Long Term High Fat Diet Treatment: An Appropriate Approach to Study the Sex-Specificity of the Autonomic and Cardiovascular Responses to Obesity in Mice

Abstract

Obesity-related cardiovascular disease (CVD) involves increased sympathetic activity in men and male animals. Although women exhibit increased visceral fat, metabolic disorders, inflammation and CVD with obesity, whether body weight gain affects autonomic control of cardiovascular function in females remain unknown. Due to the lack of adequate model to mimic the human pathology, this study aimed to develop a murine model, which would allow studying the sex-specificity of the response of the autonomic nervous system to obesity and identifying the origin of potential sex-differences. We tested the hypothesis that sexual dimorphisms in the autonomic response to obesity disappear in mice matched for changes in body weight, metabolic and inflammatory disorders. Male and female C57Bl/6 mice were submitted to control (CD) or high fat diet (HFD) for 24 weeks. Female mice gained more adipose mass and lost more lean mass than males but reached similar visceral adipose mass and body weight, as males, at the end of the diet. 24 weeks of HFD matched male and female mice for visceral adiposity, glycaemia, plasma insulin, lipids, and inflammatory cytokines levels, demonstrating the suitability of the model to study human pathology. HFD did not elevate BP, but similarly increased heart rate (HR) in males (CD: 571 ± 9 vs. HFD: 631 ± 14 bpm, P < 0.05) and females (CD: 589 ± 19 vs. HFD: 642 ± 6 bpm, P < 0.05). Indices of autonomic control of BP and HR were obtained by measuring BP and HR response to ganglionic blockade, β-adrenergic, and muscarinic receptors antagonists. HFD increased vascular but reduced cardiac sympathetic drive in males (CD: –43 ± 4 and HFD: –60 ± 7% drop in BP, P < 0.05). HFD did not alter females' vascular or cardiac sympathetic drive. HFD specifically reduced aortic α-adrenergic constriction in males and lowered HR response to muscarinic receptor antagonism in females. These data suggest that obesity-associated increases in HR could be caused by a reduced cardiac vagal tone in females, while HR increases in males may compensate for the reduced vascular adrenergic contractility to preserve baseline BP. These data suggest that obesity impairs autonomic control of cardiovascular function in males and females, via sex-specific mechanisms and independent of fat distribution, metabolic disorder or inflammation.

Sex-Specific Effect of High-Fat Diet on Glycerol Metabolism in Murine Adipose Tissue and Liver

“…However, after 24 weeks of HFD females demonstrated a more pronounced increase in relative body weight gain than males supporting that the relative resistance to diet-induced obesity (DIO) in females is attenuated after 24 weeks of HFD. This is somewhat in line with the study by Bruder-Nascimento and coworkers, where male and female C57Bl/6 mice had a similar BW after 24 weeks of 60% HFD feeding (28). However, despite a similar degree of adiposity after 24 weeks of HFD in male and female mice, then male mice still had a more severe phenotype that included more marked hyperglycemia, hypertriglyceridemia and a higher degree of hepatic steatosis.…”

Regulation of Lymphatic Function in Obesity

“…Report indicates that, 10-12 weeks of HFD feeding regime showed higher the blood glucose, insulin, liver enzymes, plasma lipids, cholesterol, adipose tissue macrophages, and circulating leukocytes in male mice compared to female (Singer et al, 2015;Ingvorsen et al, 2017). However, long term HFD regime (24 weeks) results in no differences between male and female in any of the parameters mentioned above indicating duration of high fat feeding is critical in exhibition of sexual dimorphism in HFD induced obesity (Bruder-Nascimento et al, 2017). Most common mice strains like C57BL/6J, FVB/N, 129 × 1, DBA/2 are prone for obesity upon HFD feeding but BALB/c mice strain is found to show certain degree of resistance to obesity even after HFD feeding (Montgomery et al, 2013).…”

A Calcium-Dependent Chloride Current Increases Repetitive Firing in Mouse Sympathetic Neurons

“…Although gender differences have been appreciated in GABA-mediated excitation during development, these differences are explained by the distinct expression of K + -Cl - or Na + -K + -Cl - cotransporters in male and female animals ( Galanopoulou, 2005 ; Nuñez and McCarthy, 2007 ), and not by differences in the expression of Cl - channels, particularly in the PNS. However, this differential expression of Cl - ion channels in male and female sympathetic neurons contributes to the firing frequency, which may explain the gender differences in the activation of sympathetic tone observed recently in mice ( Bruder-Nascimento et al, 2017 ).…”