NF‐κB in the age‐related increase of AT inflammation. Further research is needed to fully determine the underlying mechanisms of the observed effects and their contribution to T2D in the aged. Supported by USDA #58‐1950‐9‐001 and NIA #R01 AG009140‐10A1.

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mentioning

confidence: 76%

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Ren

Pae

et al. 2007

The Journal of Immunology

243

209

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“…TNF-␣ administration increases serum leptin levels in humans (25), and plasma sTNFR1 concentrations circulate in proportion to leptin (26). Disproportionately increased leptin (27,28) and TNF-␣ levels (27)(28)(29)(30) are observed in populations with high rates of type 2 diabetes and in elderly people, and this possibly contributes to insulin resistance and obesity. In our study subjects, we observed that plasma sTNFR2 levels strongly correlated with age.…”

Section: Tnfr2 Gene Obesity and Insulin Resistancementioning

confidence: 99%

Polymorphism of the tumor necrosis factor-alpha receptor 2 gene is associated with obesity, leptin levels, and insulin resistance in young subjects and diet-treated type 2 diabetic patients.

Fernández‐Real¹,

Vendrell²,

Ricart³

et al. 2000

Diabetes Care

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Abbreviations: EASIA, enzyme-amplified sensitivity immunoassay; FSIVGTT, frequently sampled intravenous glucose tolerance test; PCR, polymerase chain reaction; sTNFR2, soluble fraction of tumor necrosis factor-␣ receptor; TNF-␣, tumor necrosis factor-␣; TNFR1, tumor necrosis factor-␣ receptor 1; TNFR2, tumor necrosis factor-␣ receptor 2; UTR, untranslated region; WHR, waist-to-hip ratio.A OBJECTIVE -Mice lacking the tumor necrosis factor-␣ receptor 2 (TNFR2) gene fed a highfat diet gain less weight and display reduced leptin and insulin levels. In humans, plasma levels of the soluble fraction of TNFR2 (sTNFR2) circulate in proportion to the degree of insulin resistance. The purpose of this study was to evaluate a polymorphism in the 3Ј untranslated region of the TNFR2 gene on chromosome 1 in relation to BMI, leptin levels, and insulin resistance.RESEARCH DESIGN AND METHODS -Using single-strand conformation polymorphism, the polymorphism was analyzed in 107 nondiabetic subjects (60 women, 47 men) and in 110 consecutive patients with type 2 diabetes (79 women, 31 men). In a subset of 33 healthy subjects, insulin sensitivity (minimal model analysis) was also evaluated.RESULTS -Four alleles of the TNFR2 gene were identified (A1, A2, A3, and A4). BMI and serum leptin levels were significantly increased in young carriers of the A2 allele. Plasma sTNFR2 levels were similar among the different TNFR2 gene variants. However, in subjects who did not carry the A2 allele, in young subjects, and in women, plasma sTNFR2 levels were proportional to BMI and leptin levels. In the study sample, carriers of the A2 allele (n = 18) showed significantly increased BMI, fat mass, waist-to-hip ratio, serum total and VLDL triglyceride levels, and leptin levels and had a lower insulin sensitivity index than noncarriers of the A2 variant (n = 15). The frequency of the different alleles among diabetic subjects was similar to that in the control population. However, diet-treated diabetic subjects (n = 49) who were carriers of the A2 allele exhibited significantly higher BMI and leptin levels than diet-treated noncarriers of the A2 allele.CONCLUSIONS -The presence of the A2 allele in the TNFR2 gene may predispose subjects to obesity and higher leptin levels, which may in turn predispose them to insulin resistance or vice versa. The TNFR2 gene may be involved in weight-control mechanisms.

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“…La dieta disminuye los niveles de TNFa y de leptina séri-ca y se asocia a una mejora en la sensibilidad insulínica y del metabolismo lipídico. La edad aumenta los niveles de TNFα y se relaciona con aumento de la resistencia insulínica (103,104) (Fig. 5).…”

Section: Leptina Y Páncreas Endocrinounclassified

Leptina: implicaciones fisiológicas y clínicas

Carretero

Barbancho

González

et al. 2001

An. Med. Interna (Madrid)

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48 INTRODUCCIÓNLeptina, del griego leptos, que significa delgado, es una proteína que ha sido identificada hace tres años, pero de cuya acción, o por lo menos déficit, ya se conocía desde el año 1950. Sin embargo, ha sido en estos tres últimos años en los que el conocimiento de la misma, de su fisiología y de sus implicaciones clínicas se ha disparado, y su interés científico merece una revisión en el momento actual.En el año 1950, en el laboratorio Jackson de Bar Harbor, Dickie y sus colaboradores comunicaron la aparición en una de sus colonias de ratas, un mutante asociado con obesidad mórbida. El defecto genético se heredaba de forma recesiva y su manifestación era en edad temprana de la vida y se asociaba con diabetes mellitus. Se denominó ob/ob a ese mutante (1). Poco después, otro tipo de alteración genética en ratones fue descrita por Hummel y Coleman (2), que consistía en la aparición de obesidad y diabetes y que fue denominado db/db. Tras ellos, otras formas fueron descritas y denominadas fatty, tub y fat (3,4). El hecho de que los mutantes ob/ob y db/db fueran fenotípicamente idénticos pero con alteraciones genéti-cas distintas hizo pensar en la existencia de defectos en distintos pasos de una cadena enzimática aún por definir. De la misma forma, el hecho de que todos ellos tuvieran diabetes 41 [0212-7199 (2001) RESUMENLa leptina es una proteína que ha sido identificada hace tres años, pero de cuya acción, o por lo menos déficit, ya se conocía desde el año 1950. Dickie y sus colaboradores comunicaron la aparición en una de sus colonias de ratas, un mutante asociado con obesidad mórbida. El defecto genético se heredaba de forma recesiva y su manifestación era en edad temprana de la vida y se asociaba con diabetes mellitus. En diciembre de 1994 se consiguió clonar el gen ob, lo que constituyó el primer paso para que posteriormente se determinara el producto de dicho gen, la leptina, como una proteína de 167 aminoácidos que se expresaba únicamente en el tejido adiposo. Desde entonces, se ha demostrado la relación de la leptina con numerosos sistemas de regulación neuroendocrina. Los recientes descubrimientos sobre dicha proteína merecían ser puestos al día, así como su posible relevancia presente y futura en la práctica clínica.

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Advancing age and insulin resistance: role of plasma tumor necrosis factor-α

Cited by 156 publications

References 30 publications

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Polymorphism of the tumor necrosis factor-alpha receptor 2 gene is associated with obesity, leptin levels, and insulin resistance in young subjects and diet-treated type 2 diabetic patients.

Leptina: implicaciones fisiológicas y clínicas

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