1.
2.
3.
Morgen CS, Sørensen T. Obesity: global trends in the prevalence of
overweight and obesity. Nat Rev Endocrinol 10: 513–514, 2014.
doi:10.1038/nrendo.2014.124.
Bray GA, Paeratakul S, Popkin BM. Dietary fat and obesity: a review
of animal, clinical and epidemiological studies. Physiol Behav 83:
549–555, 2004. doi:10.1016/j.physbeh.2004.08.039.
Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest 106:
473–481, 2000. doi:10.1172/JCI10842.
AJP-Endocrinol Metab doi:10.1152/ajpendo.00329.2022 www.ajpendo.org
Downloaded from journals.physiology.org/journal/ajpendo at Kyoto Univ (054.066.017.246) on May 17, 2023.
INHIBITION OF GPR120 SIGNALING IN INTESTINE
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Lemieux I, Pascot A, Couillard C, Lamarche B, Tchernof A,
ras N, Bergeron J, Gaudet D, Tremblay G, Prud’homme D,
Alme
s JP. Hypertriglyceridemic waist: a marker of the
Nadeau A, Despre
atherogenic metabolic triad (hyperinsulinemia; hyperapolipoprotein
B;small, dense LDL) in men? Circulation 102: 179–184, 2000.
doi:10.1161/01.cir.102.2.179.
Petrie JR, Guzik TJ, Touyz RM. Diabetes, hypertension, and cardiovascular disease: clinical insights and vascular mechanisms. Can J
Cardiol 34: 575–584, 2018. doi:10.1016/j.cjca.2017.12.005.
Zhao YF. Free fatty acid receptors in the endocrine regulation of glucose metabolism: insight from gastrointestinal-pancreatic-adipose
interactions. Front Endocrinol (Lausanne) 13: 956277, 2022. doi:10.
3389/fendo.2022.956277.
Kimura I, Ichimura A, Ohue-Kitano R, Igarashi M. Free fatty acid
receptors in health and disease. Physiol Rev 100: 171–210, 2020.
doi:10.1152/physrev.00041.2018.
€ glund PJ, Gloriam DE, Lagerstro
€ m MC, Schio
€ th
Fredriksson R, Ho
HB. Seven evolutionarily conserved human rhodopsin G proteincouple receptors lacking close relatives. FEBS Lett 20: 381–388,
2003. doi:10.1016/s0014-5793(03)01196-7.
Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M,
Sugimoto Y, Miyazaki S, Tsujimoto G. Free fatty acids regulate gut
incretin glucagon-like peptide-1 secretion through GPR120. Nat Med
11: 90–94, 2005. doi:10.1038/nm1168.
Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan WQ, Li P,
Lu WJ, Watkins SM, Olefsky JM. GPR120 is an omega-3 fatty acid
receptor mediating potent anti-inflammatory and insulin-sensitizing
effects. Cell 142: 687–698, 2010. doi:10.1016/j.cell.2010.07.041.
Ichimura A, Hirasawa A, Poulain OG, Bonnefond A, Hara T,
Yengo L et al. Dysfunction of lipid sensor GPR120 leads to obesity
in both mouse and human. Nature 483: 350–354, 2012. doi:10.
1038/nature10798.
Talukdar S, Olefsky JM, Osborn O. Targeting GPR120 and other
fatty acid-sensing GPCRs ameliorates insulin resistance and
inflammatory diseases. Trends Pharmacol Sci 32: 543–550, 2011.
doi:10.1016/j.tips.2011.04.004.
Oh DY, Walenta E, Akiyama TE, Lagakos WS, Lackey D,
Pessentheiner AR, Sasik R, Hah N, Chi TJ, Cox JM, Powels MA,
Salvo JD, Sinz C, Watkins SM, Armando AM, Chung H, Evans
RM, Quehenberger O, McNelis J, Bogner-Strauss JG, Olefsky
JM. A Gpr120-selective agonist improves insulin resistance and
chronic inflammation in obese mice. Nat Med 20: 942–947, 2014.
doi:10.1038/nm.3614.
Paschoal VA, Walenta E, Talukdar S, Pessentheiner AR, Osborn O,
Hah N, Chi TJ, Tye GL, Armando AM, Evans RM, Chi NW,
Quehenberger O, Olefsky JM, Oh DY. Positive reinforcing mechanisms between GPR120 and PPARc modulate insulin sensitivity. Cell
Metab 31: 1173–1188.e5, 2020. doi:10.1016/j.cmet.2020.04.020.
Reimann F, Habib AM, Tolhurst G, Parker HE, Rogers GJ, Gribble
FM. Glucose sensing in L cells: a primary cell study. Cell Metab 8:
532–539, 2008. doi:10.1016/j.cmet.2008.11.002.
Iwasaki K, Harada N, Sasaki K, Yamane S, Iida K, Suzuki K,
Hamasaki A, Nasteska D, Shibue K, Joo E, Harada T, Hashimoto T,
Asakawa Y, Hirasawa A, Inagaki N. Free fatty acid receptor GPR120
is highly expressed in enteroendocrine K cells of the upper small
intestine and has a critical role in GIP secretion after fat ingestion.
Endocrinology 156: 837–846, 2015. doi:10.1210/en.2014-1653.
Kato T, Harada N, Ikeguchi-Ogura E, Sankoda A, Hatoko T, Lu X,
Yasuda T, Yamane S, Inagaki N. Gene expression of nutrient-sensing molecules in I cells of CCK reporter male mice. J Mol Endocrinol
66: 11–22, 2021. doi:10.1530/JME-20-0134.
Suzuki K, Iwasaki K, Murata Y, Harada N, Yamane S, Hamasaki A,
Shibue K, Joo E, Sankoda A, Fujiwara Y, Hayashi Y, Inagaki N.
Distribution and hormonal characterization of primary murine L cells
throughout the gastrointestinal tract. J Diabetes Investig 9: 25–32,
2018. doi:10.1111/jdi.12681.
Conwell DL, Zuccaro G, Morrow JB, Van Lente F, Obuchowski N,
Vargo JJ, Dumot JA, Trolli P, Shay SS. Cholecystokinin-stimulated peak lipase concentration in duodenal drainage fluid: a new
pancreatic function test. Am J Gastroenterol 97: 1392–1397,
2002. doi:10.1111/j.1572-0241.2002.05675.x.
Liddle RA, Goldfine ID, Rosen MS, Taplitz RA, Williams JA.
Cholecystokinin bioactivity in human plasma. Molecular forms,
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
responses to feeding, and relationship to gallbladder contraction. J
Clin Invest 75: 1144–1152, 1985. doi:10.1172/JCI111809.
Yamane S, Harada N, Inagaki N. Mechanisms of fat-induced gastric
inhibitory polypeptide/glucose-dependent insulinotropic polypeptide secretion from K cells. J Diabetes Investig 7: 20–26, 2016.
doi:10.1111/jdi.12467.
Nasteska D, Harada N, Suzuki K, Yamane S, Hamasaki A, Joo E,
Iwasaki K, Shibue K, Harada T, Inagaki N. Chronic reduction of GIP
secretion alleviates obesity and insulin resistance under high-fat diet
conditions. Diabetes 63: 2332–2343, 2014. doi:10.2337/db13-1563.
Lo CM, King A, Samuelson LC, Kindel TL, Rider T, Jandacek RJ,
Raybould HE, Woods SC, Tso P. Cholecystokinin knockout mice
are resistant to high-fat diet-induced obesity. Gastroenterology 138:
1997–2005, 2010. doi:10.1053/j.gastro.2010.01.044.
Kishikawa A, Kitaura H, Kimura K, Ogawa S, Qi J, Shen WR, Ohori
F, Noguchi T, Marahleh A, Nara Y, Ichimura A, Mizoguchi I.
Docosahexaenoic acid inhibits inflammation-induced osteoclast formation and bone resorption in vivo through GPR120 by inhibiting
TNF-a production in macrophages and directly inhibiting osteoclast
formation. Front Endocrinol (Lausanne) 10: 157, 2019. doi:10.3389/
fendo.2019.00157.
Ikeguchi E, Harada N, Kanemaru Y, Sankoda A, Yamane S, Iwasaki
K, Imajo M, Murata Y, Suzuki K, Joo E, Inagaki N. Transcriptional
factor Pdx1 is involved in age-related GIP hypersecretion in mice.
Am J Physiol Gastrointest Liver Physiol 315: G272–G282, 2018.
doi:10.1152/ajpgi.00054.2018.
Ogawa E, Hosokawa M, Harada N, Yamane S, Hamasaki A,
Toyoda K, Fujimoto S, Fujita Y, Fukuda K, Tsukiyama K, Yamada
Y, Seino Y, Inagaki N. The effect of gastric inhibitory polypeptide on
intestinal glucose absorption and intestinal motility in mice. Biochem
Biophys Res Commun 404: 115–120, 2011. doi:10.1016/j.bbrc.2010.
11.077.
Maekawa R, Seino Y, Ogata H, Murase M, Iida A, Hosokawa K, Joo
E, Harada N, Tsunekawa S, Hamada Y, Oiso Y, Inagaki N, Hayashi
Y, Arima H. Chronic high-sucrose diet increases fibroblast growth
factor 21 production and energy expenditure in mice. J Nutr
Biochem 49: 71–79, 2017. doi:10.1016/j.jnutbio.2017.07.010.
Furukawa I, Kurooka S, Arisue K, Kohda K, Hayashi C. Assays of
serum lipase by the “BALB-DTNB method” mechanized for use with
discrete and continuous-flow analyzers. Clin Chem 28: 110–113,
1982. doi:10.1093/clinchem/28.1.110.
Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem
226: 497–509, 1957. doi:10.1016/S0021-9258(18)64849-5.
Kawasaki Y, Harashima S, Sasaki M, Mukai E, Nakamura Y,
Harada N, Toyoda K, Hamasaki A, Yamane S, Yamada C, Yamada
Y, Seino Y, Inagaki N. Exendin-4 protects pancreatic beta cells from
the cytotoxic effect of rapamycin by inhibiting JNK and p38 phosphorylation. Horm Metab Res 42: 311–317, 2010. doi:10.1055/s-00301249035.
Galic S, Sachithanandan N, Kay TW, Steinberg GR. Suppressor of
cytokine signalling (SOCS) proteins as guardians of inflammatory
responses critical for regulating insulin sensitivity. Biochem J 461:
177–188, 2014. doi:10.1042/BJ20140143.
Trengove MC, Ward AC. SOCS proteins in development and disease. Am J Clin Exp Immunol 2: 1–29, 2013.
Ueki K, Kondo T, Tseng YH, Kahn CR. Central role of suppressors
of cytokine signaling proteins in hepatic steatosis, insulin resistance,
and the metabolic syndrome in the mouse. Proc Natl Acad Sci U S A
101: 10422–10427, 2004 [Erratum in Proc Natl Acad Sci USA 102:
13710, 2005]. doi:10.1073/pnas.0402511101.
Parker HE, Habib AM, Rogers GJ, Gribble FM, Reimann F. Nutrientdependent secretion of glucose-dependent insulinotropic polypeptide from primary murine K cells. Diabetologia 52: 289–298, 2009.
doi:10.1007/s00125-008-1202-x.
Sankoda A, Harada N, Kato T, Ikeguchi E, Iwasaki K, Yamane S,
Murata Y, Hirasawa A, Inagaki N. Free fatty acid receptors, G protein-coupled receptor 120 and G protein-coupled receptor 40, are
essential for oil-induced gastric inhibitory polypeptide secretion. J
Diabetes Investig 10: 1430–1437, 2019. doi:10.1111/jdi.13059.
Wu T, Bound MJ, Standfield SD, Gedulin B, Jones KL, Horowitz
M, Rayner CK. Effects of rectal administration of taurocholic acid
on glucagon-like peptide-1 and peptide YY secretion in healthy
AJP-Endocrinol Metab doi:10.1152/ajpendo.00329.2022 www.ajpendo.org
Downloaded from journals.physiology.org/journal/ajpendo at Kyoto Univ (054.066.017.246) on May 17, 2023.
E459
INHIBITION OF GPR120 SIGNALING IN INTESTINE
37.
38.
39.
40.
41.
42.
E460
humans. Diabetes Obes Metab 15: 474–477, 2013. doi:10.1111/
dom.12043.
Wu T, Bound MJ, Standfield SD, Jones KL, Horowitz M, Rayner CK.
Effects of taurocholic acid on glycemic, glucagon-like peptide-1, and
insulin responses to small intestinal glucose infusion in healthy
humans. J Clin Endocrinol Metab 98: E718–E722, 2013. doi:10.1210/
jc.2012-3961.
Joo E, Harada N, Yamane S, Fukushima F, Taura D, Iwasaki K,
Sankoda A, Shibue K, Harada T, Suzuki K, Hamasaki A, Inagaki N.
Inhibition of gastric inhibitory polypeptide receptor signaling in adipose tissue reduces insulin resistance and hepatic steatosis in highfat diet-fed mice. Diabetes 66: 868–879, 2017. doi:10.2337/db160758.
Shimazu-Kuwahara S, Harada N, Yamane S, Joo E, Sankoda A,
Kieffer TJ, Inagaki N. Attenuated secretion of glucose-dependent
insulinotropic polypeptide (GIP) does not alleviate hyperphagic obesity and insulin resistance in ob/ob mice. Mol Metab 6: 288–294,
2017. doi:10.1016/j.molmet.2017.01.006.
Yamane S, Harada N, Hamasaki A, Muraoka A, Joo E, Suzuki K,
Nasteska D, Tanaka D, Ogura M, Harashima S, Inagaki N. Effects
of glucose and meal ingestion on incretin secretion in Japanese subjects with normal glucose tolerance. J Diabetes Investig 3: 80–85,
2012. doi:10.1111/j.2040-1124.2011.00143.x.
Suzuki K, Harada N, Yamane S, Nakamura Y, Sasaki K, Nasteska
D, Joo E, Shibue K, Harada T, Hamasaki A, Toyoda K, Nagashima
K, Inagaki N. Transcriptional regulatory factor X6 (Rfx6) increases
gastric inhibitory polypeptide (GIP) expression in enteroendocrine
K-cells and is involved in GIP hypersecretion in high-fat dietinduced obesity. J Biol Chem 288: 1929–1938, 2013. doi:10.1074/
jbc.M112.423137.
Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H,
Fujimoto S, Oku A, Tsuda K, Toyokuni S, Hiai H, Mizunoya W,
43.
44.
45.
46.
47.
48.
Fushiki T, Holst JJ, Makino M, Tashita A, Kobara Y, Tsubamoto Y,
Jinnouchi T, Jomori T, Seino Y. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 8: 738–742, 2002.
doi:10.1038/nm727.
Ibrahim MM. Subcutaneous and visceral adipose tissue: structural
and functional differences. Obes Rev 11: 11–18, 2010. doi:10.1111/
j.1467-789X.2009.00623.x.
Moschen AR, Molnar C, Geiger S, Graziadei I, Ebenbichler CF,
Weiss H, Kaser S, Kaser A, Tilg H. Anti-inflammatory effects of excessive weight loss: potent suppression of adipose interleukin 6 and
tumour necrosis factor alpha expression. Gut 59: 1259–1264, 2010.
doi:10.1136/gut.2010.214577.
Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ, Barrett T, Kim JK,
Davis RJ. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322: 1539–1543, 2008. doi:10.1126/
science.1160794.
Johnston JA, O’Shea JJ. Matching SOCS with function. Nat
Immunol 4: 507–509, 2003. doi:10.1038/ni0603-507.
Murata Y, Harada N, Kishino S, Iwasaki K, Ikeguchi-Ogura E,
Yamane S, Kato T, Kanemaru Y, Sankoda A, Hatoko T, Kiyobayashi
S, Ogawa J, Hirasawa A, Inagaki N. Medium-chain triglycerides inhibit long-chain triglyceride-induced GIP secretion through GPR120dependent inhibition of CCK. iScience 24: 102963, 2021. doi:10.1016/j.
isci.2021.102963.
Murata Y, Harada N, Yamane S, Iwasaki K, Ikeguchi E, Kanemaru
Y, Harada T, Sankoda A, Shimazu-Kuwahara S, Joo E, Poudyal H,
Inagaki N. Medium-chain triglyceride diet stimulates less GIP secretion and suppresses body weight and fat mass gain compared with
long-chain triglyceride diet. Am J Physiol Endocrinol Physiol 317:
E53–E64, 2019 [Erratum in Am J Physiol Endocrinol Physiol 318:
E440, 2020]. doi:10.1152/ajpendo.00200.2018.
AJP-Endocrinol Metab doi:10.1152/ajpendo.00329.2022 www.ajpendo.org
Downloaded from journals.physiology.org/journal/ajpendo at Kyoto Univ (054.066.017.246) on May 17, 2023.
...