Impact of High Fat Diet on Heart Proteome Reprogramming and Cardiac Remodeling in Diet-Induce Obesity (DIO) Mice: The PPARs Regulators

Background: The impact of a high-fat diet (HFD) on the heart proteome and cardiac remodeling in the context of diet-induced obesity is a complex process that involves multiple molecular pathways. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that play a crucial role in regulating lipid metabolism, inflammation, and energy homeostasis. In the context of obesity, PPARs, particularly PPARα, PPARβ/δ, and PPARγ, serve as key regulators of cardiac response to metabolic stress. The aim of this work is to a detailed breakdown of how a high-fat diet might influence cardiac proteome reprogramming and remodelling via PPARs in diet-induced obesity (DIO) mice model. Methods: 14 six-week-old male C57BL/6N mice (Charles River Laboratories, Calco, Italy) were divided into two groups and fed for 20 weeks as follows: (1) normal chow diet (10% fat, CTR) and (2) high-fat (HFD) diet (60% fat). At the age of 26 weeks, the mice were sacrificed through exposure to atmosphere saturation of carbon dioxide for 15 min. Hearts were collected, immediately snapfrozen in liquid nitrogen, and stored at −80° until proteomic analyses. Bioinformatic analyses were made using Cluego software (Cytoskape release 3.8.2) and IPA software. The Italian Ministry of Health approved all animal procedures (Number 5AD83.N.G1Q). Results: Proteomic data clearly show an increase in mitochondrial fatty acid β-Oxidation and a concomitant alteration in glucose metabolism, a decrease in oxidative phosphorylation and an increase in lipid synthesis. Moreover, there is an important involvement of the PPAR signaling, especially α and γ, and the sirtuin signaling pathway important in cell survival under stressful conditions. From the IPA analysis a clear picture of cardiotoxicity emerges which also involves morphological aspects linked to alterations of the cytoskeleton. Cardiac dilatation and left ventricular fibrosis are among the disorders most likely caused by the alteration of the FHD proteome. Interesting, IL-33 is the possible up-stream regulator of cardiac damage (whose target molecules in the data set are ACAT1, APOE, EPHX2, IGHM, ITIH1, Marcks, MYLK, UCP1), produced from polarized T-helper 2 cells, upon interaction of IL-33 with its receptors and the subsequent activation of intracellular molecules in the NF-κB pathways. The induction of type 2 cytokines by IL-33 in vivo is considered to induce severe pathological changes in different organs including heart. Conclusions: Proteome network analysis demonstrated that PPARα and PPARγ driven heart remodeling through deregulation of cardiac lipid metabolism and cytokines activation, especially of IL-33 network. Acknowledgment: the study was supported by the fund of Italian Ministry of Health (PSR2023_VIANELLO) and by Italian Ministry of Health-