RESUMO
The intimate association between obesity and type II diabetes urges for a deeper understanding of adipocyte function. We and others have previously delineated a role for the tumor suppressor p53 in adipocyte biology. Here, we show that mice haploinsufficient for MDM2, a key regulator of p53, in their adipose stores suffer from overt obesity, glucose intolerance, and hepatic steatosis. These mice had decreased levels of circulating palmitoleic acid [non-esterified fatty acid (NEFA) 16:1] concomitant with impaired visceral adipose tissue expression of Scd1 and Ffar4. A similar decrease in Scd and Ffar4 expression was found in in vitro differentiated adipocytes with perturbed MDM2 expression. Lowered MDM2 levels led to nuclear exclusion of the transcriptional cofactors, MORC2 and LIPIN1, and thereby possibly hampered adipocyte function by antagonizing LIPIN1-mediated PPARγ coactivation. Collectively, these data argue for a hitherto unknown interplay between MDM2 and MORC2/LIPIN1 involved in balancing adipocyte function.
Assuntos
Tecido Adiposo Branco/metabolismo , Resistência à Insulina/fisiologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos Monoinsaturados/sangue , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Feminino , Redes Reguladoras de Genes , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Haploinsuficiência/genética , Haploinsuficiência/fisiologia , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , PPAR gama/metabolismo , Fosfatidato Fosfatase , Proteínas Proto-Oncogênicas c-mdm2/deficiência , Proteínas Proto-Oncogênicas c-mdm2/genética , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Naive CD4(+) T cells depleted of natural Treg (CD25(+)) cells proliferate extensively when exposed to a fecal extract [enteroantigen (eAg)] pulsed on antigen-presenting cells (APC). When transplanted into SCID recipient mice, the CD25-depleted T cells induce a chronic colitis with a lethal course. We observed here that if T cells, pre-activated for 48h by eAg from BALB/c or SCID mice, are removed and then reexposed to either of the two sources of antigen, these T cells have completely lost their anti-eAg proliferative capacity in vitro. This observation indicates that eAgs derived from Balb/c and SCID mice are recognized by similar subsets of T cells. However, when transferred into SCID mice, eAg-activation-depleted T cells are still capable of inducing a severe colitis fully comparable with the disease induced by naive CD4(+) T cells.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Proliferação de Células/fisiologia , Ativação Linfocitária/imunologia , Virulência/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos de Bactérias/imunologia , Colite/imunologia , Feminino , Depleção Linfocítica/métodos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Linfócitos T Reguladores/imunologiaRESUMO
BACKGROUND: Treatment with the TRPV1 agonist, capsaicin, was previously shown to protect against experimental colitis in the severe combined immunodeficiency (SCID) T-cell transfer model. Here, we investigate trpv1 gene expression in lymphoid organs and cells from SCID and BALB/c mice to identify a potential target for the anti-inflammatory effect of capsaicin. METHODS: The trpv1 expression was studied by real-time PCR in lymphoid tissues and gut of untreated and capsaicin-treated colitic SCID mice. Effects of capsaicin and a TRPV1 antagonist on T cells were studied in vitro. RESULTS: In contrast to BALB/c mice, spleen, lymph nodes, and rectum of colitic and noncolitic SCID mice express trpv1 mRNA. Capsaicin treatment in vivo attenuated T-cell transfer colitis and capsaicin in vitro also attenuated T-cell proliferation induced by enteroantigen, mitogen, and anti-CD3/CD28 beads in BALB/c, C57BL/6 mice, and B6.129X1-trpv1tm1Jul/J trpv1 knockout mice. Proliferation and cytokine secretion were fully comparable in mice with and without trpv1 expression. Likewise, enteroantigen- and mitogen-stimulated T cells from wild-type and trpv1 knockout mice were equally inhibited by capsaicin. Surprisingly, the TRPV1 antagonist BCTC also inhibited enteroantigen- and mitogen-induced T-cell proliferation. CONCLUSIONS: The trpv1 mRNA expression in lymphoid organs and the rectum of SCID mice suggests that the TRPV1 signaling in these organs could play a role in capsaicin-mediated attenuation of colitis. In addition, capsaicin-induced inhibition of T-cell proliferation of wild-type T cells lacking trpv1 expression suggests that capsaicin inhibits colitogenic T cells in a TRPV1 receptor-independent way, which might be linked to its anti-inflammatory effect.