The main goal of this study was to compare the impact of total 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 wild-type (WT), nervous system LR-deficient (LR/Nestin-Cre), and leptin deficient (ob/ob) mice. Blood pressure (BP) and heart rate (HR) were recorded by telemetry, and motor activity (MA) and oxygen consumption (V̇o2) were monitored at 24 wk 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) and hyperphagic (6.2 ± 0.5 and 6.1 ± 0.7 vs. 3.5 ± 1.0 g/day), with reduced V̇o2 (27 ± 1 and 33 ± 1 vs 49 ± 3 ml·kg-1·min-1) and decreased MA (3 ± 1 and 7 ± 2 vs 676 ± 105 cm/h). They were also hyperinsulinemic and hyperglycemic compared with WT mice. LR/Nestin-Cre mice had high levels of plasma leptin, while ob/ob mice had undetectable leptin levels. Despite comparable obesity, LR/Nestin-Cre mice had lower liver fat content, 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 and 109 ± 2 mmHg). Female LR/Nestin-Cre and ob/ob mice, however, had higher BP than WT females despite similar metabolic phenotypes compared with male LR/Nestin-Cre and ob/ob mice. These results indicate that although nervous system LRs play a crucial role in regulating body weight and glucose homeostasis, peripheral LRs regulate liver fat deposition. In addition, our results suggest potential sex differences in the impact of obesity on BP regulation.