Phosphoenolpyruvate carboxykinase (Pck1) helps regulate the triglyceride/fatty acid cycle and development of insulin resistance in mice

Carrie A. Millward, David DeSantis, Chang Wen Hsieh, Jason D. Heaney, Sorana Pisano, Yael Olswang, Lea Reshef, Michelle Beidelschies, Michelle Puchowicz, Colleen M. Croniger

Research output: Contribution to journalArticle

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Abstract

The aim of this study was to investigate the role of the cytosolic form of phosphoenolpyruvate carboxykinase (Pck1) in the development of insulin resistance. Previous studies have shown that the roles of Pck1 in white adipose tissue (WAT) in glyceroneogenesis and reesterification of free fatty acids (FFA) to generate triglyceride are vital for the prevention of diabetes. We hypothesized that insulin resistance develops when dysregulation of Pck1 occurs in the triglyceride/fatty acid cycle, which regulates lipid synthesis and transport between adipose tissue and the liver. We examined this by analyzing mice with a deletion of the PPARγ binding site in the promoter of Pck1 (PPARE-/-). This mutation reduced the fasting Pck1 mRNA expression in WAT in brown adipose tissue (BAT). To analyze insulin resistance, we performed hyperinsulinemic-euglycemic glucose clamp analyses. PPARE-/- mice were profoundly insulin resistant and had more FFA and glycerol released during the hyperinsulinemic-euglycemic clamp compared with wildtype mice (WT). Finally, we analyzed insulin secretion in isolated islets. We found a 2-fold increase in insulin secretion in the PPARE-/- mice at 16.7 mM glucose. Thus, the PPARE site in the Pck1 promoter is essential for maintenance of lipid metabolism and glucose homeostasis and disease prevention.

Original languageEnglish (US)
Pages (from-to)1452-1463
Number of pages12
JournalJournal of lipid research
Volume51
Issue number6
DOIs
StatePublished - Jun 1 2010

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Phosphoenolpyruvate
Glucose Clamp Technique
Insulin Resistance
Triglycerides
Fatty Acids
Insulin
White Adipose Tissue
Nonesterified Fatty Acids
Tissue
Clamping devices
Glucose
Peroxisome Proliferator-Activated Receptors
Brown Adipose Tissue
Lipid Metabolism
Glycerol
Adipose Tissue
Fasting
Homeostasis
Binding Sites
Maintenance

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Millward, C. A., DeSantis, D., Hsieh, C. W., Heaney, J. D., Pisano, S., Olswang, Y., ... Croniger, C. M. (2010). Phosphoenolpyruvate carboxykinase (Pck1) helps regulate the triglyceride/fatty acid cycle and development of insulin resistance in mice. Journal of lipid research, 51(6), 1452-1463. https://doi.org/10.1194/jlr.M005363

Phosphoenolpyruvate carboxykinase (Pck1) helps regulate the triglyceride/fatty acid cycle and development of insulin resistance in mice. / Millward, Carrie A.; DeSantis, David; Hsieh, Chang Wen; Heaney, Jason D.; Pisano, Sorana; Olswang, Yael; Reshef, Lea; Beidelschies, Michelle; Puchowicz, Michelle; Croniger, Colleen M.

In: Journal of lipid research, Vol. 51, No. 6, 01.06.2010, p. 1452-1463.

Research output: Contribution to journalArticle

Millward, CA, DeSantis, D, Hsieh, CW, Heaney, JD, Pisano, S, Olswang, Y, Reshef, L, Beidelschies, M, Puchowicz, M & Croniger, CM 2010, 'Phosphoenolpyruvate carboxykinase (Pck1) helps regulate the triglyceride/fatty acid cycle and development of insulin resistance in mice', Journal of lipid research, vol. 51, no. 6, pp. 1452-1463. https://doi.org/10.1194/jlr.M005363
Millward, Carrie A. ; DeSantis, David ; Hsieh, Chang Wen ; Heaney, Jason D. ; Pisano, Sorana ; Olswang, Yael ; Reshef, Lea ; Beidelschies, Michelle ; Puchowicz, Michelle ; Croniger, Colleen M. / Phosphoenolpyruvate carboxykinase (Pck1) helps regulate the triglyceride/fatty acid cycle and development of insulin resistance in mice. In: Journal of lipid research. 2010 ; Vol. 51, No. 6. pp. 1452-1463.
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