title: Apoptosis inhibitor of macrophage (AIM) diminishes lipid droplet-coating proteins leading to lipolysis in adipocytes.
abstract: Under fasting conditions, triacylglycerol in adipose tissue undergoes lipolysis to supply fatty acids as energy substrates. Such lipolysis is regulated by hormones, which activate lipases via stimulation of specific signalling cascades. We previously showed that macrophage-derived soluble protein, AIM induces obesity-associated lipolysis, triggering chronic inflammation in fat tissue which causes insulin resistance. However, the mechanism of how AIM mediates lipolysis remains unknown. Here we show that AIM induces lipolysis in a manner distinct from that of hormone-dependent lipolysis, without activation or augmentation of lipases. In vivo and in vitro, AIM did not enhance phosphorylation of hormone-sensitive lipase (HSL) in adipocytes, a hallmark of hormone-dependent lipolysis activation. Similarly, adipose tissue from obese AIM-deficient and wild-type mice showed comparable HSL phosphorylation. Consistent with the suppressive effect of AIM on fatty acid synthase activity, the amount of saturated and unsaturated fatty acids was reduced in adipocytes treated with AIM. This response ablated transcriptional activity of peroxisome proliferator-activated receptor (PPARγ), leading to diminished gene expression of lipid-droplet coating proteins including fat-specific protein 27 (FSP27) and Perilipin, which are indispensable for triacylglycerol storage in adipocytes. Accordingly, the lipolytic effect of AIM was overcome by a PPARγ-agonist or forced expression of FSP27, while it was synergized by a PPARγ-antagonist. Overall, distinct modes of lipolysis appear to take place in different physiological situations; one is a supportive response against nutritional deprivation achieved by enhancing lipase activity, and the other is a pathological consequence of obesity, causing subclinical inflammation and metabolic disorders, mediated by abolishing droplet-coating proteins.
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Iwamura
authors.forename: Mayumi
authors.initials: M
authors.lastname: Mori
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nakashima
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Mikami
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Murayama
authors.forename: Satoko
authors.initials: S
authors.lastname: Arai
authors.forename: Toru
authors.initials: T
authors.lastname: Miyazaki
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008066:Lipolysis; D051379:Mice; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D051116:Receptors, Scavenger; D002787:Sterol Esterase / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C117272:Cd5l protein, mouse; D005227:Fatty Acids; D047495:PPAR gamma; D000070778:Perilipin-1; D010750:Phosphoproteins; D011506:Proteins; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C525805:fat-specific protein 27, mouse; D002787:Sterol Esterase