Fatty acid-binding protein 5 regulates diet-induced obesity via GIP secretion from enteroendocrine K cells in response to fat ingestion Kimitaka Shibue, 1,2 Shunsuke Yamane, 1 Norio Harada, 1 Akihiro Hamasaki, 1 Kazuyo Suzuki, 1 Erina Joo, 1 Kanako Iwasaki, 1 Daniela Nasteska, 1 Takanari Harada, 1 Yoshitaka Hayashi, 3 Yasuhiro Adachi, 4 Yuji Owada, 5 Ryoichi Takayanagi, 2 and Nobuya Inagaki 1 1 Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2 Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 3 Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; 4 Department of Anatomy, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan; and 5 Department of Organ Anatomy, Yamaguchi University Graduate School of Medicine, Ube, Japan Submitted 24 November 2014; accepted in final form 23 January 2015 Shibue K, Yamane S, Harada N, Hamasaki A, Suzuki K, Joo E, Iwasaki K, Nasteska D, Harada T, Hayashi Y, Adachi Y, Owada Y, Takayanagi R, Inagaki N. Fatty acid-binding protein 5 regulates diet-induced obesity via GIP secretion from enteroen- docrine K cells in response to fat ingestion. Am J Physiol Endo- crinol Metab 308: E583–E591, 2015. First published January 27, 2015; doi:10.1152/ajpendo.00543.2014.—Gastric inhibitory poly- peptide (GIP) is an incretin released from enteroendocrine K cells in response to nutrient intake, especially fat. GIP is one of the contrib- uting factors inducing fat accumulation that results in obesity. A recent study shows that fatty acid-binding protein 5 (FABP5) is expressed in murine K cells and is involved in fat-induced GIP secretion. We investigated the mechanism of fat-induced GIP secre- tion and the impact of FABP5-related GIP response on diet-induced obesity (DIO). Single oral administration of glucose and fat resulted in a 40% reduction of GIP response to fat but not to glucose in whole body FABP5-knockout (FABP5 -/- ) mice, with no change in K cell count or GIP content in K cells. In an ex vivo experiment using isolated upper small intestine, oleic acid induced only a slight increase in GIP release, which was markedly enhanced by coadministration of bile and oleic acid together with attenuated GIP response in the FABP5 -/- sample. FABP5 -/- mice exhibited a 24% reduction in body weight gain and body fat mass under a high-fat diet compared with wild-type (FABP5 +/+ ) mice; the difference was not observed between GIP-GFP homozygous knock-in (GIP gfp/gfp )-FABP5 +/+ mice and GIP gfp/gfp -FABP5 -/- mice, in which GIP is genetically deleted. These results demonstrate that bile efficiently amplifies fat- induced GIP secretion and that FABP5 contributes to the development of DIO in a GIP-dependent manner. incretin; gastric inhibitory polypeptide; obesity; fatty acid-binding protein 5 OBESITY HAS BEEN RECOGNIZED AS A WORLDWIDE PROBLEM, espe- cially for developing insulin resistance and increasing the risk of type 2 diabetes (11). The increased adipose tissue associated with obesity secretes various kinds of cytokines, adipokines, and lipokines (2) and triggers systemic inflammatory response, resulting in the disturbance of metabolic homeostasis (9). Gastric inhibitory polypeptide (GIP) is one of the incretins, peptide hormones released from the gastrointestinal tract into circulation in response to nutrient ingestion, that potentiates glucose-stimulated insulin secretion (5, 16, 35). Dietary lipid is a very strong stimulant of GIP secretion. For example, the peak value of GIP increase in response to a high-fat meal (450 kcal containing 33.3% of fat) is three times higher than that in the 75-g oral glucose tolerance test (OGTT) in human subjects, suggesting that fat content in a mixed meal strongly stimulates GIP secretion (45). GIP binds to the GIP receptor (GIPR) on the surface of pancreatic -cells to stimulate insulin secretion (34). GIP is considered to increase the volume of adipose tissue by two major pathways: directly by binding to GIPR located on the adipocytes (15, 39) and indirectly by accelerating fat deposition and expansion of fat depots by increasing insulin secretion from -cells (32). Studies of GIPR knockout (Gipr -/- ) mice (27) describe GIP as an obesity-promoting factor in high-fat diet (HFD) conditions and show that deletion of GIPR signaling causes resistance to diet-induced obesity (DIO) (26). Additionally, we have reported that partial reduc- tion of GIP alleviates obesity and lessens the degree of insulin resistance without exacerbating glucose tolerance under HFD conditions (28). These findings suggest that regulation of GIP secretion, especially after fat intake, is a promising therapeutic approach to obesity and type 2 diabetes. However, the precise mechanism of GIP secretion has remained unclear mainly because of the inability to isolate GIP-producing enteroendo- crine K cells from intestinal epithelium. Recently, we gener- ated GIP-green fluorescent protein (GFP) knock-in mice in which K cells are labeled by enhanced GFP (EGFP). On the basis of microarray analysis of K cells isolated from GIP-GFP knockin heterozygous (GIP gfp/+ ) mice, we demonstrate that transcriptional regulatory factor X6 (Rfx6) is expressed exclu- sively in K cells, and that Rfx6 is involved in GIP hypersecre- tion in DIO (43). Very recently, It was reported that fatty acid-binding protein 5 (FABP5) is expressed in K cells and is involved in fat- induced GIP secretion (38). FABP has been known as an intracellular chaperon that transports long-chain fatty acid (LCFA) into various organelles (42). Human enterocytes are known to coexpress FABP1 and FABP2, which are thought to play distinct functional roles in fatty acid metabolism (17). Vari- ation in the FABP2 gene in Pima Indians (6) is reported to alter fatty acid transport in the reconstitution study using human cell lines (1). FABP4 and FABP5 have been reported to be expressed in adipocytes and to play a critical role in regulating fat accumu- lation and progression of insulin resistance. FABP4/FABP5 dou- ble-knockout (FABP4 -/- /FABP5 -/- ) mice have exhibited a dra- Address for reprint requests and other correspondence: N. Inagaki, Dept. of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan (e-mail: inagaki@metab.kuhp.kyoto-u.ac.jp). Am J Physiol Endocrinol Metab 308: E583–E591, 2015. First published January 27, 2015; doi:10.1152/ajpendo.00543.2014. 0193-1849/15 Copyright © 2015 the American Physiological Society http://www.ajpendo.org E583 Downloaded from journals.physiology.org/journal/ajpendo (003.235.021.012) on June 5, 2020.