Aged garlic extract suppresses the increase of plasma glycated albumin level and enhances the AMP-activated protein kinase in adipose tissue in TSOD mice.

SCOPE: In this study, we investigated the effect of aged garlic extract (AGE) on the high level of blood glucose in Tsumura Suzuki Obese-Diabetes (TSOD) mice. METHODS AND RESULTS: TSOD mice were fed standard diet with or without 2% AGE for 19 weeks. AGE treatment lowered the blood glucose level and significantly reduced the plasma level of glycated albumin in TSOD mice as compared with those without AGE treatment. In addition, AGE treatment increased the level of phosphorylated AMP-activated protein kinase (AMPK) in the adipose tissue, liver and muscle that played an important role in the maintenance of insulin sensitivity. Moreover, AGE treatment also suppressed the mRNA expression of fatty acid synthase, a known factor regulated by AMPK, and monocyte chemoattractant protein 1, one of the representative inflammatory chemokines, in the adipose tissue but not in the liver. CONCLUSION: AGE treatment suppresses the increase of plasma glycated albumin level in TSOD mice and this effect is accompanied by the activation of AMPK in adipose tissue, and suggests that AGE may play a potential role in the prevention and treatment of type 2 diabetes.

Potential contribution of vasoconstriction to suppression of heat loss and homeothermic regulation in UCP1-deficient mice.

To investigate the thermoregulatory mechanism in mice lacking uncoupling protein 1 (UCP1) from the viewpoint of heat loss, we measured oxygen consumptions (VO2), skin-surface temperatures (Tskin, an index of heat release), blood flows in the tails, and rectal temperatures (Trectal) of mice housed in an animal room under the standard thermal condition of approximately 23 degrees C. Compared with wild-type (Ucp1+/+) mice, adult UCP1-deficient (Ucp1-/-) mice tended to show a reduced VO2. Thermograhic analysis of the acute response of Ucp1-/- mice to a small change (a drop of 1-2 degrees C) in the ambient temperature revealed a sustained fall in the Tskin of Ucp1-/- mice; but this fall was only transient in Ucp1+/+ mice. Analysis of tail blood flow under anesthesia clearly showed a stronger vasoconstrictor response in Ucp1-/- mice than in Ucp1+/+ mice. Administration of a vasodilator, evodiamine, transiently increased Tskin in Ucp1+/+ and Ucp1-/- mice similarly; whereas the induction of vasodilation caused a greater and more prolonged reduction in Trectal in Ucp1-/- mice than in Ucp1+/+ mice. These results indicate that Ucp1-/- mice highly, or at least partly, rely on vasoconstriction for heat conservation to compensate for their UCP1 deficiency and to maintain homeothermy under the condition of normal housing temperature.

Indispensable role of mitochondrial UCP1 for antiobesity effect of beta3-adrenergic stimulation.

Mitochondrial uncoupling protein-1 (UCP1) has been thought to be a key molecule for thermogenesis during cold exposure and spontaneous hyperphagia and thereby in the autonomic regulation of energy expenditure and adiposity. However, UCP1 knockout (KO) mice were reported to be cold intolerant but unexpectedly did not get obese even after hyperphagia, implying that UCP1 may not be involved in the regulation of adiposity. Treatment of obese animals with beta3-adrenergic agonists is known to increase lipid mobilization, induce UCP1, and, finally, reduce body fat content. To obtain direct evidence for the role of UCP1 in the anti-obesity effect of beta3-adrenergic stimulation, in the present study, UCP1-KO and wild-type (WT) mice were fed on cafeteria diets for 8 wk and then given a beta3-adrenergic agonist, CL-316,243 (CL), or saline for 2 wk. A single injection of CL increased whole body oxygen consumption and brown fat temperature in WT mice but not in KO mice, and it elicited almost the same plasma free fatty acid response in WT and KO mice. WT and KO mice increased similarly their body and white fat pad weights on cafeteria diets compared with those on laboratory chow. Daily treatment with CL resulted in a marked reduction of white fat pad weight and the size of adipocytes in WT mice, but not in KO mice. Compared with WT mice, KO mice expressed increased levels of UCP2 in brown fat but decreased levels in white fat and comparable levels of UCP3. It was concluded that the anti-obesity effect of beta3-adrenergic stimulation is largely attributable to UCP1, but less to UCP2 and UCP3, and thereby to UCP1-dependent degradation of fatty acids released from white adipose tissue.

Uncoupling protein 1 is necessary for norepinephrine-induced glucose utilization in brown adipose tissue.

Sympathetic stimulation activates glucose utilization in parallel with fatty acid oxidation and thermogenesis in brown adipose tissue (BAT) through the beta-adrenergic receptors. To clarify the roles of the principal thermogenic molecule mitochondrial uncoupling protein 1 (UCP1) in the sympathetically stimulated glucose utilization, we investigated the uptake of 2-deoxyglucose (2-DG) into BAT and some other tissues of UCP1-knockout (KO) mice in vivo. In wild-type (WT) mice, administration of norepinephrine (NE) accelerated the disappearance of plasma 2-DG and increased 2-DG uptake into BAT and heart without any rise of plasma insulin level. In UCP1-KO mice, the stimulatory effect of NE on 2-DG uptake into BAT, but not into heart, disappeared completely. Insulin administration increased 2-DG uptake into BAT and also heart similarly in WT and UCP1-KO mice. NE also increased the activity of AMP-activated protein kinase (AMP kinase) in BAT of WT but not UCP1-KO mice. Our results, together with reports that the activation of AMP kinase increases glucose transport in myocytes, suggest that the sympathetically stimulated glucose utilization in BAT is due to the serial activation of UCP1 and AMP kinase.