Impact of leptin deficiency compared with neuronal-specific leptin receptor deletion on cardiometabolic regulation

Abstract

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.

Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity

“…The importance of peripheral LepR signaling has recently been highlighted in a study comparing LepR deficiency in neural tissues with an overall Lep ob phenotype [64]. LepR deficiency in neural tissues only partially replicates glycemic and other metabolic abnormalities observed in Lep ob male mice, whereas regulation of appetite and body composition depends entirely on the leptin action in neurons via the long isoform of LepR (LepRb) [64].…”

“…The importance of peripheral LepR signaling has recently been highlighted in a study comparing LepR deficiency in neural tissues with an overall Lep ob phenotype [64]. LepR deficiency in neural tissues only partially replicates glycemic and other metabolic abnormalities observed in Lep ob male mice, whereas regulation of appetite and body composition depends entirely on the leptin action in neurons via the long isoform of LepR (LepRb) [64]. These differences could be attributed to the presence of shorter, peripheral isoforms of LepR (i.e., LepRa, LepRc, LepRd, LepRf), which are ubiquitously expressed in peripheral tissues and are capable of increasing ERK2 phosphorylation [8].…”

Growth-Promoting Effects of Zhenqi Granules on Finishing Pigs

“…Of these, Srebf1 is one of the main regulators of de novo lipogenesis in the liver, and its overexpression contributed to lipids accumulation [ 56 ]. However, ZQ decreased the LEPR mRNA levels, LEPR is the receptor for leptin, and leptin promotes lipolysis and limits ectopic deposition in nonfatty tissues [ 57 , 58 , 59 , 60 ]. Therefore, we give the following conjecture: On the one hand, ZQ promoted fatty acid (FA) synthesis from glucose by upregulating lipogenic genes such as Srebf1, and then, the FA was esterified to TG and stored in the hepatocyte.…”

Toward the Decipherment of Molecular Interactions in the Diabetic Brain

“…The continuous infusion of leptin at supraphysiological doses directly into the brains of T1DM rats led to blood glucose normalization [ 38 ]. When leptin administration was stopped, hyperglycemia was quickly reestablished in the absence of changes in insulin, indicating the central effect of leptin on the modulation of glucose metabolism [ 39 ]. Of note, severe insulin deficiency is associated with severe leptin deficiency, whereas insulin treatment reverses hypoleptinemia [ 40 ].…”