Interplay between obesity and aging on myocardial geometry and function: Role of leptin-STAT3-stress signaling

• Published in: Biochimica et biophysica acta. General subjects Vol. 1867; no. 2; p. 130281
• Main Authors: Jin, Wei, Tu, Fei, Dong, Feng, Deng, Qinqin, Abudureyimu, Miyesaier, Yu, Wei, Cai, Guo-jun, Pei, Jian-ming, Pei, Zhaohui, Ren, Jun
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2023
• Subjects: Aging; Animals; calcium; Cardiac; cardiomyocytes; Contraction; dephosphorylation; echocardiography; fluorescence; geometry; high fat diet; Leptin; Leptin - physiology; leptin receptors; Mice; Mice, Obese; mutants; Myocardium - pathology; NAD(P)H oxidase (H2O2-forming); NADPH Oxidases; Obesity; Oxidative Stress; phosphorylation inhibition; Proto-Oncogene Proteins c-akt; Remodeling; Stress signaling; Stress, Physiological; Ventricular Remodeling; Obesity; Stress signaling; Leptin; Cardiac; Aging; Remodeling; Contraction
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2022.130281

Uncorrected obesity facilitates premature aging and cardiovascular anomalies. This study examined the interaction between obesity and aging on cardiac remodeling and contractile function. Methods: Cardiac echocardiographic geometry, function, morphology, intracellular Ca2+ handling, oxidative stress (DHE fluorescence), STAT3 and stress signaling were evaluated in young (3-mo) and old (12- and 18-mo) lean and leptin deficient ob/ob obese mice. Cardiomyocytes from young and old lean and ob/ob mice were treated with leptin (1 nM) for 4 h in vitro prior to assessment of mechanical and biochemical properties. High fat diet (45% calorie from fat) and the leptin receptor mutant db/db obese mice at young and old age were evaluated for comparison. Results: Our results displayed reduced survival in ob/ob mice. Obesity but less likely older age dampened echocardiographic, geometric, cardiomyocyte function and intracellular Ca2+ properties, elevated O2− and p47phox NADPH oxidase levels with a more pronounced geometric change at older age. Immunoblot analysis revealed elevated p47phox NADPH oxidase and dampened phosphorylation of STAT3, with a more pronounced response in old ob/ob mice, the effects were restored by leptin. Obesity and aging inhibited phosphorylation of Akt, eNOS, AMPK, and p38 while promoting phosphorylation of JNK and IκB. Leptin reconciled cardiomyocyte dysfunction, O2− yield, p47phox upregulation, STAT3 dephosphorylation and stress signaling in ob/ob mice although its action on stress signaling cascades were lost at old age. High fat diet-induced and db/db obesity displayed aging-associated cardiomyocyte anomalies reminiscent of ob/ob model albeit lost leptin response. Our data suggest disparate age-associated obesity response in cardiac remodeling and contractile dysfunction due to phosphorylation of Akt, eNOS and stress signaling-related oxidative stress. •Obesity but less likely early aging dampened geometric, cardiac contractile and intracellular Ca2+ properties,•Elevated NADPH oxidase and dampened phosphorylation of STAT3 played a role in cardiac anomalies in ob/ob mice•Leptin alleviated dephosphorylation of eNOS, AMPK, p38 while promoting phosphorylation of JNK and IκB in young not old age•Disparate obesity response in cardiac remodeling and contractile dysfunction exists with aging involving stress signaling.