Sex Differences in Cardiac Mitochondria in the New Zealand Obese Mouse.

Cathleen John,Arne Kühne,Ulrich Kintscher,Kerstin Nowotny,Christiane Ott,Carola Schubert,Jana Grune,Stefanie Deubel,Tilman Grune,Vera Regitz-Zagrosek

doi:10.3389/fendo.2018.00732

Abstract

Background: Obesity is a risk factor for diseases including type 2 diabetes mellitus (T2DM) and cardiovascular disorders. Diabetes itself contributes to cardiac damage. Thus, studying cardiovascular events and establishing therapeutic intervention in the period of type T2DM onset and manifestation are of highest importance. Mitochondrial dysfunction is one of the pathophysiological mechanisms leading to impaired cardiac function.Methods: An adequate animal model for studying pathophysiology of T2DM is the New Zealand Obese (NZO) mouse. These mice were maintained on a high-fat diet (HFD) without carbohydrates for 13 weeks followed by 4 week HFD with carbohydrates. NZO mice developed severe obesity and only male mice developed manifest T2DM. We determined cardiac phenotypes and mitochondrial function as well as cardiomyocyte signaling in this model.Results: The development of an obese phenotype and T2DM in male mice was accompanied by an impaired systolic function as judged by echocardiography and MyH6/7 expression. Moreover, the mitochondrial function only in male NZO hearts was significantly reduced and ERK1/2 and AMPK protein levels were altered.Conclusions: This is the first report demonstrating that the cardiac phenotype in male diabetic NZO mice is associated with impaired cardiac energy function and signaling events.

Highlights

Diabetes as Cardiovascular Risk FactorObesity and its related diseases, such as type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD), developed through increasing caloric intake and/or reduced energy expenditure, are a present critical global health problem
We investigated whether changes in the diabetic state are associated with sex, and this correlates with changes in cardiac mitochondrial function or expression of metabolicallyassociated proteins and contractile proteins and cardiac function in the New Zealand Obese (NZO) mouse
Blood glucose levels of NZO males and females were increased in comparison to B6 mice, but only if mice were treated for 4 weeks with high carbohydrate diet (HCD) (Figure 1B)

Summary

Introduction

Obesity and its related diseases, such as type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD), developed through increasing caloric intake and/or reduced energy expenditure, are a present critical global health problem. Men develop diabetes at a lower body mass index and are predestined to be more insulin-resistant [4]. The authors addressed that trials investigating lifestyle or pharmacological intervention in males and females at risk were promising so far, but that there is more need to analyze biological and psychosocial differences among women and men. T2DM increases the risk of CVD, known to be a major cause of morbidity and mortality in diabetic men and women [6,7,8]. Obesity is a risk factor for diseases including type 2 diabetes mellitus (T2DM) and cardiovascular disorders. Mitochondrial dysfunction is one of the pathophysiological mechanisms leading to impaired cardiac function

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