Recovery of insulin sensitivity and Slc2a4 mRNA expression depend on T3 hormone during refeeding.

OBJECTIVE: GLUT4 protein, encoded by the Slc2a4 gene, plays a key role in muscle glucose uptake, and its expression decreases in muscles under insulin resistance. Slc2a4/GLUT4 decreases with fasting and rapidly increases with refeeding and the same occurs to plasma glucose, amino acids, insulin and T3. Thus, they might be potential regulators of the Slc2a4 gene, which makes them promising targets for strategies to improve GLUT4 expression. Herein, we investigate the role of metabolic-hormonal parameters triggered by refeeding upon the Slc2a4 expression. MATERIALS/METHODS: Plasma glucose/insulin/T3, and gastrocnemius Slc2a4 mRNA contents were measured in rats studied at the end of 48-h fasting, and subsequently at: i) 2-4h after spontaneous refeeding; ii) 2-4h after T3 injection, without refeeding; and iii) 0.5-2h after intravenous infusion of insulin, insulin+glucose and insulin+amino acids, without refeeding. RESULTS: Refeeding increased plasma glucose/insulin/T3 and muscle Slc2a4 mRNA, reverting insulin resistance. Post-fasting infusions surprisingly induced a further Slc2a4 mRNA decrease (~20%, P<0.05 vs. fasting), but T3 injection induced a ~2-fold increase in Slc2a4 mRNA, 2-4h later (P<0.001). Moreover, T3 increased glycemia and insulinemia to the 2h-refed rats levels, suggesting that T3 elevation is a key factor to the mechanisms of metabolic balance during refeeding. CONCLUSIONS: Refeeding induces a rapid increase in muscle Slc2a4 expression, not associated with increased plasma glucose, insulin or amino acids, but highly correlated to increased plasma T3 concentration. This result points out T3 hormone as a powerful Slc2a4 enhancer, an effect that may be acutely explored in situations of insulin resistance.

Expression of clock genes in human subcutaneous and visceral adipose tissues.

Disrupted circadian rhythms are associated with obesity and metabolic alterations, but little is known about the participation of peripheral circadian clock machinery in these processes. The aim of the present study was to analyze RNA expression of clock genes in subcutaneous (SAT) and visceral (VAT) adipose tissues of male and female subjects in AM (morning) and PM (afternoon) periods, and its interactions with body mass index (BMI). Ninety-one subjects (41 ± 11 yrs of age) presenting a wide range of BMI (21.4 to 48.6 kg/m(2)) were included. SAT and VAT biopsies were obtained from patients undergoing abdominal surgeries. Clock genes expressions were evaluated by qRT-PCR. The only clock gene that showed higher expression (p < .0001) in SAT in comparison to VAT was PER1 of female (372%) and male (326%) subjects. Different patterns of expression between the AM and PM periods were observed, in particular REV-ERBα, which was reduced (p < .05) at the PM period in SAT and VAT of both women and men (women: ∼53% lower; men: ∼78% lower), whereas CLOCK expression was not altered. Relationships between clock genes were different in SAT vs. VAT. BMI was negatively correlated with SATPER1 (r = -.549; p = .001) and SATPER2 (r = -.613; p = .0001) and positively with VATCLOCK (r = .541; p = .001) and VATBMAL1 (r = .468; p = .007) only in women. These data suggest that the circadian clock machinery of adipose tissue depots differs between female and male subjects, with a sex-specific effect observed for some genes. BMI correlated with clock genes, but at this moment it is not possible to establish the cause-effect relationship.

Participation of beta-adrenergic activity in modulation of GLUT4 expression during fasting and refeeding in rats.

Through in vitro studies, several factors have been reported as modulators of GLUT4 gene expression. However, the role(s) of each potential GLUT4 modulator is not completely understood in the in vivo setting. The present study has investigated the hypothesis that beta-adrenergic stimulation participates in modulation of GLUT4 expression during fasting and refeeding. As such, GLUT4 messenger RNA (mRNA) and protein were investigated in insulin-sensitive tissues during a 48-hour fast. In addition, the effects of 8-hour refeeding on GLUT4 mRNA in the gastrocnemius muscle and interscapular brown adipose tissue (BAT) were investigated. Whether beta-adrenoceptor blockade by propranolol (20 mg/kg) treatment influenced the responsiveness to fasting/refeeding was also investigated. The results show that fasting repressed GLUT4 gene and protein expression in BAT, white adipose tissue, and soleus muscle, but had no effect on the gastrocnemius muscle. Refeeding induced a rapid overexpression of GLUT4 mRNA in both gastrocnemius (approximately 25%, P < .05) and BAT (approximately 200%, P < .001). Propranolol treatment induced an increase (approximately 60%, P < .05) in GLUT4 mRNA at the end of the fasting period. In contrast, propranolol treatment attenuated GLUT4 mRNA induction after refeeding; the latter may be due to attenuation of postprandial insulin levels. These results suggest that sympathetic activity is important for the repression of GLUT4 gene expression during fasting. In contrast, sympathetic control of the GLUT4 gene seems to be overbalanced by metabolic/hormonal modulators during refeeding stage. Taken together, the results suggest that feeding behavior influences GLUT4 gene expression pattern through changes in sympathetic activity, especially during long-term starvation periods.