Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis

Area of Science:

• Metabolic disease research
• Cardiovascular research
• Lipid metabolism

Background:

• Ectopic lipid deposition and altered circulating lipids are key risk factors for cardiometabolic diseases.
• Angiopoietin-like protein 4 (ANGPTL4) regulates fatty acid uptake and circulating triglycerides but global depletion causes severe metabolic issues.
• Understanding ANGPTL4's specific role in metabolic disorders is limited due to these global effects.

Purpose of the Study:

• To investigate the specific role of adipose tissue (AT)-derived ANGPTL4 in regulating lipid metabolism and cardiometabolic disease progression.
• To determine if targeted ablation of ANGPTL4 in AT can prevent diet-induced metabolic dysfunction.

Main Methods:

• Generated adipose tissue-specific Angptl4 knockout (AT-specific Angptl4-KO) mice.
• Fed mice a high-fat diet (HFD) to induce metabolic stress.
• Assessed LPL activity, lipolysis, FA oxidation/synthesis, ectopic lipid deposition, insulin signaling, glucose tolerance, inflammation, and atherosclerosis.

Main Results:

• AT-specific Angptl4 deletion enhanced LPL activity, accelerated triglyceride clearance, and increased AT lipolysis and FA oxidation.
• Absence of ANGPTL4 in AT prevented ectopic lipid deposition in the liver and muscle, improving insulin signaling and glucose tolerance.
• Lack of AT ANGPTL4 reduced proatherogenic lipoproteins, attenuated inflammation, and decreased atherosclerosis progression.

Conclusions:

• Adipose tissue ANGPTL4 plays a critical role in regulating peripheral lipid deposition and whole-body metabolic homeostasis.
• Targeting ANGPTL4 specifically in adipose tissue offers a potential therapeutic strategy for metabolic disorders and atherosclerosis.
• AT ANGPTL4 influences systemic lipid and glucose metabolism and the development of atherosclerosis.