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

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Author: Berg, S.A.A. van den · Heemskerk, M.M. · Geerling, J.J. · Klinken, J.B. van · Schaap, F.G. · Bijland, S. · Berbée, J.F.P. · Harmelen, V.J.A. van · Pronk, A.C.M. · Schreurs, M. · Havekes, L.M. · Rensen, P.C.N. · Dijk, K.W. van
Source:FASEB Journal, 8, 27, 3354-3362
Identifier: 477623
doi: doi:10.1096/fj.12-225367
Keywords: Biology · APOA5 · Central nervous system · Hyperphagia · Triglyceride metabolism · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · EELS - Earth, Environmental and Life Sciences


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. © FASEB.