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<0.01). These data indicate that the increased HFD-induced obesity of Apoa5-/- mice as compared to WT mice is at least partly explained by hyperphagia and that APOA5 plays a role in the central regulation of food intake.-Van den Berg, S. A. A., Heemskerk, M. M., Geerling, J. J., van Klinken, J.-B., Schaap, F. G., Bijland, S., Berbee, J. F. P., van Harmelen, V. J. A., Pronk, A. C. M., Schreurs, M., Havekes, L. M., Rensen, P. C. N., van Dijk, K. W. Apolipoprotein A5 deficiency aggravates high-fat diet-induced obesity due to impaired central regulation of food intake.