Pancreatic expression of CPT1A is essential for whole body glucose homeostasis by supporting glucose-stimulated insulin secretion

被引：0

作者：

Ducote, Maggie P. ^{[1
]}

Cothern, Caroline R. ^{[1
]}

Batdorf, Heidi M. ^{[2
,3
]}

Fontenot, Molly S. ^{[1
]}

Martin, Thomas M. ^{[2
]}

Iftesum, Maria ^{[4
]}

Gartia, Manas R. ^{[4
]}

Noland, Robert C. ^{[5
]}

Burk, David H. ^{[6
]}

Ghosh, Sujoy ^{[7
]}

Burke, Susan J. ^{[1
,3
]}

机构：

[1] Pennington Biomed Res Ctr, Lab Immunogenet, Baton Rouge, LA 70808 USA

[2] Pennington Biomed Res Ctr, Lab Islet Biol & flammat, Baton Rouge, LA USA

[3] Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70802 USA

[4] Louisiana State Univ, Dept Mech & Ind Engn, Baton Rouge, LA USA

[5] Pennington Biomed Res Ctr, Skeletal Muscle Metab Lab, Baton Rouge, LA USA

[6] Pennington Biomed Res Ctr, Cell Biol & Bioimaging Core, Baton Rouge, LA USA

[7] Pennington Biomed Res Ctr, Lab Computat Biol, Baton Rouge, LA USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2025年 / 301卷 / 02期

基金：

美国国家科学基金会;

关键词：

CARNITINE PALMITOYLTRANSFERASE-I; METABOLIC COUPLING FACTORS; FATTY-ACID OXIDATION; MALONYL-COA; CELL FUNCTION; LINES; OBESITY; ISLETS; GENE; RATS;

D O I：

10.1016/j.jbc.2025.108187

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Pancreatic islet (3-cells express the Cpt1a gene, which encodes the enzyme carnitine palmitoyltransferase 1A (CPT1A), an enzyme that facilitates entry of long-chain fatty acids into the mitochondria. Because fatty acids are required for glucose- stimulated insulin secretion, we tested the hypothesis that CPT1A is essential to support islet (3-cell function and mass. In this study, we describe genetic deletion of Cpt1a in pancreatic tissue (Cpt1aPdx1-/-) using C57BL/6J mice. Islet morphology, (3-cell transcription factor abundance, islet ATP levels, glucose transporter 2 abundance, and expression of the dedifferentiation marker ALDH1A3 were analyzed by immunofluorescent staining. Glucose and insulin tolerance were assessed to investigate the metabolic status of genetic reductions in Cpt1a. Glucose-stimulated insulin secretion was evaluated in vivo and in isolated islets ex vivo by perifusion. Pancreatic deletion of Cpt1a reduced glucose tolerance but did not alter insulin sensitivity. Glucose-stimulated insulin secretion was reduced both in vivo and in islets isolated from Cpt1aPdx1-/- mice relative to control islets. Pancreatic islets from Cpt1aPdx1-/- mice displayed elevations in ALDH1A3, a marker of dedifferentiation, but no reduction in nuclear abundance of the (3-cell transcription factors MafA and Nkx6.1 or the GLUT2 glucose transporter. However, intracellular ATP abundance was markedly decreased in islets isolated from Cpt1aPdx1-/- relative to littermate control mice. We conclude that there is an important physiological role for pancreatic CPT1A to maintain whole body glucose homeostasis by supporting glucose- stimulated insulin secretion and maintaining intracellular ATP levels in male mice.

引用

页数：17

共 56 条

[1] Yaney G.C., Corkey B.E., Fatty acid metabolism and insulin secretion in pancreatic beta cells, Diabetologia, 46, pp. 1297-1312, (2003)
[2] Stein D.T., Esser V., Stevenson B.E., Lane K.E., Whiteside J.H., Daniels M.B., Et al., Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat, J. Clin. Invest., 97, pp. 2728-2735, (1996)
[3] Koyama K., Chen G., Wang M.Y., Lee Y., Shimabukuro M., Newgard C.B., Et al., beta-cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy, Diabetes, 46, pp. 1276-1280, (1997)
[4] Boucher A., Lu D., Burgess S.C., Telemaque-Potts S., Jensen M.V., Mulder H., Et al., Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue, J. Biol. Chem., 279, pp. 27263-27271, (2004)
[5] Liang K., Mitochondrial CPT1A: insights into structure, function, and basis for drug development, Front. Pharmacol., 14, (2023)
[6] Kuok I.T., Rountree A.M., Jung S.R., Sweet I.R., Palmitate is not an effective fuel for pancreatic islets and amplifies insulin secretion independent of calcium release from endoplasmic reticulum, Islets, 11, pp. 51-64, (2019)
[7] Chen S., Ogawa A., Ohneda M., Unger R.H., Foster D.W., McGarry J.D., More direct evidence for a malonyl-CoA-carnitine palmitoyltransferase I interaction as a key event in pancreatic beta-cell signaling, Diabetes, 43, pp. 878-883, (1994)
[8] Zhou Y.P., Berggren P.O., Grill V., A fatty acid-induced decrease in pyruvate dehydrogenase activity is an important determinant of beta-cell dysfunction in the obese diabetic db/db mouse, Diabetes, 45, pp. 580-586, (1996)
[9] Burke S.J., Batdorf H.M., Huang T.Y., Jackson J.W., Jones K.A., Martin T.M., Et al., One week of continuous corticosterone exposure impairs hepatic metabolic flexibility, promotes islet beta-cell proliferation, and reduces physical activity in male C57BL/6 J mice, J. Steroid Biochem. Mol. Biol., 195, (2019)
[10] Stamateris R.E., Sharma R.B., Hollern D.A., Alonso L.C., Adaptive beta-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression, Am. J. Physiol. Endocrinol. Metab., 305, pp. E149-E159, (2013)

← 1 2 3 4 5 6 →