PGC-1/Spargel Counteracts High-Fat-Diet-Induced Obesity and Cardiac Lipotoxicity Downstream of TOR and Brummer ATGL Lipase.

Soda Balla Diop,Jumana Bisharat-Kernizan,Karen Ocorr,Sean Oldham,Rolf Bodmer,Ryan Tyge Birse

doi:10.1016/j.celrep.2015.02.022

Soda Balla Diop, Jumana Bisharat-Kernizan + Show 4 more

Open Access

https://doi.org/10.1016/j.celrep.2015.02.022

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Abstract

Obesity and metabolic syndrome are associated withan increased risk for lipotoxic cardiomyopathy, which is strongly correlated with excessive accumulation of lipids in the heart. Obesity- and type-2-diabetes-related disorders have been linked to altered expression of the transcriptional cofactor PGC-1α, which regulates the expression of genes involved inenergy metabolism. Using Drosophila, we identify PGC-1/spargel (PGC-1/srl) as a key antagonist of high-fat diet (HFD)-induced lipotoxic cardiomyopathy. We find that HFD-induced lipid accumulation and cardiac dysfunction are mimicked by reduced PGC-1/srl function and reversed by PGC-1/srl overexpression. Moreover, HFD feeding lowers PGC-1/srl expression by elevating TOR signaling and inhibiting expression of the Drosophila adipocyte triglyceride lipase (ATGL) (Brummer), both of which function as upstream modulators of PGC-1/srl. The lipogenic transcription factor SREBP also contributes to HFD-induced cardiac lipotoxicity, likely in parallel with PGC-1/srl. These results suggest a regulatory network of key metabolic genes that modulates lipotoxic heart dysfunction.

Highlights

Heart failure is a major cause of mortality in modern society
We found that flies with reduced PGC-1/srl function had elevated TAG levels compared with wildtype flies, and TAG levels were further increased when the mutant or systemic PGC-1/srl KD flies (Arm>PGC-1RNAi) were fed a high-fat diet (HFD) (Figures 1A, 1B, S1A)
We found that these flies (PGC-1XP/PGC-1GR) have a significantly lower TAG level compared to PGC-1 heterozygous flies (PGC-1XP/+) under normal fly food (NF) or HFD (Figure 1A)

Summary

Introduction

Heart failure is a major cause of mortality in modern society. The high prevalence of obesity and related diseases, including type 2 diabetes, plays a significant role in the increased incidence of cardiovascular disease, which affects more than a billion people worldwide. The high incidence of obesity-associated heart dysfunction is aggravated by changes in nutritional habits, such as consumption of high caloric diets, combined with reduced physical activity. A major challenge in developing targeted therapeutics for this type of heart disease is to understand how the molecular and genetic changes induced by high caloric diets lead to metabolic imbalances that culminate in cardiac dysfunction. Drosophila is unique in that it is the only invertebrate model organism with a beating heart for which suitable genetic tools and assays are available to study heart function (Bier and Bodmer, 2004; Ocorr et al, 2007; Wessells et al, 2004; Wolf et al, 2006; Ocorr et al, 2014)

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