Pyridostigmine Bromide: Autonomic Nervous System Modulation Reduces Adipose and Splenic Tissue Weight in Leptin‐Deficienty Ob/Ob Mice

Abstract

BackgroundObesity, a major contributor to the development of cardiovascular diseases, is associated with an autonomic imbalance characterized by sympathetic hyperactivity and diminished vagal activity. Pyridostigmine bromide (PYR), a reversible inhibitor, can augment acetylcholine availability at the neuroeffector junction may have beneficial effects. Researchers reported decreases in body weight and fat in obese rats following vagal nerve stimulation. Besides, recent studies have shown the PYR ameliorated cardiomyopathy and facilitated the browning of white adipose tissue while activating brown adipose tissue. These results have inspired many groups to propose vagal nerve stimulation as a potential therapeutic approach to control obesity‐associated inflammation.ObjectivesTo assess the effects of PYR on organs/tissues weight, autonomic, hemodynamic and metabolic parameters in female ob/ob mice models.MethodsAll procedures and animal care were approved by the Committee on the Ethics of Animal Experimentation (085/17). Experiments were performed on female ob/ob mice (60 days old). Females received by gavage 3 mg/kg of PYR (PYR group) or water (C group) for 20 days. Blood arterial pressure (AP) and heart rate (HR) were evaluated by direct recording of biological signals. Metabolic parameters (blood glucose, triglycerides and cholesterol) were measured after 4 hours fasting. Transthoracic echocardiograms were used to assess cardiac function in both groups after of treatment.ResultsAt the end of the protocol PYR and C groups presented body weight gain in relation to initial values, p≤0.05. PYR group presented reduction in spleen weight in relation to C group (p≤0.05) (PYR: 0.04±0.002 g vs. C: 0.08±0.005 g). Similarly, abdominal adipose tissue weight was also lower in PYR group (PYR: 2.9±0.32 g and 4.3±0.27 g). Regarding, PYR group exhibited increase of LF band of AP variability (2.42±0.26 ms2) when compared to the C group (7.71±1.64 ms2); p≤0.05. HR variability, PYR presented increased the HF component (13.6±5.6 ms2) when compared to C group (3.4±0.71 ms2), p≤0.05. There were no differences in the direct hemodynamic measurements of systolic (120.3±1.96 vs. 124.7±3.27 mmHg), diastolic (86.4±1.75 vs. 87.8±2.46 mmHg) and mean AP (103.3±2.90 vs. 106.4±1.71 mmHg) as well as HR (508.8±17.33 vs. 556.8±34.71 bpm) between the PYR and C groups, respectively; p≥0.05. Morphometric and functional cardiac parameters were not different among groups; p≥0.05. No differences were observed regarding blood glucose (157.3±18.14 vs. 148.6±9.12 mg/dL), total cholesterol (160.3±2.56 vs. 164.0±1.64 mg/dL) and triglycerides (149.80±18.87 vs. 127.90±24.06 mg/dL) between the PYR and control groups, respectively; p≥0.05.ConclusionInterestingly, vagal activation by PYR plays important roles in decreased abdominal adipose and splenic tissue weight. Although, PYR treatment does not change metabolic and hemodynamic parameters in ob/ob mice models. In contrast, low doses of PYR were able to modulate the LF and HF indicating that cholinergic stimulation may be used to modulate autonomic nervous system.Support or Funding InformationCAPES and CNPq (150183/2017‐8)