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MOLECULAR AND CELLULAR MARKERS OF INFLAMMATION IN MORBID OBESITY
F. Enrique Gómez Ph.D1 and Martha Kaufer-Horwitz, D.Sc2.
1
Departamento de Fisiología de la Nutrición &
2
Clinica de Obesidad y Trastornos de la Conducta Alimentaria
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ)
México, D.F. MEXICO
Obesity, and its associated complications, had increased worlwide. Obesity increases the risk to
develop atherosclerosis, cardiovascular disease, diabetes, certain types of cancer and some
immunologically-mediated diseases like asthma. Obesity has been described as a “chronic
inflammatory state”, characterized by an increase in the serum levels of acute phase proteins
produced by the liver, such as C-reactive protein and complement C3 and C4 factors.
Recent reports have documented an interaction between obesity and the immune system,
which is mediated by soluble factors produced by both, lymphoid cells and adipocytes. Among
those substances, collectivelly termed as “adipokines” , some have proinflammatory activities
(leptin, resistin, visfatin) while others are antinflamatory (adiponectin). Adipocytes also produce
other substances previously thought to be synthesized exclusively by macrophages such as
tumor necrosis alpha (TNF) and interleukin 6 (IL-6). It has been reported that visceral
adipocytes contribute with up to one-third of the serum levels of IL-6.
Obese patients have elevated levels of serum leptin, which besides its “classical” functions as
regulator of energy balance, angiogenesis and hematopoiesis, also regulates immune function
via an increase in the synthesis of TNF and IL-6 by macrophages, activation of neutrophils and
monocytes, and augmentation in the expression of activation markers suchs as CD25 (the IL-2
receptor). T cells, but not B cells, express the leptin receptor (OBR) on their surface. Leptin
stimulates the proliferation of T helper 1 (Th1) cells by stimulating the synthesis of IL-2 and
gamma interferon (IFN), which in turn inhibit the proliferation of Th2 cells and the sysnthesis of
IL-4.
Our studies have focused on the role of regulatory T cells (Tregs) on the inflammation
observed in obese patients. Tregs are a specialized subset of T cells that play an
important role in maintaining immune homeostasis, and are characterized by the CD4+
and CD25+ phenotype, and express the forkhead family transcription factor FoxP3.
Recent work has shown that the forkhead/winged-helix protein Foxp3 is expressed
predominantly in Tregs and is both necessary and sufficient for their development and
function.
We studied morbidly obese patients (BMI ≥ 40.0 Kg/m2) who attended the outpatient Clinic
of Obesity at the INCMNSZ in Mexico City. Serum levels of glucose, insulin, leptin, adiponectin,
TNF, IL-6, IL-1 and IL-8 were quantified and compared to those in healthy non-obese (IMC <
23.0 Kg/m2) volunteers. The percentage Tregs in peripheral blood was determined by flow
cytometry (CD4+, FoxP3+), and the level of transcription of the FOXP3 gene by “real time
polymerase-chain reaction” (RT-PCR) after the isolation of total RNA from mononuclear cells.
FoxP3 mRNA levels were adjusted to ribosomal 18S, as the housekeeping gene.
Positive and significant correlations were determined between percent of body fat (%BF) with
some, but not all, serum proteins. Serum levels of insulin, leptin, TNF and IL-6 were increased
1
in morbidly obese patients compared to healthy non-obese subjects. Adiponectin levels were
reduced in the morbidly obese patients, whereas IL-1 and IL-8 were not different.
Surprisingly, a higher percentage of Tregs was observed in peripheral blood of morbidly obese
patients, as well as an increase in the transcription rate of FOXP3.
Our results suggest that the inflammatory state observed in morbidly obese patients, can be
attributed to an increase in body fat, since TNF and IL-6 were increased (produced by the
adipocytes), whereas IL-1 and IL-8 (produced by immune cells) were not. Despite the increase in
the percentage of circulating Tregs and in the levels of FoxP3 mRNA, this did not result in the
reduction of the inflammation process. Further analysis of intracellular levels of FoxP3 and
function of Tregs from morbidly obese patients, are required.
2