Interaction between Age and Obesity on Cardiomyocyte Contractile Function: Role of Leptin and Stress Signaling

Jun Ren,Guo-Jun Cai,Jennifer M Nunn,Feng Dong,Peng Zhao,Loren E Wold,Jainming Pei

doi:10.1371/journal.pone.0010085

Abstract

ObjectivesThis study was designed to evaluate the interaction between aging and obesity on cardiac contractile and intracellular Ca2+ properties.MethodsCardiomyocytes from young (4-mo) and aging (12- and 18-mo) male lean and the leptin deficient ob/ob obese mice were treated with leptin (0.5, 1.0 and 50 nM) for 4 hrs in vitro. High fat diet (45% calorie from fat) and the leptin receptor mutant db/db obesity models at young and older age were used for comparison. Cardiomyocyte contractile and intracellular Ca2+ properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (± dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), intracellular Ca2+ levels and decay. O2 − levels were measured by dihydroethidium fluorescence.ResultsOur results revealed reduced survival in ob/ob mice. Aging and obesity reduced PS, ± dL/dt, intracellular Ca2+ rise, prolonged TR90 and intracellular Ca2+ decay, enhanced O2 − production and p 47phox expression without an additive effect of the two, with the exception of intracellular Ca2+ rise. Western blot analysis exhibited reduced Ob-R expression and STAT-3 phosphorylation in both young and aging ob/ob mice, which was restored by leptin. Aging and obesity reduced phosphorylation of Akt, eNOS and p38 while promoting pJNK and pIκB. Low levels of leptin reconciled contractile, intracellular Ca2+ and cell signaling defects as well as O2 − production and p 47phox upregulation in young but not aging ob/ob mice. High level of leptin (50 nM) compromised contractile and intracellular Ca2+ response as well as O2 − production and stress signaling in all groups. High fat diet-induced and db/db obesity displayed somewhat comparable aging-induced mechanical but not leptin response.ConclusionsTaken together, our data suggest that aging and obesity compromise cardiac contractile function possibly via phosphorylation of Akt, eNOS and stress signaling-associated O2 − release.

Highlights

Obesity is a devastating health problem afflicting all ages, races and socioeconomic classes in both genders
There were no significant differences in tibial length and fasting glucose levels among the four mouse groups, excluding growth-related factor and the presence of full-blown diabetes mellitus (Table 1)
To determine whether O22 production plays a role in the disparate leptin effects between young and aging ob/ob mice, we evaluated O22 production and expression of the rate-limiting enzyme for O22 production NADPH oxidase (p47phox subunit) [25] using DHE

Summary

Introduction

Obesity is a devastating health problem afflicting all ages, races and socioeconomic classes in both genders. With today’s prolonged human lifespan, aging has been considered as an obesogenic factor given the increased visceral fat associated with aging [4]. Visceral fat accumulation may in turn influence longevity, prompting the speculation that obesity could be a condition of premature aging [4]. Effective physiological adjustments are present to counterbalance the potentially detrimental health outcome of obesity such as altered respiratory mechanical/muscular function peculiar to the aging condition [5], a number of obesity-associated comorbidities such as cancer, endocrine, cardiovascular and immune disorders may contribute to premature aging and the shortened lifespan. The concept of health promotion, especially on nutrition and life style, has become an important part of health care in older adults [6]

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