VEGA 2/0147/23

Untangling the roles of obesity, diet, and diabetes in the development of cardiomyopathy in the female ZDF rat

Principal Investigator: Michal Cagalinec

Duration: January 2023 – December 2026
Coordinating Organization: Institute of Experimental Endocrinology BRC SAS

Annotation:

Cardiovascular diseases (CVDs) are the leading cause of morbidity worldwide. Accumulating evidence indicates that although pre-menopausal women have a lower risk of CVDs, compared to age-matched men, this advantage is lost in diabetic premenopausal women where the leading case of the CVD is the development of diabetic cardiomyopathy (DCM). DCM relates to heart remodeling and functional changes. Few human, as well as rodent studies, including the Zucker Diabetic Fatty (ZDF) rat model, have assessed molecular and cellular mechanisms regarding gender differences of DCM. For male ZDF rats diastolic dysfunction, calcium signaling disturbance, and myocyte hypertrophy has been reported. Therefore, we aim to characterize intracellular calcium dynamics and ultrastructure of cardiomyocytes in female ZDF rats and compare them between the lean and obese models with or without developed DCM to reveal the mechanisms behind diet-, obesity-, and diabetes-induced pathology.

Keywords:

cardiomyopathy, diabetes, obesity, high-fat diet, calcium transients, electron microscopy

Objectives:

This project aims to characterize cardiomyocytes of female ZDF rats, especially their intracellular calcium dynamics and ultrastructure, and compare them between lean (fa/+) vs. obese (fa/fa) models with or without diabetic cardiomyopathy (DCM) induced by high-fat diet (HFD) to reveal the mechanisms behind diet-, obesity-, and diabetes-induced pathological changes.

The first hypothesis to support this aim is that the female cardiomyopathy (CM) developing in the fa/fa HFD group results from obesity and/or HFD, not from hyperglycemia itself. To validate this hypothesis, we will examine cardiac pathology in non-diabetic animals, i.e., normoglycemic obese females on the standard diet (fa/fa StD) and lean females on the high-fat diet (fa/+ HFD). We will analyze the cardiac phenotype in all four groups of the female rats, i.e. fa/fa HFD, fa/fa StD, fa/+ HFD, and fa/+ StD (Fig. 1 A). We expect a clear difference between the cardiac phenotype in the control fa/+ StD group (i.e., absence of CM) and that in the fa/fa HFD group (presence of DCM). If CM will manifest in the fa/+ HFD but not in the fa/fa StD group, this will indicate a strong effect of HFD on cardiac pathology. On the contrary, if CM will be present in the fa/fa StD but not in the fa/+ HFD group, this will indicate that the CM is instigated by obesity. If neither the fa/fa StD nor the fa/+ HFD groups will show CM, this will suggest a specific intrinsic mechanism developing only when all factors (HFD, obesity, and diabetes) are present.

The second hypothesis states that HFD is crucial for the persistence of DCM in female fa/fa ZDF rats. The diabetic state, i.e. hyperglycemia and insulinopenia, is maintained in fa/fa females even after switching to StD after diabetes had fully developed. If HFD is not necessary to maintain DCM, the DCM phenotype should progress even after the diabetic females are switched to StD. On the other hand, if maintaining cardiomyopathy requires HFD, cardiac pathology should not progress or should even reverse after switching to StD.