Anthocyanins from purple corn activate free fatty acid-receptor 1 and glucokinase enhancing in vitro insulin secretion and hepatic glucose uptake

Movement and phagocytosis characterize the fundamental actions of macrophages. Although it is known that the free fatty acid receptor GPR120 is expressed in macrophages and regulates cytokine expression to exert anti-inflammatory activities, the effects of GPR120 activation on the motility and phagocytosis of macrophages are not clear. In this study, mouse alveolar macrophages (AM) were stimulated with the GPR120 agonist TUG-891, and the changes in cell motility, intracellular Ca2+ concentration ([Ca2+]i), and the ability of phagocytosis were measured. Mouse AM in controls exhibited active movement in vitro, and TUG-891 significantly restrained AM movement. Meanwhile, TUG-891 stimulated a quick increase in [Ca2+]i in AM, which was blocked separately by the Gq protein inhibitor YM-254890, the phospholipase C (PLC) inhibitor U73122, or depletion of endoplasmic reticulum (ER) Ca2+ store by thapsigargin. The inhibition of AM movement by TUG-891 was eliminated by YM-254890, U73122, thapsigargin, and chelation of cytosolic Ca2+ by BAPTA. Moreover, TUG-891 inhibited AM phagocytosis of fluorescent microspheres, which was also blocked by YM-254890, U73122, thapsigargin, and BAPTA. In conclusion, GPR120 activation in mouse AM increases [Ca2+]i but inhibits the motility and phagocytosis via Gq protein/PLC-mediated Ca2+ release from ER Ca2+ store.

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Free fatty acid receptor 3 differentially contributes to β-cell compensation under high-fat diet and streptozotocin stress

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00128.2019 ◽

2020 ◽

Vol 318 (4) ◽

pp. R691-R700 ◽

Cited By ~ 1

Author(s):

Medha Priyadarshini ◽

Connor Cole ◽

Gautham Oroskar ◽

Anton E. Ludvik ◽

Barton Wicksteed ◽

...

Keyword(s):

Insulin Secretion ◽

Fatty Acid ◽

Free Fatty Acid ◽

Cell Mass ◽

Insulin Response ◽

High Fat ◽

Β Cell ◽

Acid Receptor ◽

Free Fatty Acid Receptor ◽

Fatty Acid Receptor

The free fatty acid receptor 3 (FFA3) is a nutrient sensor of gut microbiota-generated nutrients, the short-chain fatty acids. Previously, we have shown that FFA3 is expressed in β-cells and inhibits islet insulin secretion ex vivo. Here, we determined the physiological relevance of the above observation by challenging wild-type (WT) and FFA3 knockout (KO) male mice with 1) hyperglycemia and monitoring insulin response via highly sensitive hyperglycemic clamps, 2) dietary high fat (HF), and 3) chemical-induced diabetes. As expected, FFA3 KO mice exhibited significantly higher insulin secretion and glucose infusion rate in hyperglycemic clamps. Predictably, under metabolic stress induced by HF-diet feeding, FFA3 KO mice exhibited less glucose intolerance compared with the WT mice. Moreover, similar islet architecture and β-cell area in HF diet-fed FFA3 KO and WT mice was observed. Upon challenge with streptozotocin (STZ), FFA3 KO mice initially exhibited a tendency for an accelerated incidence of diabetes compared with the WT mice. However, this difference was not maintained. Similar glycemia and β-cell mass loss was observed in both genotypes 10 days post-STZ challenge. Higher resistance to STZ-induced diabetes in WT mice could be due to higher basal islet autophagy. However, this difference was not protective because in response to STZ, similar autophagy induction was observed in both WT and FFA3 KO islets. These data demonstrate that FFA3 plays a role in modulating insulin secretion and β-cell response to stressors. The β-cell FFA3 and autophagy link warrant further research.

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Identification of a Potent and Selective Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist with Favorable Physicochemical and in Vitro ADME Properties

Journal of Medicinal Chemistry ◽

10.1021/jm2005699 ◽

2011 ◽

Vol 54 (19) ◽

pp. 6691-6703 ◽

Cited By ~ 51

Author(s):

Elisabeth Christiansen ◽

Christian Urban ◽

Manuel Grundmann ◽

Maria E. Due-Hansen ◽

Ellen Hagesaether ◽

...

Keyword(s):

Fatty Acid ◽

Free Fatty Acid ◽

Acid Receptor ◽

Free Fatty Acid Receptor ◽

Adme Properties ◽

Fatty Acid Receptor

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Discovery of a novel oxime ether scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists

RSC Advances ◽

10.1039/c6ra07356e ◽

2016 ◽

Vol 6 (52) ◽

pp. 46356-46365 ◽

Cited By ~ 17

Author(s):

Zheng Li ◽

Jianyong Yang ◽

Weijie Gu ◽

Guoshen Cao ◽

Xiaoting Fu ◽

...

Keyword(s):

Insulin Secretion ◽

Fatty Acid ◽

Free Fatty Acid ◽

Β Cells ◽

Pancreatic Β Cells ◽

Acid Receptor ◽

Free Fatty Acid Receptor ◽

Orally Bioavailable ◽

Glucose Stimulated Insulin Secretion ◽

Fatty Acid Receptor

The free fatty acid receptor 1 (FFA1) plays a key role in amplifying glucose-stimulated insulin secretion in pancreatic β-cells.

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Oleic, myristic and linoleic acid stimulate insulin secretion through free fatty acid receptor 1 from pancreatic β-cells

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-2007-972212 ◽

2007 ◽

Vol 115 (S 1) ◽

Author(s):

S Schnell ◽

M Schaefer ◽

C Schöfl

Keyword(s):

Insulin Secretion ◽

Fatty Acid ◽

Linoleic Acid ◽

Free Fatty Acid ◽

Β Cells ◽

Pancreatic Β Cells ◽

Acid Receptor ◽

Stimulate Insulin Secretion ◽

Free Fatty Acid Receptor ◽

Fatty Acid Receptor

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Prevailing hyperglycemia is critical in the regulation of glucose metabolism during exercise in poorly controlled alloxan-diabetic dogs

Journal of Applied Physiology ◽

10.1152/japplphysiol.00687.2004 ◽

2005 ◽

Vol 98 (3) ◽

pp. 930-939 ◽

Cited By ~ 9

Author(s):

Michael J. Christopher ◽

Christian Rantzau ◽

Glenn McConell ◽

Bruce E. Kemp ◽

Frank P. Alford

Keyword(s):

Fatty Acid ◽

Free Fatty Acid ◽

Glucose Uptake ◽

Plasma Glucose ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Plasma Free Fatty Acid ◽

Glucose Turnover ◽

Metabolic Clearance ◽

Hepatic Glucose

The separate impacts of the chronic diabetic state and the prevailing hyperglycemia on plasma substrates and hormones, in vivo glucose turnover, and ex vivo skeletal muscle (SkM) during exercise were examined in the same six dogs before alloxan-induced diabetes (prealloxan) and after 4–5 wk of poorly controlled hyperglycemic diabetes (HGD) in the absence and presence of ∼300-min phlorizin-induced (glycosuria mediated) normoglycemia (NGD). For each treatment state, the ∼15-h-fasted dog underwent a primed continuous 150-min infusion of [3-3H]glucose, followed by a 30-min treadmill exercise test (∼65% maximal oxygen capacity), with SkM biopsies taken from the thigh (vastus lateralis) before and after exercise. In the HGD and NGD states, preexercise hepatic glucose production rose by 130 and 160%, and the metabolic clearance rate of glucose (MCRg) fell by 70 and 37%, respectively, compared with the corresponding prealloxan state, but the rates of glucose uptake into peripheral tissues (Rdtissue) and total glycolysis (GF) were unchanged, despite an increased availability of plasma free fatty acid in the NGD state. Exercise-induced increments in hepatic glucose production, Rdtissue, and plasma-derived GF were severely blunted by ∼30–50% in the NGD state, but increments in MCRg remained markedly reduced by ∼70–75% in both diabetic states. SkM intracellular glucose concentrations were significantly elevated only in the HGD state. Although Rdtissue during exercise in the diabetic states correlated positively with preexercise plasma glucose and insulin and GF and negatively with preexercise plasma free fatty acid, stepwise regression analysis revealed that an individual's preexercise glucose and GF accounted for 88% of Rdtissue during exercise. In conclusion, the prevailing hyperglycemia in poorly controlled diabetes is critical in maintaining a sufficient supply of plasma glucose for SkM glucose uptake during exercise. During phlorizin-induced NGD, increments in both Rdtissue and GF are impaired due to a diminished fuel supply from plasma glucose and a sustained reduction in increments of MCRg.

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