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Cardiac autophagy deficiency attenuates ANP production and disrupts myocardial-adipose crosstalk leading to increased fat accumulation and metabolic dysfunction

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posted on 12.10.2020 by Ada Admin, Erfei Song, Daniel Da Eira, Shailee Jani, Diane Sepa-Kishi, Vivian Vu, Howard Hunter, Mi Lai, Michael B. Wheeler, Rolando B. Ceddia, Gary Sweeney
Increased myocardial autophagy has been established as an important stress-induced cardioprotective response. Three weeks after generating cardiomyocyte-specific autophagy deficiency, via inducible deletion of autophagy related protein 7 (Atg7), we found these mice (AKO) increased body weight and fat mass without altered food intake. Glucose and insulin tolerance tests indicated reduced insulin sensitivity in AKO mice. Metabolic cage analysis showed reduced ambulatory activity and oxygen consumption with a trend of elevated respiratory exchange ratio in AKO mice. Direct analysis of metabolism in subcutaneous and visceral adipocytes showed increased glucose oxidation and reduced ATGL expression and HSL phosphorylation with no change in lipid synthesis or fatty acid oxidation. Importantly, we found AKO mice had reduced myocardial and circulating levels of atrial natriuretic peptide (ANP), an established mediator of myocardial-adipose crosstalk. When normal ANP levels were restored to AKO mice using osmotic pump, the metabolic dysfunction evident in AKO mice was corrected. We conclude that cardiac autophagy deficiency alters myocardial-adipose crosstalk via decreased ANP levels with adverse metabolic consequences.

Funding

This work was supported by an operating grant to GS from Canadian Institutes of Health Research, to ES from National Natural Science Foundation of China to SEF (81900779) and to RBC from National Science and Engineering Research Council. GS also gratefully acknowledges support from Heart & Stroke Foundation of Ontario via a Career Investigator Award.

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