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An. R. Acad. Nac. Farm., 2007, 73 (4): 987-1008

Revisión

Contribution of TNF-a to Obesity-Associated
Insulin Resistance

Recibido el 25 de octubre de 2007

MARGARITA LORENZO* , SONIA FERNÁNDEZ-VELEDO, ROCÍO
VILA-BÉDMAR, LUCÍA GARCÍA-GUERRA, CRISTINA DE ÁLVA-

RO AND IRIA NIETO-VÁZQUEZ
Departamento de Bioquimica y Biología Molecular II, Facultad de

Farmacia, Universidad Complutense, 28040-Madrid, Spain

ABSTRACT

Insulin resistance is an important contributor to the pathogenesis of type 2
diabetes, and obesity is a risk factor for its development, due in part to the fact
that adipose tissue secretes proteins called adipokines, that may influence insulin
sensitivity. Among these molecules, TNF-a has been proposed as a link between
obesity and insulin resistance because TNF-a is overexpressed in adipose tissues
of obese animals and humans, and obese mice lacking either TNF-a or its receptor
show protection for developing insulin resistance. The direct exposure to TNF-a
induced a state of insulin resistance on glucose uptake in myocytes and brown
adipocytes, due to the activation of pro-inflammatory pathways that impair insu-
lin-signaling at the level of the IRS proteins. In this regard the residue Ser307 in
IRS-1 has been identified as a site for TNF-a-inhibitory effects in myotubes, with

* Corresponding author: Margarita Lorenzo. Tel: 34-913941858, Fax 34-:913941779,
e-mail: mlorenzo@farm.ucm.es
Abbreviations: AMPK, AMP-activated protein kinase; AS160, AKT substrate of 160
kDa; BAT, brown adipose tissue; ERK, extracelullar-signal regulated kinase; FFA, free
fatty acids; GLUT4, insulin-regulated glucose transporter; HSL, hormone sensitive li-
pase; IGF, insulin-like growth factor; IKK, inhibitor kB kinase; IR, insulin receptor;
IRS, insulin receptor substrate; JNK, c-Jun N-terminal kinase; LPL, lipoprotein lipase;
LXR, liver X receptor; MAPK, mitogen-activated protein kinase; PI3K, phosphatidyli-
nositol 3-kinase; PLC, phospholipase C; PP, protein-phosphatase; PPAR, peroxisome
proliferator activated receptor; PTP, protein-tyrosine phosphatase; TNF, tumor necro-
sis factor; TZD, thiazolidinediones; UCP, uncoupling-protein; WAT, white adipose tis-
sue.

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