Glucose-stimulated insulin secretion depends on FFA1 and Gq in neonatal mouse islets
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Glucose-stimulated insulin secretion depends on FFA1 and Gq in neonatal mouse islets. / Lorza-Gil, Estela; Kaiser, Gabriele; Carlein, Christopher; Hoffmann, Markus D.A.; König, Gabriele M.; Haug, Sieglinde; Prates Roma, Leticia; Rexen Ulven, Elisabeth; Ulven, Trond; Kostenis, Evi; Birkenfeld, Andreas L.; Häring, Hans Ulrich; Ullrich, Susanne; Gerst, Felicia.
I: Diabetologia, Bind 66, 2023, s. 1501–1515.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Glucose-stimulated insulin secretion depends on FFA1 and Gq in neonatal mouse islets
AU - Lorza-Gil, Estela
AU - Kaiser, Gabriele
AU - Carlein, Christopher
AU - Hoffmann, Markus D.A.
AU - König, Gabriele M.
AU - Haug, Sieglinde
AU - Prates Roma, Leticia
AU - Rexen Ulven, Elisabeth
AU - Ulven, Trond
AU - Kostenis, Evi
AU - Birkenfeld, Andreas L.
AU - Häring, Hans Ulrich
AU - Ullrich, Susanne
AU - Gerst, Felicia
N1 - Funding Information: Open Access funding enabled and organized by Projekt DEAL. This study was supported by a grant (01GI0925) from the Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.). ERU is funded by the Lundbeck Foundation (grant R307-2018-2950). EK and GMK gratefully acknowledge support of this work by the DFG-funded Research Unit FOR2372 with the grants 290847012/FOR2372 (to EK), as well as 290827466/FOR2372 (to GMK).
PY - 2023
Y1 - 2023
N2 - Aims/hypothesis: After birth, the neonatal islets gradually acquire glucose-responsive insulin secretion, a process that is subjected to maternal imprinting. Although NEFA are major components of breastmilk and insulin secretagogues, their role for functional maturation of neonatal beta cells is still unclear. NEFA are the endogenous ligands of fatty acid receptor 1 (FFA1, encoded by Ffar1 in mice), a Gq-coupled receptor with stimulatory effect on insulin secretion. This study investigates the role of FFA1 in neonatal beta cell function and in the adaptation of offspring beta cells to parental high-fat feeding. Methods: Wild-type (WT) and Ffar1−/− mice were fed high-fat (HFD) or chow diet (CD) for 8 weeks before mating, and during gestation and lactation. Blood variables, pancreas weight and insulin content were assessed in 1-, 6-, 11- and 26-day old (P1–P26) offspring. Beta cell mass and proliferation were determined in P1–P26 pancreatic tissue sections. FFA1/Gq dependence of insulin secretion was evaluated in isolated islets and INS-1E cells using pharmacological inhibitors and siRNA strategy. Transcriptome analysis was conducted in isolated islets. Results: Blood glucose levels were higher in CD-fed Ffar1−/− P6-offspring compared with CD-fed WT P6-offspring. Accordingly, glucose-stimulated insulin secretion (GSIS) and its potentiation by palmitate were impaired in CD Ffar1−/− P6-islets. In CD WT P6-islets, insulin secretion was stimulated four- to fivefold by glucose and five- and sixfold over GSIS by palmitate and exendin-4, respectively. Although parental HFD increased blood glucose in WT P6-offspring, it did not change insulin secretion from WT P6-islets. In contrast, parental HFD abolished glucose responsiveness (i.e. GSIS) in Ffar1−/− P6-islets. Inhibition of Gq by FR900359 or YM-254890 in WT P6-islets mimicked the effect of Ffar1 deletion, i.e. suppression of GSIS and of palmitate-augmented GSIS. The blockage of Gi/o by pertussis toxin (PTX) enhanced (100-fold) GSIS in WT P6-islets and rendered Ffar1−/− P6-islets glucose responsive, suggesting constitutive activation of Gi/o. In WT P6-islets, FR900359 cancelled 90% of PTX-mediated stimulation, while in Ffar1−/− P6-islets it completely abolished PTX-elevated GSIS. The secretory defect of Ffar1−/− P6-islets did not originate from insufficient beta cells, since beta cell mass increased with the offspring’s age irrespective of genotype and diet. In spite of that, in the breastfed offspring (i.e. P1–P11) beta cell proliferation and pancreatic insulin content had a genotype- and diet-driven dynamic. Under CD, the highest proliferation rate was reached by the Ffar1−/− P6 offspring (3.95% vs 1.88% in WT P6), whose islets also showed increased mRNA levels of genes (e.g. Fos, Egr1, Jun) typically high in immature beta cells. Although parental HFD increased beta cell proliferation in both WT (4.48%) and Ffar1−/− (5.19%) P11 offspring, only the WT offspring significantly increased their pancreatic insulin content upon parental HFD (5.18 µg under CD to 16.93 µg under HFD). Conclusions/interpretation: FFA1 promotes glucose-responsive insulin secretion and functional maturation of newborn islets and is required for adaptive offspring insulin secretion in the face of metabolic challenge, such as parental HFD. Graphical Abstract: [Figure not available: see fulltext.]
AB - Aims/hypothesis: After birth, the neonatal islets gradually acquire glucose-responsive insulin secretion, a process that is subjected to maternal imprinting. Although NEFA are major components of breastmilk and insulin secretagogues, their role for functional maturation of neonatal beta cells is still unclear. NEFA are the endogenous ligands of fatty acid receptor 1 (FFA1, encoded by Ffar1 in mice), a Gq-coupled receptor with stimulatory effect on insulin secretion. This study investigates the role of FFA1 in neonatal beta cell function and in the adaptation of offspring beta cells to parental high-fat feeding. Methods: Wild-type (WT) and Ffar1−/− mice were fed high-fat (HFD) or chow diet (CD) for 8 weeks before mating, and during gestation and lactation. Blood variables, pancreas weight and insulin content were assessed in 1-, 6-, 11- and 26-day old (P1–P26) offspring. Beta cell mass and proliferation were determined in P1–P26 pancreatic tissue sections. FFA1/Gq dependence of insulin secretion was evaluated in isolated islets and INS-1E cells using pharmacological inhibitors and siRNA strategy. Transcriptome analysis was conducted in isolated islets. Results: Blood glucose levels were higher in CD-fed Ffar1−/− P6-offspring compared with CD-fed WT P6-offspring. Accordingly, glucose-stimulated insulin secretion (GSIS) and its potentiation by palmitate were impaired in CD Ffar1−/− P6-islets. In CD WT P6-islets, insulin secretion was stimulated four- to fivefold by glucose and five- and sixfold over GSIS by palmitate and exendin-4, respectively. Although parental HFD increased blood glucose in WT P6-offspring, it did not change insulin secretion from WT P6-islets. In contrast, parental HFD abolished glucose responsiveness (i.e. GSIS) in Ffar1−/− P6-islets. Inhibition of Gq by FR900359 or YM-254890 in WT P6-islets mimicked the effect of Ffar1 deletion, i.e. suppression of GSIS and of palmitate-augmented GSIS. The blockage of Gi/o by pertussis toxin (PTX) enhanced (100-fold) GSIS in WT P6-islets and rendered Ffar1−/− P6-islets glucose responsive, suggesting constitutive activation of Gi/o. In WT P6-islets, FR900359 cancelled 90% of PTX-mediated stimulation, while in Ffar1−/− P6-islets it completely abolished PTX-elevated GSIS. The secretory defect of Ffar1−/− P6-islets did not originate from insufficient beta cells, since beta cell mass increased with the offspring’s age irrespective of genotype and diet. In spite of that, in the breastfed offspring (i.e. P1–P11) beta cell proliferation and pancreatic insulin content had a genotype- and diet-driven dynamic. Under CD, the highest proliferation rate was reached by the Ffar1−/− P6 offspring (3.95% vs 1.88% in WT P6), whose islets also showed increased mRNA levels of genes (e.g. Fos, Egr1, Jun) typically high in immature beta cells. Although parental HFD increased beta cell proliferation in both WT (4.48%) and Ffar1−/− (5.19%) P11 offspring, only the WT offspring significantly increased their pancreatic insulin content upon parental HFD (5.18 µg under CD to 16.93 µg under HFD). Conclusions/interpretation: FFA1 promotes glucose-responsive insulin secretion and functional maturation of newborn islets and is required for adaptive offspring insulin secretion in the face of metabolic challenge, such as parental HFD. Graphical Abstract: [Figure not available: see fulltext.]
KW - Ffar1 mice
KW - Gq
KW - Insulin secretion
KW - Offspring islets
KW - Parental high-fat diet
U2 - 10.1007/s00125-023-05932-5
DO - 10.1007/s00125-023-05932-5
M3 - Journal article
C2 - 37217659
AN - SCOPUS:85160063670
VL - 66
SP - 1501
EP - 1515
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
ER -
ID: 357511640