RESUMEN
This study explored sex differences in 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity and gene expression in isolated adipocytes and adipose tissue (AT), obtained via subcutaneous biopsies from non-diabetic subjects [58 M, 64 F; age 48.3 ± 15.3 years, body mass index (BMI) 27.2 ± 3.9 kg/m²]. Relationships with adiposity and insulin resistance (IR) were addressed. Males exhibited higher 11ß-HSD1 activity in adipocytes than females, but there was no such difference for AT. In both men and women, adipocyte 11ß-HSD1 activity correlated positively with BMI, waist circumference, % body fat, adipocyte size and with serum glucose, triglycerides and low-density lipoprotein:high-density lipoprotein (LDL:HDL) ratio. Positive correlations with insulin, HOMA-IR and haemoglobin A1c (HbA1c) and a negative correlation with HDL-cholesterol were significant only in males. Conversely, 11ß-HSD1 activity in AT correlated with several markers of IR and adiposity in females but not in males, but the opposite pattern was found with respect to 11ß-HSD1 mRNA expression. This study suggests that there are sex differences in 11ß-HSD1 regulation and in its associations with markers of obesity and IR.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adiposidad , Regulación Enzimológica de la Expresión Génica , Resistencia a la Insulina , Sobrepeso/metabolismo , Grasa Subcutánea/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Biomarcadores/sangre , Biomarcadores/metabolismo , Biopsia , Índice de Masa Corporal , Tamaño de la Célula , Células Cultivadas , Femenino , Hemoglobina Glucada/análisis , Humanos , Hiperlipidemias/etiología , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Sobrepeso/complicaciones , Sobrepeso/patología , Sobrepeso/fisiopatología , ARN Mensajero/metabolismo , Caracteres Sexuales , Grasa Subcutánea/enzimología , Grasa Subcutánea/patologíaRESUMEN
AIMS/HYPOTHESIS: The aim of the study was to address the role of protein kinase C-delta (PKCdelta) on phosphorylation of signal transducer and activator of transcription 3 (STAT3) and activation of inflammatory genes in response to IL-6 in adipose cells. METHODS: Differentiated mouse 3T3-L1 adipocytes preincubated with the PKCdelta inhibitor rottlerin and mouse embryonic fibroblasts (MEFs) lacking PKCdelta were incubated with IL-6 and/or insulin. RNA was extracted and the gene expression was analysed by real-time PCR, while the proteins from total, nuclear and cytoplasmic lysates were analysed by immunoblotting. RESULTS: Inhibition of PKCdelta by rottlerin significantly reduced both Ser-727 and Tyr-705 phosphorylation of STAT3. Consequently, nuclear translocation of STAT3 and the IL-6-induced gene transcription and protein release of the inflammatory molecule serum amyloid A 3 (SAA3) were reduced. Similarly, the IL-6-regulated gene transcription of Il-6 (also known as Il6) to Hp and the feedback inhibitor of IL-6, Socs3, were also attenuated by rottlerin. Furthermore, PKCdelta was found to translocate to the nucleus following IL-6 treatment and this was also reduced by rottlerin. In agreement with the effect of rottlerin, Pkcdelta (also known as Prkcd) ( -/- ) MEFs also displayed a markedly reduced ability of IL-6 to activate the transcription of Saa3, Hp, Socs3 and Il6 genes compared with wild-type MEFs. These results correlated with a reduced nuclear translocation and phosphorylation of STAT3. CONCLUSIONS/INTERPRETATION: These results show that PKCdelta plays a key role in the inflammatory effect of IL-6 in adipose cells and may be a suitable target for novel anti-inflammatory agents.