Abstract
Prolonged obesity causes “selective leptin resistance” (SLR), in which cardiovascular responses to leptin are intact but metabolic responses are lost. High fat diet (HFD) for 10 weeks causes SLR in C57BL/6J mice, as it attenuates metabolic (adipose) sympathetic nervous activity (SNA) responses to leptin but has no effect on cardiovascular SNA responses. Using single-nucleus RNAsequencing, we recently discovered disruption of leptin and CREB signaling specifically in Agouti-related peptide ( Agrp ) neurons of the arcuate nucleus of the hypothalamus (ARC) after 10-week HFD. Because C57BL/6J mice are generally resistant to diet-induced changes in blood pressure (BP), one goal of this study was to examine BP in this model. Further, we sought to examine effects of prolonged HFD on CREB signaling and Agrp mRNA within the ARC. Male C57BL/6J mice were maintained on chow (2920x) or HFD (D12451) from 8-18 weeks of age. Intake behaviors were studied in metabolic cages and bomb calorimetry; body composition via nuclear magnetic resonance; BP and HR via radiotelemetry; and cardiac function via echocardiography. ARC biopsies were analyzed for Agrp mRNA via qPCR and for CREB and ERK proteins using capillary electrophoresis-based Western. HFD increased caloric uptake, leading to increases in body and fat mass (p<0.05). HFD had no effect on BP (24h MAP: chow 110±2 vs HFD 103±9 mmHg, n=8 each), but heart rate (HR; 555±12 vs 601±3 bpm, p<0.05) and HR variability (low/high freq. ratio: 0.6±0.08 vs 0.8±0.09, p<0.05) were increased by HFD, consistent with increased cardiac SNA. Stroke volume (41±2 vs 18±3 uL, n=10 each, p<0.05) and thus cardiac output (13±0.9 vs 6±1 mL/min, p<0.05) were significantly reduced with HFD, explaining normal BP despite increased cardiovascular SNA. HFD increased plasma leptin (p<0.05), decreased CREB (pCREB/CREB ratio: 0.7±0.1 n=4, vs 0.4±0.1, n=5, p<0.05) but increased ERK (pERK/ERK ratio: 8.4±1.2 vs 12.5±1.1, p<0.05) phosphorylation, and failed to suppress Agrp mRNA in the ARC. We conclude that prolonged HFD increases cardiovascular SNA in C57BL/6J mice without effect on BP because of cardiac compensation. Further, this model causes SLR at the level of the ARC Agrp neuron, in a mechanism likely involving alterations in CREB- and ERK-mediated signaling.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
