Obesity, type 2 diabetes (T2DM) and insulin resistance are independent risk factors for heart failure, which affects a rapidly increasing segment of the US population. The long-term goal of this proposal is to understand the mechanisms linking these metabolic disorders and left ventricular (LV) dysfunction prior to and in concert with heart failure. Obesity is associated with insulin resistance, hyperlipidemia, glucose intolerance and hyperinsulinemia. Epidemiological studies suggest that hyperinsulinemia is an independent risk factor for heart failure. In humans and mouse models, the heart may retain its insulin sensitivity in terms of insulin?s ability to activate IRS1, PI3K and Akt signaling, despite insulin resistance in other organs such as the liver and skeletal muscle. This hyperinsulinemia also accelerates adverse LV remodeling in pressure overload hypertrophy and genetic reduction of insulin signaling in cardiomyocytes limits hypertrophic remodeling and reduces apoptosis in pressure overload, thereby preserving LV function. Our recent studies reveal that hyperinsulinemia desensitizes ?-AR-mediated stimulation of cardiac contractility, which represents a novel mechanism linking insulin resistance, hyperinsulinemia and LV dysfunction. This proposal, will therefore focus on the hypothesis that hyperinsulinemia might attenuate LV contractility by directly impairing ?{1} or ?{2} -adrenergic (?AR) signaling. Specifically, activation of cardiomyocyte insulin receptors (IR) in hyperinsulinemic states, impairs ?AR signaling via two distinct mechanisms: (1) Increased ?{2}AR/G{i} coupling that inhibits adenylyl cyclase and cAMP production, and (2) Increased expression of PDE4D that increases cAMP degradation. This multi PI proposal reflects an active collaboration by the laboratories of Evan Dale Abel (University of Iowa) and Yang Kevin Xiang (University of California ?Davis). Our combined expertise in myocardial insulin signaling and myocardial adrenergic signaling will address this hypothesis in the following two specific aims.
Aim 1 (Xiang). Will define the molecular mechanisms by which insulin impairs ?AR signaling in cardiomyocytes by testing the following hypotheses: Insulin signaling increases ?{2}AR/G{i} coupling via a complex containing ?{2}AR, IR, IRS, and GRK2 that inhibits adenylyl cyclase-mediated cAMP generation. Insulin signaling enhances cardiac PDE4 levels via ?{2}AR-ERK dependent modulation of PDE4 transcription and protein turnover.
Aim 2 (Abel). Will determine the physiological consequences of ?AR-IR interactions in hearts in vivo by testing the hypotheses that: Acute or chronic hyperinsulinemia will impair myocardial ?AR signaling and reduce contractility or inotropic reserve and that hyperinsulinemia in obesity, T2DM and heart failure will exacerbate cardiac dysfunction by impairing inotropic reserve. By using novel molecular biosensors to define subcellular adrenergic signaling domains in cardiomyocytes and a comprehensive array of mutant mouse models with perturbed IR or ?AR signaling, we will dissect the mechanism for IR??AR crosstalk that limits myocardial contractility in insulin resistant states.

Public Health Relevance

Heart failure is a leading cause of mortality in the United States. Obesity and insulin resistance are independent risk factors for heart failure. The present study will address the critical question of the role of altered beta-adrenergic signaling in the pathophysiology of cardiac dysfunction in obesity, type 2 diabetes, and other insulin-resistant states. We will determine if augmented myocardial insulin signaling, as a consequence of the hyperinsulinemia that develops in obesity and type 2 diabetes, directly impairs the ability of adrenergic signaling to enhance cardiac contractility. These studies will provide novel information regarding modulation of beta-adrenergic signaling pathways in the prevention or treatment of cardiac dysfunction in obesity and type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL112413-01A1
Application #
8791981
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schwartz, Lisa
Project Start
2015-06-01
Project End
2019-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52246
Patriarchi, Tommaso; Shen, Ao; He, Wei et al. (2018) Nanodelivery of a functional membrane receptor to manipulate cellular phenotype. Sci Rep 8:3556
Zhang, Jianyi; Abel, E Dale (2018) Effective Metabolic Approaches for the Energy Starved Failing Heart: Bioenergetic Resiliency via Redundancy or Something Else? Circ Res 123:329-331
Reddy, Gopireddy Raghavender; West, Toni M; Jian, Zhong et al. (2018) Illuminating cell signaling with genetically encoded FRET biosensors in adult mouse cardiomyocytes. J Gen Physiol 150:1567-1582
Steinhorn, Benjamin; Sartoretto, Juliano L; Sorrentino, Andrea et al. (2017) Insulin-dependent metabolic and inotropic responses in the heart are modulated by hydrogen peroxide from NADPH-oxidase isoforms NOX2 and NOX4. Free Radic Biol Med 113:16-25
Fu, Qin; Wang, Qingtong; Xiang, Yang K (2017) Insulin and ? Adrenergic Receptor Signaling: Crosstalk in Heart. Trends Endocrinol Metab 28:416-427
Fu, Qin; Hu, Yuting; Wang, Qingtong et al. (2017) High-fat diet induces protein kinase A and G-protein receptor kinase phosphorylation of ?2 -adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts. J Physiol 595:1973-1986
Park, Misun; Reddy, Gopireddy R; Wallukat, Gerd et al. (2017) ?1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes. Sci Rep 7:7890
Pires, Karla Maria; Buffolo, Marcio; Schaaf, Christin et al. (2017) Activation of IGF-1 receptors and Akt signaling by systemic hyperinsulinemia contributes to cardiac hypertrophy but does not regulate cardiac autophagy in obese diabetic mice. J Mol Cell Cardiol 113:39-50
Wang, Qingtong; Liu, Yongming; Fu, Qin et al. (2017) Inhibiting Insulin-Mediated ?2-Adrenergic Receptor Activation Prevents Diabetes-Associated Cardiac Dysfunction. Circulation 135:73-88
Shi, Qian; Li, Minghui; Mika, Delphine et al. (2017) Heterologous desensitization of cardiac ?-adrenergic signal via hormone-induced ?AR/arrestin/PDE4 complexes. Cardiovasc Res 113:656-670

Showing the most recent 10 out of 16 publications