Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart. / Uddin, Golam; Karwi, Qutuba; Pherwani, Simran; Gopal, Keshav; Wagg, Cory; Biswas, Dipsikha; Atnasious, Mariam; Wu, Yikuan; Wu, Guoqing; Zhang, Liyan; Ho, Kim; Pulinilkunnil, Thomas; Ussher, John; Lopuschuk, Gary.
In: Metabolism: clinical and experimental, 11.2021.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart
AU - Uddin, Golam
AU - Karwi, Qutuba
AU - Pherwani, Simran
AU - Gopal, Keshav
AU - Wagg, Cory
AU - Biswas, Dipsikha
AU - Atnasious, Mariam
AU - Wu, Yikuan
AU - Wu, Guoqing
AU - Zhang, Liyan
AU - Ho, Kim
AU - Pulinilkunnil, Thomas
AU - Ussher, John
AU - Lopuschuk, Gary
PY - 2021/11
Y1 - 2021/11
N2 - Backgrounds: Branched chain amino acid (BCAA) oxidation is impaired in cardiac insulin resistance, leading to the accumulation of BCAAs and the first products of BCAA oxidation, the branched chain ketoacids. However, it is not clear whether it is the BCAAs, BCKAs or both that are mediating cardiac insulin resistance. To determine this, we produced mice with a cardiac-specific deletion of BCAA aminotransferase (BCATm-/-), the first enzyme in the BCAA oxidation pathway that is responsible for converting BCAAs to BCKAs.Methods: Eight-week-old BCATm cardiac specific knockout (BCATm-/-) male mice and their α-MHC (myosin heavy chain) - Cre expressing wild type littermates (WT-Cre+/+) received tamoxifen (50 mg/kg i.p. 6 times over 8 days). At 16-weeks of age, cardiac energy metabolism was assessed in isolated working hearts.Results: BCATm-/- mice have decreased cardiac BCAA oxidation rates, increased cardiac BCAAs and a reduction in cardiac BCKAs. Hearts from BCATm-/- mice showed an increase in insulin stimulation of glucose oxidation and an increase in p-AKT. To determine the impact of reversing these events, we perfused isolated working mice hearts with high levels of BCKAs, which completely abolished insulin-stimulated glucose oxidation rates, an effect associated with decreased p-AKT and inactivation of pyruvate dehydrogenase (PDH), the rate-limiting enzyme in glucose oxidation.Conclusion: This implicates the BCKAs, and not BCAAs, as the actual mediators of cardiac insulin resistance and suggests that lowering cardiac BCKAs can be used as a therapeutic strategy to improve insulin sensitivity in the heart.
AB - Backgrounds: Branched chain amino acid (BCAA) oxidation is impaired in cardiac insulin resistance, leading to the accumulation of BCAAs and the first products of BCAA oxidation, the branched chain ketoacids. However, it is not clear whether it is the BCAAs, BCKAs or both that are mediating cardiac insulin resistance. To determine this, we produced mice with a cardiac-specific deletion of BCAA aminotransferase (BCATm-/-), the first enzyme in the BCAA oxidation pathway that is responsible for converting BCAAs to BCKAs.Methods: Eight-week-old BCATm cardiac specific knockout (BCATm-/-) male mice and their α-MHC (myosin heavy chain) - Cre expressing wild type littermates (WT-Cre+/+) received tamoxifen (50 mg/kg i.p. 6 times over 8 days). At 16-weeks of age, cardiac energy metabolism was assessed in isolated working hearts.Results: BCATm-/- mice have decreased cardiac BCAA oxidation rates, increased cardiac BCAAs and a reduction in cardiac BCKAs. Hearts from BCATm-/- mice showed an increase in insulin stimulation of glucose oxidation and an increase in p-AKT. To determine the impact of reversing these events, we perfused isolated working mice hearts with high levels of BCKAs, which completely abolished insulin-stimulated glucose oxidation rates, an effect associated with decreased p-AKT and inactivation of pyruvate dehydrogenase (PDH), the rate-limiting enzyme in glucose oxidation.Conclusion: This implicates the BCKAs, and not BCAAs, as the actual mediators of cardiac insulin resistance and suggests that lowering cardiac BCKAs can be used as a therapeutic strategy to improve insulin sensitivity in the heart.
M3 - Journal article
JO - Metabolism: clinical and experimental
JF - Metabolism: clinical and experimental
ER -
ID: 327139832