Loss of βENaC Prevents Hepatic Steatosis but Promotes Abdominal Fat Deposition Associated with a High-Fat Diet

TL;DR

Reducing βENaC in mice lowers liver fat but increases abdominal fat when on a high-fat diet, suggesting a new role in fat distribution and metabolic health.

Contribution

The study reveals a novel role for βENaC in regulating fat distribution and metabolic health in response to a high-fat diet.

Findings

Male mice with reduced βENaC had less liver fat but more abdominal fat on a high-fat diet.

βENaC hypomorph mice showed altered body composition and fat distribution without changes in energy expenditure or food intake.

Female βMUT mice had lower heart mass when fed a high-fat diet.

Abstract

The purpose of this study was to determine if loss of βENaC impacts energy balance and fat distribution associated with a high-fat diet. We examined body fat and lean mass, energy expenditure, food consumption, motor activity, and fat distribution in the liver and surrounding the gonads and abdominal organs. We found that male mice with reduced expression of βENaC tended to weigh less and have less fat deposition in the liver than controls. However, male mice with reduced βENaC had larger gonadal and abdominal organ fat depots. These findings suggest that βENaC plays a novel role in fat distribution, an important determinant of metabolic health.

Background: Degenerin proteins, such as Acid-Sensing Ion Channel 2 (ASIC2) and β Epithelial Na+ Channel (βENaC), have been implicated in cardiovascular function. We previously demonstrated that mice lacking normal levels of βENaC and ASIC2 are protected from diet-induced obesity, metabolic disruption, and hepatic steatosis. Methods: To investigate the specific role of βENaC proteins in the progression of metabolic disease, we examined the impact of a high-fat diet (HFD) in the βENaC hypomorph mouse model (βMUT). Body composition and metabolic and behavioral phenotypes were examined in male and female and βMUT and WT mice (n = 6–14/group) fed a normal chow diet (NFD) from weaning until 16 weeks of age, then a 60% kcal-fat diet for 5 weeks. Results: Compared to WT mice, βMUT male mice have reduced lean and total body mass. No remarkable differences in energy expenditure, motor activity, or food consumption patterns were detected. HFD-fed male βMUT mice exhibited reduced liver fat content (mass and Oil Red O staining) yet increased abdominal fat depots. HFD-fed female βMUT mice exhibited lower heart mass. Conclusions: These novel findings suggest a role for βENaC in the maintenance of metabolic homeostasis and adipose tissue distribution.

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