Apolipoprotein A5 deficiency aggravates high-fat diet-induced obesity due to impaired central regulation of food intake

Mutations in apolipoprotein A5 (APOA5) have been associated with hypertriglyceridemia in humans and mice. This has been attributed to a stimulating role for APOA5 in lipoprotein lipase-mediated triglyceride hydrolysis and hepatic clearance of lipoprotein remnant particles. However, because of the low APOA5 plasma abundance, we investigated an additional signaling role for APOA5 in high-fat diet (HFD)-induced obesity. Wild-type (WT) and Apoa5(-/-) mice fed a chow diet showed no difference in body weight or 24-h food intake (Apoa5(-/-), 4.5 +/- 0.6 g; WT, 4.2 +/- 0.5 g), while Apoa5(-/-) mice fed an HFD ate more in 24 h (Apoa5(-/-), 2.8 +/- 0.4 g; WT, 2.5 +/- 0.3 g, P <0.05) and became more obese than WT mice. Also, intravenous injection of APOA5-loaded VLDL-like particles lowered food intake (VLDL control, 0.26 +/- 0.04 g; VLDL+APOA5, 0.11 +/- 0.07 g, P <0.01). In addition, the HFD-induced hyperphagia of Apoa5(-/-) mice was prevented by adenovirus-mediated hepatic overexpression of APOA5. Finally, intracerebroventricular injection of APOA5 reduced food intake compared to injection of the same mouse with artificial cerebral spinal fluid (0.40 +/- 0.11 g; APOA5, 0.23 +/- 0.08 g, P