LAUSR

The main goal of this study was to compare the impact of whole-body leptin deficiency with neuronal specific leptin receptor (LR) deletion on metabolic and cardiovascular regulation. Liver fat, diacylglycerol acyltransferase-2 (DGTA2) and CD36 protein content were measured in male and female wild-type (WT, n=5/sex), nervous system LR deficient (LR/Nestin-Cre, n=6/sex), and leptin deficient (ob/ob, n=5) mice. Blood pressure (BP) and heart rate (HR) were recorded by telemetry, and motor activity (MA) and oxygen consumption (VO 2 ) were monitored at 24 weeks of age. Female and male LR/Nestin-Cre and ob/ob mice were heavier than WT mice (62±5 and 61±3 vs 31±1 g), hyperphagic (6.2±0.5 and 6.1±0.7 vs 3.5±1.0 g/day), with reduced VO 2 (27±1 and 33±1 vs 49±3 ml/kg/min) and decreased MA (3±1 and 7±2 vs 676±105 cm/hr). LR/Nestin-Cre and ob/ob mice were also hyperinsulinemic and hyperglycemic compared to WT mice. LR/Nestin-Cre mice had high plasma leptin levels while ob/ob mice had undetectable leptin levels. Despite comparable obesity, LR/Nestin-Cre mice had lower liver fat content (83% reduced) and DGTA2 and CD36 protein levels than ob/ob mice. Male WT, LR/Nestin-Cre, and ob/ob mice exhibited similar BP (111±3, 110±1 and109±2 mmHg), whereas female LR/Nestin-Cre mice had higher BP compared to WT females despite similar metabolic phenotypes compared to male LR/Nestin-Cre mice. No significant increases in plasma aldosterone concentration was observed in male LR/Nestin-Cre compared to WT mice (495±48 vs. 440±62 pg/ml); however, female LR/Nestin-Cre mice had ~14 fold higher plasma aldosterone concentration compared to female WT mice (707±97 vs. 50±3 pg/ml). These results indicate that although nervous system LRs play a crucial role in regulating body weight and glucose homeostasis, peripheral LRs also regulate liver fat deposition and modulate BP in a sex dependent manner. (NHLBI-PO1HL51971, NIGMS P20GM104357 and U54GM115428)