title: Regulation of energy balance by the hypothalamic lipoprotein lipase regulator Angptl3.
abstract: Hypothalamic lipid sensing is important for the maintenance of energy balance. Angiopoietin-like protein 3 (Angptl3) critically regulates the clearance of circulating lipids by inhibiting lipoprotein lipase (LPL). The current study demonstrated that Angptl3 is highly expressed in the neurons of the mediobasal hypothalamus, an important area in brain lipid sensing. Suppression of hypothalamic Angptl3 increased food intake but reduced energy expenditure and fat oxidation, thereby promoting weight gain. Consistently, intracerebroventricular (ICV) administration of Angptl3 caused the opposite metabolic changes, supporting an important role for hypothalamic Angptl3 in the control of energy balance. Notably, ICV Angptl3 significantly stimulated hypothalamic LPL activity. Moreover, coadministration of the LPL inhibitor apolipoprotein C3 antagonized the effects of Angptl3 on energy metabolism, indicating that LPL activation is critical for the central metabolic actions of Angptl3. Increased LPL activity is expected to promote lipid uptake by hypothalamic neurons, leading to enhanced brain lipid sensing. Indeed, ICV injection of Angptl3 increased long-chain fatty acid (LCFA) and LCFA-CoA levels in the hypothalamus. Furthermore, inhibitors of hypothalamic lipid-sensing pathways prevented Angptl3-induced anorexia and weight loss. These findings identify Angptl3 as a novel regulator of the hypothalamic lipid-sensing pathway.
authors.affiliation: Appetite Regulation Laboratory, ASAN Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Hyun-Kyong
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Mi-Seon
authors.initials: MS
authors.lastname: Shin
authors.affiliation: Department of Anatomy, Wonkwang University School of Medicine, Iksan, Republic of Korea.
authors.forename: Byung-Soo
authors.initials: BS
authors.lastname: Youn
authors.affiliation: Appetite Regulation Laboratory, ASAN Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Gil Myoung
authors.initials: GM
authors.lastname: Kang
authors.affiliation: Appetite Regulation Laboratory, ASAN Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Gil
authors.affiliation: Appetite Regulation Laboratory, ASAN Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Chan Hee
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Appetite Regulation Laboratory, ASAN Institute for Life Sciences, Seoul, Republic of Korea Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jong Han
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Appetite Regulation Laboratory, ASAN Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Hyo Sun
authors.initials: HS
authors.lastname: Lim
authors.affiliation: Biomedical Research Center, ASAN Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Yoo
authors.affiliation: Appetite Regulation Laboratory, ASAN Institute for Life Sciences, Seoul, Republic of Korea Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea mskim@amc.seoul.kr.
authors.forename: Min-Seon
authors.initials: MS
authors.lastname: Kim
mesh_terms: D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008297:Male; D051379:Mice; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C404495:Angptl3 protein, mouse; D005227:Fatty Acids; D008071:Lipoprotein Lipase