Obesity and diabetes are characterized by a disruption in energy balance and glucose homeostasis in association with leptin resistance. Leptin action in the hypothalamus regulates glucose levels and body weight, but whether other brain regions facilitate leptin action remain unclear. Here, we investigate whether the nucleus of the solitary tract (NTS) of the brainstem is a crucial site for leptin action in regulating glucose homeostasis in 3d high-fat (HF) -fed male rats, as recent studies report leptin activates leptin receptor in the NTS to regulate feeding. In this study, we performed brain stereotaxic bilateral surgery targeting the NTS followed one week later by catheterization of the left carotid artery and right internal jugular vein for infusion/sampling purposes. Rats that attained >90% of presurgical weight received 3d of Lard oil enriched HF diet and were fasted 4-6 hr before undergoing a 2min pancreatic (basal insulin) -euglycemic clamp studies together with tracer glucose infusion to assess glucose metabolism independent of changes in plasma insulin and glucagon levels. Leptin (91.7 ng/uL at 0.33 ul/hr) or saline was infused into the NTS throughout the duration of the clamp studies. Correct placement of the NTS catheter was verified by infusion of bromophenol blue dye through the brain cannula. For the first time, we found that leptin vs. saline infusion into the NTS markedly increased the exogenous glucose infusion [lep: 4.6±0.2 vs. sal: 1.3±0.4 mg/kg/min; p<0.005; n=12, 5] required to maintain euglycemia [lep: 137.5±2.2 vs. sal: 145±3.1 mg/dl; p>0.05; n=12, 5], during the clamps. The drop in plasma glucose levels was due to an inhibition of glucose production [lep: 4.9±0.1 vs. sal: 8.4±0.7 mg/kg/min; p<0.01; n=12, 5], but not an increase in glucose uptake [lep: 10.4±0.5 vs. sal: 9.7±0.3 mg/kg/min; p>0.05; n=12, 5]. These findings demonstrate that the NTS mediates leptin action on glucose homeostasis. Future studies are needed to investigate the NTS leptin signaling cascade in glucose homeostasis in obesity and diabetes.
K.Bruce: None. R.Li: None. Y.Lim: None. J.T.Yue: None. T.K.Lam: None.
Canadian Institutes of Health Research Foundation Grant (FDN-143204)