A Cardiac Amino-Terminal GRK2 Peptide Inhibits Maladaptive Adipocyte Hypertrophy and Insulin Resistance During Diet-Induced Obesity

Iyad H Manaserh; Kamila M Bledzka; Alex Junker; Jessica Grondolsky; Sarah M Schumacher

doi:10.1016/j.jacbts.2022.01.010

A Cardiac Amino-Terminal GRK2 Peptide Inhibits Maladaptive Adipocyte Hypertrophy and Insulin Resistance During Diet-Induced Obesity

JACC Basic Transl Sci. 2022 Apr 27;7(6):563-579. doi: 10.1016/j.jacbts.2022.01.010. eCollection 2022 Jun.

Authors

Iyad H Manaserh¹, Kamila M Bledzka¹, Alex Junker¹, Jessica Grondolsky¹, Sarah M Schumacher¹

Affiliation

¹ Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Abstract

Heart disease remains the leading cause of death, and mortality rates positively correlate with the presence of obesity and diabetes. Despite the correlation between cardiac and metabolic dysregulation, the mechanistic pathway(s) of interorgan crosstalk still remain undefined. This study reveals that cardiac-restricted expression of an amino-terminal peptide of GRK2 (βARKnt) preserves systemic and cardiac insulin responsiveness, and protects against adipocyte maladaptive hypertrophy in a diet-induced obesity model. These data suggest a cardiac-driven mechanism to ameliorate maladaptive cardiac remodeling and improve systemic metabolic homeostasis that may lead to new treatment modalities for cardioprotection in obesity and obesity-related metabolic syndromes.

Keywords: AS160, Akt substrate of 160 kilodaltons; BAT, brown adipose tissue; GRK2; GRK2, G protein-coupled receptor kinase 2; HFD, high-fat diet; HOMA-IR, homeostatic model assessment of insulin resistance; NLC, nontransgenic littermate control; NP, natriuretic peptide; NPR, natriuretic peptide receptor; RER, respiratory exchange ratio; T2D, type II diabetes; Tg, transgenic; beiging; cardioprotection; gWAT, gonadal white adipose tissue; mTOR, mechanistic target of rapamycin protein kinase; metabolism; obesity; βARKct, cardiac restricted expression of C-terminus domain of GRK2; βARKnt, cardiac-restricted expression of N-terminus domain of GRK2.