APPL1 transgenic mice are protected from high-fat diet-induced cardiac dysfunction

Area of Science:

• Cardiovascular Biology
• Metabolic Disease Research
• Molecular Signaling Pathways

Background:

• High-fat diet (HFD) consumption is a major cause of cardiac dysfunction and cardiomyopathy.
• Adaptor protein APPL1 (adaptor protein containing PH domain, PTB domain, and leucine zipper motif 1) plays a key role in insulin and adiponectin signaling.
• Understanding the protective mechanisms against HFD-induced cardiac damage is crucial for developing therapeutic strategies.

Purpose of the Study:

• To investigate the protective effects of transgenic (Tg) APPL1 overexpression against high-fat diet-induced cardiomyopathy in mice.
• To elucidate the molecular mechanisms underlying APPL1-mediated protection in the context of metabolic stress.
• To assess the impact of APPL1 on cardiac function, lipid metabolism, and insulin sensitivity under HFD conditions.

Main Methods:

• Generation of APPL1 transgenic (Tg) mice and comparison with wild-type (WT) littermates.
• Induction of cardiac dysfunction using a 16-week high-fat diet (HFD) regimen.
• Assessment of cardiac function via echocardiography and speckle tracking.
• Analysis of circulating non-esterified fatty acids, myocardial lipid accumulation, and cardiac lipotoxicity markers.
• Lipidomic profiling using LC-MS-MS to quantify specific lipid species.
• Evaluation of insulin sensitivity through glucose tolerance tests and assessment of cardiac Akt phosphorylation and cardiomyocyte glucose uptake.

Main Results:

• HFD induced significant cardiac dysfunction in WT mice, characterized by reduced ejection fraction and fractional shortening.
• APPL1 Tg mice were protected from HFD-induced cardiac dysfunction, exhibiting preserved cardiac function.
• APPL1 Tg mice showed reduced HFD-induced increases in circulating non-esterified fatty acids and myocardial lipid accumulation, particularly specific ceramide and diacylglycerol species.
• Transgenic APPL1 overexpression attenuated peripheral insulin resistance and improved cardiac insulin signaling and glucose uptake in response to HFD.
• APPL1 Tg mice demonstrated reduced cardiac lipotoxicity and improved metabolic parameters compared to WT mice on HFD.

Conclusions:

• Transgenic overexpression of APPL1 confers significant protection against high-fat diet-induced cardiomyopathy in mice.
• APPL1 enhances peripheral metabolism and insulin sensitivity, contributing to reduced cardiac lipotoxicity.
• These findings highlight APPL1 as a potential therapeutic target for preventing or treating metabolic-related heart disease.