CNS‐Specific Leptin Receptor Deficiency Impairs Cardiac Reserve

Abstract

We previously showed that leptin deficiency leads to reduced myocardial reserve independent of changes in body weight, and that leptin replacement in non‐obese ob/ob mice completely restored ejection fraction (EF) responses to a cardiovascular stress test. Whether central nervous system (CNS) leptin receptor (LepR) activation contributes to normal myocardial reserve during increased cardiac stress is unknown. In this study we examined if deletion of LepR specifically in the CNS alters cardiovascular responses to a stress test induced by dobutamine in 22 week old mice. LepR/Nestin‐Cre mice with LepR deleted in the CNS were generated by breeding LepRflox/flox mice with Nestin‐Cre mice. Male LepR/Nestin‐Cre (n=4) and WT control (n=5) mice were instrumented for continuous infusion of saline and progressively increasing doses of dobutamine (2–12 ng/g body wt/min, 2 min at each dose). Long and short axis left ventricle dimensions were obtained before and one minute after each dose of dobutamine using a 30 MHZ transducer (VEVO2100®). Compared to WT, LepR/Nestin‐Cre mice were heavier (73±3 vs 34±1 g) due to hyperphagia (5.5±0.5 vs 3.8±0.5 g food/day), normoglycemic (174±10 vs 180±11 mg/dL), hyperleptinemic (109±1.5 vs 6.5±0.9 ng/mL), and hyperinsulinemic (119±23 vs 10±3 mU/mL). Baseline heart rate (HR) was similar in LepR/Nestin‐Cre (433±16 bpm) and WT (421±28 bpm) mice. Baseline EF was significantly higher in LepR/Nestin‐Cre (80±2%) compared to WT (66±4%) mice. Dobutamine infusion (4 ng/g/min) decreased average HR by 47±15 in LepR/Nestin‐Cre and increased HR by 41±11 bpm in WT mice. Dobutamine increased EF by 28±5% in WT mice but no significant change (4±4%) occurred in LepR/Nestin‐Cre mice. These results show that despite significant increases in plasma leptin concentration and presumably stimulation of cardiac LepR, CNS LepR deficiency leads to reduced myocardial reserve in response to a cardiovascular stress test in male mice. (NHLBI‐PO1HL51971, NIGMS P20GM104357)Support or Funding InformationNHLBI‐PO1HL51971, NIGMS P20GM104357This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.