Metabolic syndrome and mineralocorticoid antagonists
Yoyo dieting leads to a succession of weight gains and losses. Our hypothesis is that the mineralocorticoid receptor (MR) and its ligand aldosterone are involved in weight-cycling-induced cardiovascular dysfunctions in overweight women and contributes to post-menopausal aggravation. We have developed a model showing that female mice subjected to three biphasic cycles of a high-fat diet followed by a standard diet, develop metabolic syndrome (MetS) and heart failure with preserved ejection fraction, worsened in ovariectomized mice in post-menopausal condition.
We propose to investigate if aldosterone is directly involved in an aggravation of the phenotype using an unique transgenic mouse model with adrenal inducible aldosterone overproduction. On the other hand, by administrating the highly selective MR antagonist (MRA) eplerenone to wild-type mice throughout the 3rd cycle of biphasic diet, we will evaluate, after a final weight loss, the benefits of the treatment on cardiac, coronary and peripheral arteries dysfunctions, as well as on the exercise capacity of the animals. In addition, a treatment with MRA restricted to the first phase of weight gain and then interrupted, will make it possible to assess the impact on metabolic memory with a view to limiting the worsening of the phenotype during the two subsequent phases of weight gain, and at the end of the protocol. We will also follow the benefits of MRA on glucose and lipid homeostasis, adipose tissue, kidney and adrenal dysfunction associated with this model. Indeed, this project will shed new light on adrenal dysfunction as a factor of comorbidity in the MetS. In summary, this project is about the preclinical evaluation of a pharmacological strategy in MetS to improve the benefits of weight loss on cardiovascular recovery.
Theoretically, the candidate will have knowledge about the functions of aldosterone and its mineralocorticoid receptor in heart, vessels, adipose tissue and kidney. He will have notions of endocrinology of the renin-angiotensin-aldosterone system, knowledge concerning heart failure, notably heart failure with preserved ejection fraction (HFpEF) and concerning the metabolic syndrome.
In practice, the following skills are desirable: i) in vivo functional analyzes by echocardiography and ex vivo in isolated resistance mesenteric arteries, ii) in vivo metabolic measurements of glucose and insulin sensitivity, iii) in vivo measurements and analysis fundus retinal vasculature, iv) measurement of exercise capacity in mice on treadmill, v) monitoring of animals in a long-term protocol (authorization for animal experimentation, level-2) vi) organ collection (heart, kidney, adipose tissue), vii) immuno-histology and image analysis